NTA Level 6 • Semester 1 • PST06103

Pharmaceutical Production – Complete Full Notes

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UNITED REPUBLIC OF TANZANIA

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Ministry of Health, Community Development, Gender, Elderly and Children

Facilitator Guide

Children – 2019

Table of Contents

Background iv

Acknowledgment v

Introduction vii

Abbreviations x

Session 1: Introduction to Pharmaceutical Production 1

Session 2: Registration and Regulation of Pharmaceutical Manufacturing in

Tanzania 8

Session 3: Environmental Impact Assessment (EIA) 15

Session 4: Standard Operating Procedure (SOP) 25

Session 5: SOP on SOPs (SOP on Standard Operating Procedures) 37

Session 6: Validation of Pharmaceutical Raw Materials 43

Session 7: Dispensing of Pharmaceutical Materials 49

Session 8: Pharmaceutical Powders 55

Session 9: Mixing of Pharmaceutical Powders 65

Session 10: Introduction to Capsules 74

Session 11: Gelatin Capsule Shells 80

Session 12: Formulation of Capsule Content 86

Session 13: Filling Hard Gelatin Capsules 93

Session 14: Soft Gelatin Capsules 101

Session 15: Introduction to Tablets 109

Session 16: Formulation of Tablets 117

Session 17: Granulation 124

Session 18: Compression 133

Session 19: Tablet Coating 141

Session 20: Packaging of Tablets and Capsules 150

Session 21: Quality Assurance nd Quality Control 157

Session 22: In-process Quality Control (IPQC) 173

Session 24: GMP for Pharmaceutical Equipments 187

Session 25: Management of Pharmaceutical Wastes 194

Background

There is currently an ever increasing demand for pharmaceutical personnel

in Tanzania. This is due to expanding investment in public and private

pharmaceutical sector. Shortage of trained pharmaceutical human resource

contributes to poor quality of pharmaceutical services and low access to

medicines in the country (GIZ, 2012).

Through Public-Private-Partnership (PPP) the Pharmacy Council (PC) together

with Development Partners (DPs) in Germany and Pharmaceutical Training

Institutions (PTIs) worked together to address the shortage of human

resource for pharmacy by designing a project named “Supporting Training

Institutions for Improved Pharmaceutical Services in Tanzania” in order to

improve quality and capacity of PTIs in training, particularly of lower

cadre pharmaceutical personnel.

The Pharmacy Council formed a Steering committee that conducted a

stakeholder’s workshop from18th to 22ndAugust 2014 in Morogoro to initiate

the implementation of the project.

Key activities in the implementation of this project included carrying out

situational analysis, curriculum review and harmonization, development of

training manual/facilitators guide, development of assessment plan,

training of trainers and supportive supervision.

After the curricula were reviewed and harmonized, the process of developing

standardized training materials was started in August 2015 through Writer’s

Workshop (WW) approach.

The approach included two workshops (of two weeks each) for developing

draft documents and a one-week workshop for reviewing, editing and

formatting the sessions of the modules.

The goals of Writers Workshops were to build capacity of tutors in the

development of training materials and to develop high-quality, standardized

teaching materials.

The training package for pharmacy cadres includes a Facilitator Guide,

Assessment plan and Practicum. There are 12 modules for NTA level 6 making

12 Facilitator guides and one Practicum guide.

Acknowledgment

The development of standardized training materials of a competence-based

curriculum for pharmaceutical sciences has been accomplished through

involvement of different stakeholders.

Special thanks go to the Pharmacy Council for spearheading the

harmonization of training materials in the pharmacy after noticing that

training institutions in Tanzania were using different curricula and train

their students differently.

I would also like to extend my gratitude to Christian Social Service

Commission (CSSC) for their tireless efforts to mobilize funds from

development partners (German Ministry of Industry and action medeor). It

is through the implementation of the Multi-Actors Partnership (MAP)

project, CSSC has been able to provide the financial and technical

support needed during the development of this training material.

Many thanks go to the Centre for Educational Development in Health Arusha

(CEDHA) experts on health material development and training who coordinated

the development of these module sessions particularly Ms. Diana H. Gamuya

for her commitment in coordinating and facilitating the planning and

development to its completion.

Particular acknowledgements are sent to Mr. Dickson Mtalitinya and Members

from the secretariat of National Council for Technical Education (NACTE)

for facilitating and providing their expertise to the success of this work.

It will be unfair if I will not recognize the efforts and contributions of

all CEDHA supportive staff that made this process a success; accountant,

secretary, drivers and printers

Finally, I very much appreciate the contributions of the tutors and content

experts representing PTIs, hospitals, and other health training

institutions. Their participation in meetings and workshops, and their

input in the development of this training manual/facilitators guide have

been invaluable.

These participants are listed with our gratitude below:

Ms. Elizabeth Shekalaghe Registrar, Pharmacy Council of

Tanzania

Dr. Fadhili Lyimo Assistant Director Allied Health,

MoHCDGEC

Dr. Jacqueline Uriyo Acting Principal, CEDHA

Dr. Sungwa N. Kabissi Project Manager – MAP,

CSSC

Ms. Diana H. Gamuya CEDHA

Ms. Grace Mallange PC

Ms. Emily Mwakibolwa Pharmacy Council

Ms. Tumaini H. Lyombe MUHAS

Ms. Dilisi J. Makawia KSP

Director of Human Resources Development

Ministry of Health, Community Development, Gender, Elderly and Children

Introduction

Module Overview

This module content is a guide for tutors of Pharmaceutical schools for

training of students. The session contents are based on sub-enabling

outcomes and their related tasks of the curriculum for Basic Technician

Course in Pharmaceutical Sciences. The module sub-enabling outcomes and

their related tasks are as indicated in the in the Basic Technician

Certificate in Pharmaceutical Sciences (NTA Level 6) Curriculum

Target Audience

This module is intended for use primarily by tutors of pharmaceutical

schools. The module’s sessions give guidance on the time, activities and

provide information on how to teach the session. The sessions include

different activities which focus on increasing students’ knowledge, skills

and attitudes.

Organization of the Module

The module consists of twenty five (25) sessions; each session is divided

into several parts as indicated below:

• Session Title: The name of the session

• Total Session Time: The estimated time for teaching the session,

indicated in minutes

• Pre-requisites: A module or session which needs to be covered before

teaching the session.

• Learning Tasks: Statements which indicate what the student is expected to

learn by the end of the session

• Resources Needed: All resources needed for the session are listed

including handouts and worksheets

• Session Overview: The session overview box lists the steps, time for each

step, the activity or method used in each step and the step title

• Session Content: All the session contents are divided into steps. Each

step has a heading and an estimated time to teach that step as shown in

the overview box. Also, this section includes instructions for the tutor

and activities with their instructions to be done during teaching of the

contents

• Key Points: Key messages for concluding the session contents at the end

of a session This step summarizes the main points and ideas from the

session, based on the learning tasks of the session

• Evaluation: The last section of the session consists of short questions

based on the learning tasks to check the understanding of students.

• Handouts: Additional information which can be used in the classroom while

teaching or later for students’ further learning. Handouts are used to

provide extra information related to the session topic that cannot fit

into the session time. Handouts can be used by the students to study

material on their own and to refer to them after the session. Sometimes,

a handout will have questions or an exercise for the participants

including the answers to the questions.

Instructions for Use and Facilitators Preparation

• Tutors are expected to use the module as a guide to train students in the

classroom and skills laboratory

• The contents of the modules are the basis for teaching and learning

dispensing.

• Use the session contents as a guide

• The tutors are therefore advised to read each session and the relevant

handouts and worksheets as preparation before facilitating the session

• Tutors need to prepare all the resources, as indicated in the resource

section or any other item, for an effective teaching and learning process

• Plan a schedule (timetable) of the training activities

• Facilitators are expected to be innovative to make the teaching and

learning process effective

• Read the sessions before facilitation; make sure you understand the

contents in order to clarify points during facilitation

• Time allocated is estimated, but you are advised to follow the time as

much as possible, and adjust as needed

• Use session activities and exercises suggested in the sessions as a guide

• Always involve students in their own learning. When students are

involved, they learn more effectively

• Facilitators are encouraged to use real life examples to make learning

more realistic

• Make use of appropriate reference materials and teaching resources

available locally

Preparation with Handouts and Worksheets

• Go through the session and identify handouts and worksheets needed for

the session

• Reproduce pages of these handouts and worksheets for student use while

teaching the session. This will enable students to refer to handouts and

worksheets during the session in the class. You can reproduce enough

copies for students or for sharing

• Give clear instructions to students on the student activity in order for

the students to follow the instructions of the activity

• Refer students to the specific page in the student manual as instructed

in the facilitator guide

Using Students Manual When Teaching

• The student manual is a document which has the same content as the

facilitator guide, which excludes facilitator instructions and answers

for exercises.

• The student manual is for assisting students to learn effectively and

acts as a reference document during and after teaching the session

• Some of the activities included in facilitator guide are in the student

manual without facilitator instructions

Abbreviations

BMR Batch Manufacturing Record

BRELA Business Registration and Licensing Agency

CEDHA Centre for Education Development in Health Arusha

CUHAS Catholic University of Heal and Allied Sciences

EIA Environmental Impact Assessment

GMP Good Manufacturing Practices

HKMU Herbert Kairuki Memorial University

IPQC In-Process Quality Control

KIUT Kampala International University in Tanzania

KSP Kilimanjaro School of Pharmacy

MFR Master Formula Record

MoHCGC Ministry of health, Community development, Gender, Elderly and

Children

MSF Site Master File

NACTE National Council for Technical Education

NEMC National Environmental Management Council

OSHA Occupational Safety Health Agency

QA Quality Assurance

QC Quality Control

RuCU Ruaha Catholic University

SIBS Spring Institute of Business and Science

SOP Standard Operating Procedures

TFDA Tanzania Food and Drugs Authority

TIC Tanzania Investment Centre

TIN Tax Identification Number

WHO World Health Organization

Session 1: Introduction to Pharmaceutical Production

Total Session Time: 60 minutes

Pre-requisites

• None

Learning Tasks

By the end of this session students are expected to be able to:

• Define terminologies used in pharmaceutical production

• List the general requirements for pharmaceutical production

• Outline products manufactured in Pharmaceutical Productions

Resources Needed

• Flip charts, marker pens, and masking tape

• Black/white board and chalk/whiteboard markers

• LCD projector and computer

SESSION OVERVIEW

SESSION CONTENTS

STEP 1: Presentation of Session Title and Learning Tasks (5 minutes)

READ or ASK students to read the learning tasks and clarify

ASK students if they have any questions before continuing

STEP 2: Definitions (25 minutes)

|Activity: Buzzing (5 minutes) |

| |

|ASK students to pair up and buzz on the following question for 2 |

|minutes |

| |

|Define Good Manufacturing Practices |

| |

|ALLOW few pairs to respond and let other pairs to add on points not |

|mentioned |

| |

|WRITE their response on the flip chart/board |

| |

|CLARIFY and SUMMARIZE by using the content below |

• Pharmaceutical production (pharmaceutical manufacturing)

o This is the process of industrial (large) scale synthesis of

pharmaceutical drugs by pharmaceutical companies

• Batch, batch size an batch number

o A batch is a quantity or consignment of pharmaceutical products

produced in a single manufacturing run

o The total number of items in one batch is the batch size

o Each batch is given a specific identification code called the batch

number

• Batch production

o This is a technique used in manufacturing, in which the object in

question is created stage by stage over a series of workstations, and

different batches of products are made

• Batch Manufacturing Record (BMR)

o A batch manufacturing record is a document designed to provide a

complete record of the manufacturing history of a batch of product

o BMR is also known as;

▪ BPR-Batch processing record

▪ BPCR-Batch processing and control record

• Master Formula Record

o A document or set of documents specifying the starting materials with

their quantities and the packaging materials, together with a

description of the procedures and precautions required to produce a

specified quantity of the product as well as the processing

instructions including the in-process controls

o There are must be a master formula record for each product and batch

size to be manufactured

• Mixing is a process whereby different ingredients are put together to

form a mixture

• Weighing and Measuring

o Weighing is a process of determining weight of ingredients (for

example by using a weighing balance)

o Measuring is the determination of volume of liquid ingredients by

using graduated measures such as measuring cylinders, pipettes etc.

• Tableting

o This is a process of compressing powders or granules to form tablets

• Tablet Press

o This is an equipment that is used for manufacturing of tablets

• Encapsulation

o This is a process of enclosing powders, tablets, pellets, granules or

liquids in shells commonly made up of gelatin to form capsules

• Quality Assurance (QA)

o It is a wide ranging concept covering all matters that individually or

collectively influence the quality of a product

• Good Manufacturing Practices (GMP)

o GMP is a part of quality assurance (which sets out principles and

procedures) that ensures that products are consistently manufactured

and controlled to the quality standards appropriate to their intended

use

• Quality Control (QC)

o It is part of GMP concerned with sampling, specifications and testing

and with the organization, documentation and release procedures which

ensure that the necessary the necessary and relevant tests are carried

out and the materials are neither released for use nor products are

used for sale or supply until their quality has been satisfactory

• Active Pharmaceutical Ingredient (API) “Drug substance”

o An ingredient which gives a drug its chief therapeutic value; i.e.

responsible for pharmacological action. OR

o Any substance or mixture of substances intended to be used in the

manufacture of a pharmaceutical dosage form and that, when used in

production of a drug, becomes an active ingredient of that drug.

• Drug

o Any chemical compound used on or administered to humans or animals as

an aid in the diagnosis, treatment or prevention of disease or other

abnormal condition, for the relief of pain or suffering, or to control

or improve any physiologic or pathologic state. OR

o Medicine, pharmaceutical substance which when absorbed into a living

organism may modify one or more of its functions.

• Drug Product

o A unique combination of drug(s), strength and dosage form in which a

drug is administered.

• Finished Pharmaceutical Product

o A medicinal product/dosage form which has undergone all stages of

manufacture or production, including packaging in its final container

and labeling.

• Pharmaceutical Dosage form:

o Is the form in which drugs are formulated and ready for delivery to

the patients. E.g. solution, mixture, emulsion, suspension,

injectable, tablets, capsules etc

• Excipients or Additives or adjutants.

o A chemical substance/additive with no pharmacological action, used in

the formulation of dosage forms. Vehicle for the drug.

o A substance, other than the active ingredient, which has been

appropriately evaluated for safety and is included in a drug delivery

system to:

▪ aid in the processing of the drug delivery system during its

manufacture,

▪ protect, support or enhance stability, bioavailability, or

patient acceptability,

▪ assist in product identification or

▪ Enhance any other attribute of the overall safety and

effectiveness of the drug during storage or use.

• Pharmaceutical production (pharmaceutical manufacturing)

o All operations involved in the preparation of a medicinal product,

from receipt of materials, through processing and packaging, to its

completion as a finished product.

o It involves both small and large industrial scale synthesis of

pharmaceutical drugs by pharmaceutical companies2

• Pharmaceutical Formulation

o The process whereby a drug or drugs (active ingredient/s) are combined

with other substances (pharmaceutical adjutants or excipients or

additives) to produce a dosage form (or formulation) suitable for

administration to a patient.

• In-process quality control (IPQC)

o It is the provision of accurate, specific and definite description of

the procedures to be employed from receipt of raw materials to release

of finished product by carrying out tests at critical stages of the

production process to ensure batch uniformity and integrity of a drug

product

STEP 3: Requirements for Pharmaceutical Production (10 minutes)

• Pharmaceutical production is broken down into a series of unit operations

such as milling, drying, compression, coating etc.

• Pharmaceutical production is carried out in premises authorized by

competent authority to produce medicines by using validated equipment and

methods.

• Important requirements for pharmaceutical production include;

o Premises

o Processes

o Equipment and machines

o Human resource

o Raw materials

o Packaging materials

• Qualified personnel are a key to pharmaceutical production. These include

head of production (production manager) and head of quality control.

STEP 4: Products in Pharmaceutical Productions (10 minutes)

|Activity: Buzzing (5 minutes) |

| |

|ASK students to pair up and buzz on the following question for 2 |

|minutes |

| |

|What are the forms of drugs produced in pharmaceutical manufacturing |

|processes? |

| |

|ALLOW few pairs to respond and let other pairs to add on points not |

|mentioned |

| |

|WRITE their response on the flip chart/board |

| |

|CLARIFY and SUMMARIZE by using the content below |

• Drugs are prepared in various forms for administration (dosage forms or

drugs delivery systems)

• Dosage forms are available in liquid, solid, semi-solid and gaseous

formulations

• Solid dosages are the most common forms in which drugs are administered

• Solid dosage forms are classified into;

o Tablets

o Capsules

o Powders

o Granules

• The popularity of solid dosage forms is due to the following reasons;

o Convenience of administration

o Convenient to carry (light and compact)

o Accuracy of dosing

o Increased stability

o Easy of mass production

STEP 5: Key Points (5 minutes)

• Pharmaceutical production is the process of industrial (large) scale

synthesis of pharmaceutical drugs by pharmaceutical companies

• Good Manufacturing Practices is a sets out principles and procedures

which ensures that products are consistently manufactured and controlled

to the quality standards appropriate to their intended use

• Pharmaceutical production is carried out in a series of unit operations

such as milling, mixing, drying, compression and coating

STEP 6: Evaluation (5 minutes)

• What is pharmaceutical production?

• What are general requirements for pharmaceutical production?

• What is GMP?

• Differentiate between quality control and quality assurance

References

Aulton, M.E, & Kevin, M.G., Eds: (2013) Pharmaceutics: The design and

manufacture of medicines, (4th ed.) Churchill Livingstone.

Hugo and Russell (2011), Pharmaceutical Microbiology (8th ed.) Willey-

Blackwel publications.

Gennaro, R. A, et al. (Eds) 1995 Remington: The Science and Practice of

Pharmacy, Volume I & II, (19th ed.): Mack Publishing Company, Easton,

Pennsylvania 18042

Liebsch, B et al. (1988): Tanzania Pharmaceutical Handbook, Dar es Salaam

University Press.

Lund, W. Editor (1994). The Pharmaceutical Codex, Principles and Practice

of Pharmaceutics (12th ed.): The Pharmaceutical Press, London

Polderman, J. (1990). Introduction to Pharmaceutical Production: Novib, The

Hague

Rawlins E.A, Editor: (1977) Bentley’s Textbook of Pharmaceutics, (8th ed.)

Baillie're Tindall. London Kamm, G. and Kohler, B. Editors: (1995)

Manual for Decentralized Infusion Production, Infusion Unit Project

Tanzania

Schmidt, O. (ed) (2000) Pharmaceutical Quality systems, Interpharm Press,

Colorado.

Shayne C et al (2008), Pharmaceutical Manufacturing Handbook: Production

and processes, John Wiley & Sons

Watson, D. G. (1999) Pharmaceutical Analysis: A Textbook for Pharmacy

Students and Pharmaceutical Chemists: Churchill Livingstone,

Edinburgh.

Session 2: Registration and Regulation of Pharmaceutical Manufacturing in

Tanzania

Total Session Time: 120 minutes

Pre-requisites

• None

Learning Tasks

By the end of this session students are expected to be able to:

• Explain the registration of businesses in Tanzania

• Explain the role of Tanzania investment centre in promoting

pharmaceutical manufacturing

• Outline the licensing of businesses in Tanzania

• Explain the role of TFDA in establishing and regulating manufacturing of

pharmaceuticals

• Explain the role of TRA pharmaceutical manufacturing

Resources Needed:

• Flip charts, marker pens, and masking tape

• Black/white board and chalk/whiteboard markers

• LCD projector and computer

SESSION OVERVIEW

SESSION CONTENTS

STEP 1: Presentation of Session Title and Learning Tasks (5 minutes)

READ or ASK students to read the learning tasks and clarify

ASK students if they have any questions before continuing

STEP 2: Company Registration (25 minutes)

|Activity: Buzzing (5 minutes) |

| |

|ASK students to pair up and buzz on the following question for 2 |

|minutes |

| |

|How are companies or businesses registered in Tanzania? |

| |

|ALLOW few pairs to respond and let other pairs to add on points not |

|mentioned |

| |

|WRITE their response on the flip chart/board |

| |

|CLARIFY and SUMMARIZE by using the content below |

• In order to do business in Tanzania, a business entity in form of a sole

proprietorship, partnership or limited liability company needs to be

formed

• The business entity in form of sole proprietorship, partnership must be

registered with the Business Registration and Licensing Agency (BRELA)

which is under the Ministry of Industries and Trade

• The first step in registration of the business name is to obtain name

clearance from BRELA

• Generally, the following documents are required for in the process of

forming a company;

o Name of the company

o The address of the company in Tanzania

o Names, residential addresses and nationalities of the first

subscribers and directors (at least two)

o Memorandum of Association (stating in details the objects of the

company) and Articles of Association (stating in details the

management structure and processes)

▪ At least two copies of the documents each documents are required

o Filling a prescribed form to declare that a company has complied with

the requirements of the Tanzania company law, and

o Payment of filing fees, registration fee and the stamp duty

• A certificate of registration (for sole proprietorship and partnership)

or Incorporation (for a limited company) is issued after completion of

the registration process

• After registering the name of the company, Tax Identification Number

(TIN) should be obtained from Tanzania Revenue Authority (TRA)

STEP 3: Investment Approval (20 minutes)

• In order to make investment incentives from Tanzania Investment Centre

(TIC), the following documents are required;

o Project’s business plan/feasibility study

▪ Intended project should aim at foreign exchange generation and

savings, import substitution, creation of employment opportunities,

linkage benefits, transfer of technology, expansion of production

of goods and services etc.

▪ The feasibility study should contain clear statement of the

project objective, information regarding the investor, details of

investments costs (foreign and local expected capital expenditure),

how the proposed investment will be financed, specific sources(s)

of finance for the project, terms and condition of loans if

applicable, sources of technology if applicable, project financial

and economic analysis, market study, project capacity, production

process if applicable, environmental impact assessment, expected

employment generation, proposed implementation schedule, etc.

o Filled application form from issued by TIC

o In case of expansion/rehabilitation, a copy of audited account for the

past three years

o A copy of the company’s Memorandum and Articles of Association

o Certified copy of the Certificate of company incorporation

o A brief profile of the investor(s)

o Evidence of sufficient financial capital available to implement the

project

o Evidence of land ownership for the location of the project

o Project implementation schedule, and

o An overall covering letter to which all the above are attached

• The role of TIC in promoting investment in pharmaceutical industry are;

o Aftercare service

▪ This is a core functional unit in investment promotion and

facilitation whose role to facilitate both the successful start-up

and continuing development of the investment with a view towards

maximizing its contribution to the local economic development

▪ Aftercare unit offers assistance in ensuring that the investment

project is implemented free of unnecessary obstacles

o Access to various services related to permits, licenses and approvals

in the TIC One Stop Facilitation Centre

▪ Companies Registration (BRELA) for registration of company

▪ Tanzania Revenue Authority (TRA) for issues related to taxes

▪ National Environment Council (NEMC) for environmental impact

assessment

▪ Tanzania Foods and Drugs Authority for licensing in manufacturing

of pharmaceutical products

▪ Tanzania Electric Supply Company (TANESCO) for electric power

supply

▪ IOccupational Health and Safety Authority (OSHA) for issues

related to occupational health

▪ Facilitates the process of obtaining work permit, resident

permit, business license and land acquisition

o Issuance of Certificate of incentives to investors

▪ Incentives offered;

▪ The recognition of private property and protection against any

non-commercial risks. Tanzania is an active member of the World

Bank Foreign Investment Insurance wing, MIGA (Multilateral

Investment Guarantees Agency)

▪ Zero percent (0%) Import Duty on Project Capital Goods,

Computers and Computer Accessories, Raw Materials and Replacement

Parts for Agriculture, Animal Husbandry and Fishing, Human and

Livestock Pharmaceuticals and Medicaments, Motor Vehicle in

Completely Knocked down (CKD) form and inputs for Manufacturing

Pharmaceutical Products

▪ Ten percent (10%) – Import Duty for Semi-processed/semi

finished goods)

▪ Introduction of pay and refund scheme for excise duty paid on

fuel purchased by eligible companies

▪ The Income Tax Laws allows 50% Capital allowances in the first

year of use for Plant and Machinery used in manufacturing

processes and fixed in a factory

▪ VAT Deferment granted on project capital Goods such as Plant &

Machinery. However the persons have to keep proper VAT records

and file returns, has no Tax outstanding and VAT payable in

respect of each unit of the Capital goods is twenty million

Shillings or above

STEP 4: Business Licensing (20 minutes)

• Type and number of required licenses differ from one sector to another

depending on the degree of regulation in the sector involved

• For investment in pharmaceutical industry, the following specific

licenses are required;

o Industrial license issued by the Ministry of Industries and Trade

▪ Issued after application is made to the Industrial Licensing

Board

▪ The requirements for obtaining an industrial license are;

▪ Filling an application

▪ Submission of copies of memorandum and Articles of

Association, Certificate of incorporation on the company

▪ Submission of a Business plan

▪ Submission of a Lease agreement/Title Deed

o Special license/permits issued by Tanzania Food and Drugs Authority

(TFDA)

• General Business License

o Apart from fulfilling the sector specific requirement (in this case

pharmaceutical sector), all businesses must obtain a general business

license issued under the Business Licensing Act, 1972. To obtain this

general license, the applicant must submit the following documents;

▪ Copy of certificate of incorporation or certificate of compliance

(in case of a company) or certificate of registration or extract

(in case of partnership or sole traders)

▪ Memorandum and Articles of Association showing among other things

the objectives of the company allowing it to the business which the

license is being applied for

▪ Proof of Tanzania citizenship e.g. photocopy of passport, birth

certificate, or in case of non-citizen –a resident permit Class A

(showing the holder to be the investor in the company/business)

▪ In case of the shareholders of the company are non-residents, a

Power of Attorney to a citizen/resident must be submitted

▪ Proof by the applicant having a suitable business premises for

the business applied

▪ Proof that can be submitted includes title deed, tenancy

agreements, receipt of rent or property tax payment

▪ Tax Identification Number (TIN) issued by Tanzania Revenue

Authority (TRA)

STEP 5: Medicine Manufacturing Licence (30 minutes)

|Activity: Small Group Discussion (15 minutes) |

| |

|DIVIDE students into small manageable groups |

| |

|ASK students to discuss on the following question |

|What is the role of TFDA in establishing and regulation of |

|pharmaceutical manufacturing in Tanzania? |

| |

|ALLOW students to discuss for 15 minutes |

| |

|ALLOW few groups to present and the rest to add points not mentioned |

| |

|CLARIFY and SUMMARIZE by using the contents below |

• Medicines are one of the groups of items regulated by the Tanzania Food,

Drugs and Cosmetics Act, 2003. The others are food and cosmetic products

• The Act is enforced by the Tanzania Food and Drugs Authority (TFDA)

• TFDA issues license for manufacturing processes for all products

regulated under the Act, including medicines

• Any investor in pharmaceutical manufacturing must obtain a manufacturing

license from TFDA after fulfilling the following conditions;

o The premises in which the applicant proposes to manufacture the

respective products have been inspected and registered by TFDA for

that purpose

o Provide evidence that the substances he intends to use are of a

quality satisfactory of the standards prescribed by TFDA in respect of

the product he proposes to manufacture

o Provide evidence of having sufficient financial resources such as

would enable him, in relation to the manufacture of products regulated

under the TFDA Act, to maintain the standards of quality prescribed by

or under the act

o The applicant must have not, within twelve months immediately

preceding present application, been convicted of an offence under this

Act or any other written law relating to quality standards of products

regulated by TFDA Act

o The applicant must have adequate expertise or skill or has personnel

qualified to execute the business for which he is seeking to be

licensed

o The applicant must have adequate facilities such as would enable him

to maintain the standards of quality prescribed in relation to the

manufacture of the products for which he is seeking to be licensed

STEP 6: Taxes in Pharmaceutical Manufacturing (10 minutes)

• Tanzania Revenue Authority (TRA) is responsible for all issues related to

taxes

• In the process of the pharmaceutical company (like any other company), a

Tax Identification Number (TIN) should be obtained from the TRA

o In application for a TIN, the following are required;

▪ Filling of a TIN application form

▪ Submission of Business registration or Certificate of

Incorporation and Memorandum and Articles of Association

▪ Fulfilment of immigration procedures (for non-citizens)

• All taxes and duties payable and exemptions (whenever

applicable) are communicated to the investors by TRA

STEP 6: Key Points (5 minutes)

• In order to do business in Tanzania, a business entity in form of a sole

proprietorship, partnership or limited liability company needs to be

formed

• The business entity in form of sole proprietorship, partnership must be

registered with the Business Registration and Licensing Agency (BRELA)

which is under the Ministry of Industries and Trade

• Tanzania Investment Centre (TIC) has a core functional of promoting

investment and facilitating both the successful start-up and continuing

development of the investment with a view towards maximizing its

contribution to the local economic development

STEP 7: Evaluation (5 minutes)

• What is the role of BRELA in establishing a pharmaceutical manufacturing

company?

• How is TIC involved in investment in manufacturing of pharmaceuticals in

the country?

• What is the role of TFDA in pharmaceutical manufacturing?

References

URT, The Tanzania Investment Act, 1997

URT, The Tanzania Business Licensing Act, 1972

URT, National Industries (Registration and Licensing) Act, 2002

URT, Business Names (Registration) Act, 2002

ONLINE TAXPAYER REGISTRATION USER GUIDE. (n.d.). Retrieved from

https://gateway.tra.go.tz/OnlineTin/USER_GUIDE.pdf

Administration – tfda.go.tz. (n.d.). Retrieved from

https://www.tfda.go.tz/sites/default/files/tfdaact_1.pdf

Session 3: Environmental Impact Assessment (EIA)

Total Session Time: 120 minutes

Pre-requisites

• None

Learning Tasks

By the end of this session students are expected to be able to:

• Describe environmental management in Tanzania

• Define environmental impact assessment

• List key features and elements of environment impact assessment

• Explain the importance of environmental impact assessment

• List stakeholders of environmental impact assessment

• Outline the steps in conducting environmental impact assessment

Resources Needed

• Flip charts, marker pens, and masking tape

• Black/white board and chalk/whiteboard markers

• LCD projector and computer

• Handout 3.1: Steps to Conduct Environmental Impact Assessment

SESSION OVERVIEW

SESSION CONTENTS

STEP 1: Presentation of Session Title and Learning Tasks (5 minutes)

READ or ASK students to read the learning tasks and clarify

ASK students if they have any questions before continuing

STEP 2: Environment Management in Tanzania (15 minutes)

• Management of environment in Tanzania is carried out by the National

Environment Management Council (NEMC) which came into being in 1983 when

the Government of Tanzania enacted the National Environment Management

Act No. 19 of 1983

• NEMC was established with a broad mandate in response to the national

need for such an institution to oversee environmental management issues

and also implement the resolutions of the Stockholm conference (1972),

which called upon all nations to establish and strengthen national

environmental Councils to advise governments and the international

community on environmental issues

• The Environmental Management (EMA) Act No. 20 of 2004 provides for a

legal and institutional framework for sustainable management of the

environment, prevention and control pollution, waste management,

environmental quality standards, public participation, environmental

compliance and enforcement

• EMA also gives NEMC mandates to undertake enforcement, compliance ,

review and monitoring of environmental impacts assessments, research,

facilitate public participation in environmental decision-making, raise

environmental awareness and collect and disseminate environmental

information

• Some of the objectives of NEMC are;

o To enforce and ensure compliance of the national environmental quality

standards.

o To review of Environmental Impact Statements (EIS) and conduct

environmental monitoring and auditing of projects and facilities

o To undertake and co-ordinate research, investigation and surveys in

the field of environment and collect, and disseminate information

o To carry-out research and surveys for the proper management and

conservation of environment

o To render advise and technical support to entities engaged in natural

resources and environmental management

o To initiate and evolve procedures and safeguards for the prevention of

accidents which may cause environmental degradation

o To enhance environmental education and public awareness; and establish

and operate national environmental information system for sound

environmental management

o To publish and disseminate manuals, codes and guidelines relating to

environmental management and prevention or abatement of environmental

degradation

o To issue restoration and recommend for easements orders, and save

prohibition notice

STEP 3: Environment Impact Assessment –EIA (15 minutes)

• Environmental Impact Assessment (EIA) is a process of evaluating the

likely environmental impacts of a proposed project or development, taking

into account inter-related socio-economic, cultural and human-health

impacts, both beneficial and adverse

• EIA is a national instrument that is undertaken for proposed activities

that are likely to have a significant adverse impact on the environment

and are subject to a decision of a competent national authority

• EIA is used to improve decision-making and ensure that development

options under consideration are environmentally, socially and

economically sound and sustainable

• EIA is concerned with identifying, predicting and evaluating the

foreseeable impacts, both beneficial and adverse, of proposed development

projects and alternatives

• EIA aims to eliminate or minimise negative impacts and optimise positive

impacts through mitigation and enhancement measures

• EIA relates to a process rather than a particular activity, t 0he

environmental impact study itself being only one component of the process

STEP 4: Features and Key Elements of an Effective EIA (20 minutes)

• EIA is a continuous and integral component of planning that should run

continuously throughout the planning cycle of any development initiative

• EIA facilitates dialogue, prediction and response and provides a forum

for proponents, decision-makers and the public, to consider the potential

impacts of a project on local communities, natural resources and

environmental quality

• EIA helps to enhance social and economic opportunities, and to promote

conservation and provides a mechanism for enhancing new economic and

social opportunities and for introducing long-term environmental

protection and conservation measures into project design

• EIA provides a framework for stakeholder participation in decision-

making, experience has shown that development projects imposed on local

communities often fail to address issues of local concern and priority,

and hence fail to engender a perception of local ownership

• EIA is a tool to improve decision-making, and provides project-specific

and strategic information before project implementation decisions are

reached

o It is also a mechanism for addressing cross-sectoral and cross-

boundary issues

o EIA helps to avoid inadvertent( Unplanned) problems and their

associated costs during project design

• The key elements of effective EIA system

o A legal basis with accompanying regulations

o Appropriate institutional arrangements for co-ordination and

regulation of EIA system, e.g. by an environment agency

o Provision for stakeholder involvement and public participation

o High level political commitment and awareness

o Availability of national technical capacity and EIA expertise

o Normal review system of EIA reports established by government

o Transparency in decision making processes on proposed development

actions

o In addition to these certain basic resources and conditions are

required if EIA is to make an effective contribution to the design of

projects, plans and policies

STEP 5: Stakeholders in EIA (10 minutes)

|Activity: Brainstorming (5 minutes) |

| |

|ASK students to brainstorm on the following question: |

| |

|Who is involved in EIA? |

| |

|ALLOW few students to respond |

| |

|WRITE their responses on the flip chart/ board |

| |

|CLARIFY and SUMMARISE by using the content below |

• Project proponents(supporter)

o They are responsible for commissioning(instruction) and paying for the

EIA process

o Include government ministries and departments, private sector

companies and development agencies

• EIA practitioners or service providers

o These undertake or provide inputs to the EIA process

o They include individuals; organisations; research and academic

institutes; NGOs; and both local and international consulting

companies

• Reviewers

o They are responsible for determining the level of environmental

assessment required (screening), and ensuring that the EIA process

proceeds according to agreed, clear and comprehensive terms of

reference

o They also review the EIA process and communicate their findings to

decision-makers and other stakeholders

• Decision-makers

o They are responsible for making decisions on project development once

an environmental impact statement (EIS) has been submitted

o They may include central government, local authorities and development

agencies. ·

• The public

o They are the most important stakeholders

o They contribute ideas and information that can help to avoid

unforeseen problems, improve project design and contribute to

monitoring

o They are involved in decision-making

STEP 6: Importances of EIA (10 minutes)

|Activity: Buzzing (5 minutes) |

| |

|ASK students to pair up and buzz on the following question for 2 |

|minutes |

| |

|What are the Importances of EIA? |

| |

|ALLOW few pairs to respond and let other pairs to add on points not |

|mentioned |

| |

|WRITE their response on the flip chart/board |

| |

|CLARIFY and SUMMARIZE by using the content below |

• EIA is a management tool for improving the long-term viability of

projects

• EIA helps to avoid mistakes that can be expensive and damaging in

environmental, social and economic terms

• EIA is used for early warning planning of a wide range of resource use,

development, and conservation initiatives in order to make the most of

options for achieving sustainability

• EIA helps choosing the best project or options that can help in the

achievement of sustainable development

• EIA improves accountability, planning and decision making

• EIA helps avoid conflict, especially with public and stakeholder

involvement

STEP 7: Steps to Conduct EIA (35 minutes)

• Registration

o Registration is a simple administrative procedure which requires

project proponents to officially register their intention to undertake

a development activity

• Screening

o It is the initial review of projects by NEMC to determine if an EIA is

required, and to avoid the unnecessary expense of a full EIA for a

project which does not need it

• Scoping

o Scoping, sometimes referred to as preliminary assessment, is used to

focus the EIA on the key issues for decision-making

• Compiling Terms of Reference

o Terms of reference (ToR) are normally prepared following the screening

stage and after a decision for a partial or full project EIA and

therefore are usually the product of scoping

• Organising the EIA Study

o Organising the EIA study involves acquisition of relevant

environmental standards and guidelines and knowledge of relevant

policies, laws and institutional arrangements

• Undertaking the EIA study

o EIA studies attempt to predict which impacts will occur as a result of

the project and their likely significance

• EIA Report

o The final report from an EIA is also often termed an Environmental

Impact Statement (EIS)

o For the EIA process to achieve its objectives it is important that any

report produced is accurate, contains all the relevant information, is

clearly written and understood by the public, non-technical people and

decision makers

• The review of EIA

o Provides interpretation that allows for decision making

• Environmental management and monitoring

o Monitoring assesses the effect of the project on the natural and

cultural environment

• Environmental auditing

o Environmental auditing refers to the systematic, documented, periodic

and objective review of practices related to meeting environmental

requirements

o An audit can help EIA process managers to learn from experience, and

further refine and improve the EIA process as a whole

• Decision making

o Decision-making takes place throughout the EIA process

o The main decision in the EIA process, whether or not to allow the

proposal to proceed is made by the government agency (NEMC), following

consultation and public participation

[pic][pic] Handout 3.1: Steps to Conduct Environmental Impact Assessment

STEP 8: Key Points (5 minutes)

• Management of environment in Tanzania is carried out by the National

Environment Management Council (NEMC) which came into being in 1983 when

the Government of Tanzania enacted the National Environment Management

Act No. 19 of 1983

• EIA is a national instrument that is undertaken for proposed activities

that are likely to have a significant adverse impact on the environment

and are subject to a decision of a competent national authority

• EIA is a continuous and integral component of planning that should run

continuously throughout the planning cycle of any development initiative

• EIA is used for early warning planning of a wide range of resource use,

development, and conservation initiatives in order to make the most of

options for achieving sustainability

• Steps to conduct EIA are Registration, screening, scoping, compiling

terms of reference, organizing the EIA, conducting EIA study, EIA

reporting, EIA review, Environmental management and monitoring,

Environmental auditing, Decision making

STEP 9: Evaluation (5 minutes)

• What is NEMC?

• What are the roles of NEMC?

• What is EIA?

• What is the importance of EIA?

• What are the steps for conducting EIA?

References

Brew, D., & Lee, N. (1996). Monitoring Environmental Management Plans and

Post-Project Analysis. EIA Newsletter 12: 10-11, University of

Manchester.

Canter, L., & Sadler, B. (1997). A Tool Kit for Effective EIA Practice –

Review of Methods and Perspectives on their Application: A

Supplementary report of the International study of the effectiveness

of Environmental Assessment. IAIA, June (1997.)

Clark, B.D., (1993). Environmental Assessment, Environmental Management and

Sustainable Development. Paper presented at the 14th International

Seminar on EA and Management, (1993 27 June-10 July ). CEMP,

University of Aberdeen.

Department of Wildlife, (1996). Policy of Wildlife Conservation. Revised

Final draft. Ministry of Natural Resources and tourism. United

Republic of Tanzania.

Donnelly, A., Hughes, R. and Dalal-Clayton, B (1998). A directory of impact

assessment guidelines. Second edition. IIED, London

Ebisemiju, F.S. (1993). Environmental Impact Assessment: making it work in

developing countries. J. Environmental. Management, 38(4), pp 247-273.

Gennaro, R. A, et.al (eds) 1995 Remington: The Science and Practice of

Pharmacy, Volume I & II, (19th ed.): Mack Publishing Company, Easton,

Pennsylvania 18042

Glasson, J., Therivel, R., and Chadwick, A. (1995). Introduction to

Environmental Impact Assessment. The Natural and Built environment

Series. UCL, London.

Goodland, R., Mercier, J.R. Muntemba, S (editors). (1996). Environmental

Assessment (EA) in Africa – A World Bank Commitment. Proceedings of

the Durban, World bank Workshop (1995 June 25.). World Bank,

Washington D.C.

Howlett D.J.B. & Nagu J. (1997). Agricultural project planning in Tanzania.

Institute of Development Management, Mzumbe and Development and

Project Planning Centre, Bradford, UK.

MTNRE (1994). National Environment Conservation Policy, Draft. Ministry of

Tourism Natural Resources and Environment. United republic of

Tanzania, Dar es Salaam

|[pic] |Handout 3.1: Steps to Conduct Environmental Impact Assessment |

• Registration

o Registration is a simple administrative procedure which requires

project proponents to officially register their intention to undertake

a development activity

o Registration allows all new projects to be screened for their

potential impacts by the appropriate authority

• Screening

o It is the initial review of projects to determine if an EIA is

required, and to avoid the unnecessary expense of a full EIA for a

project which does not need it

o It is done by the government body (NEMC)

o After the screening of a project the decision will fall into one of

the following four categories

▪ EIA not required, preliminary assessment required, full EIA

required, Project proposal rejected

• Scoping

o Scoping, sometimes referred to as preliminary assessment, is used to

focus the EIA on the key issues for decision-making

o It is a key stage in the EIA process in that it rejects projects that

have major adverse impacts without any possibility of mitigation and

allows projects with no major or significant impacts to proceed to

implementation without a full EIA

• Compiling Terms of Reference

o Terms of reference (ToR) are normally prepared following the screening

stage and after a decision for a partial or full project EIA and

therefore are usually the product of scoping

• Organising the EIA Study

o Organising the EIA study involves acquisition of relevant

environmental standards and guidelines; and knowledge of relevant

policies, laws and institutional arrangements

o Also, it ensures that the EIA team has appropriate expertise for the

EIA study, adequate time for and proper timing of initiation of the

study; stakeholders have been identified and techniques for their

involvement decided upon; and that financial resources for the work

are available and adequate

• Undertaking the EIA study

o EIA studies attempt to predict which impacts will occur as a result of

the project and their likely significance

EIA identifies measures to mitigate or avoid these impacts, or

optimise the benefits of the project

• EIA Report

o The final report from an EIA is also often termed an Environmental

Impact Statement (EIS)

o For the EIA process to achieve its objectives it is important that any

report produced is accurate, contains all the relevant information, is

clearly written and understood by the public, non-technical people and

decision makers

o This report comprises of the following parts; Executive Summary,

Introduction, Project Description, Project stakeholders and public

involvement, Description of Institutional, Policy and Legislative

Environment, Description of Existing Social and Biophysical

Environment, Environmental Planning and Design, Assessment of

Environmental Impacts, Impact Planning and Management, Economic

Evaluation, Summary and Recommendations, and Appendices

• The review of EIA

o Allows for decision making. This includes;

▪ Sufficiency of information provided

▪ Attention to the EIA process

▪ Reliability of analysis or interpretation

▪ Utility for decision making

• Environmental management and monitoring

o Monitoring assesses the effect of the project on the natural and

cultural environment

o Inclusion of a framework for monitoring can significantly improve the

effectiveness of EIA since it can provide a mechanism for ensuring

that approval conditions and mitigation measures have been carried-out

and testing whether predictions were accurate

• Environmental auditing

o Environmental auditing refers to the systematic, documented, periodic

and objective review of practices related to meeting environmental

requirements

o In EIA, audit refers to the comparison of actual and predicted impacts

for the purpose of assessing the accuracy of predictions and the

effectiveness of impact management practices and procedures

o In most instances, the auditing process will depend heavily on the

existence of relevant and good quality monitoring data

o An audit can help EIA process managers to learn from experience, and

further refine and improve the EIA process as a whole

• Decision making

o Decision-making takes place throughout the EIA process

o Many decisions are made by the proponent (e.g. choices between various

alternatives and project designs)

o Other decisions may be made jointly by the proponent and the decision-

making/environmental authorities (e.g. screening and scoping

decisions)

o The main decision in the EIA process, whether or not to allow the

proposal to proceed is made by the government agency (NEMC), following

consultation and public participation

o This final decision usually involves a consideration of a range of

factors including environmental, political and economic

Session 4: Standard Operating Procedure (SOP)

Total Session Time: 120 minutes + 240 minutes of Assignment

Pre-requisites

• None

Learning Tasks

By the end of this session students are expected to be able to:

• Define standard operating procedure (SOP)

• Explain the importance of SOP

• Outline types of SOPs

• Explain the components of SOP

• Explain the development and approval processes of SOP

Resources Needed

• Flip charts, marker pens, and masking tape

• Black/white board and chalk/whiteboard markers

• LCD projector and computer

• Handout 4.1: Sample format for Writing SOP

• Handout 4.2: Sample Guide for Writing Procedure Part of SOP

SESSION OVERVIEW

SESSION CONTENTS

STEP 1: Presentation of Session Title and Learning Tasks (5 minutes)

READ or ASK students to read the learning tasks and clarify

ASK students if they have any questions before continuing

STEP 2: Meaning of Standard Operating Procedure (SOP) (20 minutes)

• Standard Operating Procedure (SOP) is a set of written instructions that

document a routine or repetitive activity which is followed by employees

in an organization

• It is a set of compulsory instructions, systems, procedures or steps

which is written so that other individuals can follow to complete the job

safely and ensure quality

• SOP maximizes operational and production requirements

• The purpose of a SOP is to carry out the operations correctly and always

in the same manner

• SOP should be available at the place where the work is performed

(original copies are securely kept)

• There are two main types of SOPs

o Technical SOP

▪ This focuses more on technical activities such as how to weigh

pharmaceutical powders on dispensing balance or how to clean a

tablet press

o Administrative SOP

▪ This type focuses on administrative processes such as reviewing

contract documentation and determining organizational training

needs

STEP 3: Importances of SOPs (10 minutes)

• Standard Operating Procedures are integral part of all pharmaceutical

industries

• To obtain a standard quality product intended for human use, the

manufactured product must have undergone through current Good

Manufacturing Practices (cGMP) rules and regulations

• SOPs are part of cGMP and Good Documentation Practices (GDP)

• An SOP guides any process, procedure or activity being performed in the

pharmaceutical plant

• SOPs minimizes variation and promotes quality through consistent of a

process or procedure even in cases of personnel changes

• SOP can be used as part of personnel on-job training as it offers

instruction on how to a job

• SOPs minimizes opportunities for miscommunication and can address safety

concerns

• A typical pharmaceutical industry has an average of 1200 to 1300 SOPs

o The guide on writing all these SOPs are provided by the Mother SOP

(the SOP on SOPs)

STEP 4: Characteristics of SOPs (15 minutes)

• SOPs have a format and length that depends on the steps that are taken to

describe the procedure of the work

o An SOP can be a simple one page hierarchical steps, graphic procedures

or a flow chart

• SOP can be written by individuals or team performing processes such as

operating a tumbler mixer or cleaning of an equipment

• SOPs are written by subject expert considering the GMP working

feasibility, accountability and authorized by authorized persons

• The SOP is meant for people who will perform a particular job

• The SOP should be written before the job is began

• SOP should be tested (and revised as needed) before putting it into final

application

• SOP should be revised when there is any change to the process or

equipment used

• SOP should be re-written when new information indicate new process or

performance

• SOP should be updated regularly depending on internal and external

factors

STEP 5: General Format of SOPs (35 minutes)

• Various formats exist for preparation of SOP

• All Standard Operating Procedures shall be written in a certain format

specified in the mother SOP (SOP on SOPs)

• Choice of a format depends on the organization and type of activity for

which the SOP is prepared

• Generally, a technical SOP consists of the following components

o Title Page

▪ This is the first page or cover page of the SOP

▪ This part contains the following information

▪ Title (which clearly identifies the activity or procedure)

▪ SOP identification number

▪ Supersedes (number of previous SOP on which the current one

is based or reviews)

▪ Date of issue and/or revision

▪ Name of the organization or company

▪ Department to which the SOP applies

▪ Signatures of individuals who prepared the SOP

▪ Signatures of individuals who approved the SOP

o Table of Contents

▪ Needed for quick reference, especially if the SOP is long

▪ It is also needed for locating information and to denote changes

or revision made only in certain sections of an SOP

o Purpose/Objective

▪ This describes the purpose of the work or process including any

regulatory information or standards that are appropriate to the SOP

o Scope

▪ This indicates what is covered e.g. this procedure is applicable

to all operation of this company (company name and location)

▪ It also includes limit to the use of the procedure

o Definition (s)

▪ Definitions of technical/scientific or unusual terms used in the

SOP

o Responsibility

▪ This designates the department directly responsible for the

activity mentioned in the SOP e.g. Head-Quality Assurance is

responsible for the implementation/compliance

o Accountability

▪ Persons to be held accountable during the implementation of the

SOP

▪ Examples, Head –Site QA

o Cautions

▪ This part indicates activities that could result in equipment

damage, degradation of sample, or possible invalidation of results

(also listed in the critical steps of the procedure)

o Interference

▪ This part describes any component of the process that may

interfere with the accuracy/quality of the final product

o Personnel Qualification/Responsibilities

▪ This denotes the minimal experience the user should have to

complete the task satisfactorily

▪ It also cites any applicable requirement e.g. certification

o Equipment and Supplies

▪ This part lists and specifies where necessary, the equipment,

materials, reagents or chemical standards required for the

procedure

o Procedure

▪ All pertinent steps, in orderly manner, and the materials needed

to accomplish the procedure

▪ The activities to be carried out as part of SOP should be

described in sentences of that are short, sequential, unambiguous

and instructive

▪ These activities are such as;

▪ Instrument or method calibration and standardization

▪ Sample collection

▪ Sample handling and preservation

▪ Sample preparation and analysis (extracting, digestion,

analysis, identification and counting procedures)

▪ Troubleshooting

▪ Data acquisition, calculations and data reduction requirement

(such as listing any mathematical steps to be followed)

▪ Computer hardware and software (used to store field sampling

records, manipulate analytical results and /or report data

▪ Data records management (e.g. indentifying any calculations to

be performed, forms to be used, reports to be written and data

and record storage information)

▪ Writing guidelines and styles such as font type, font size and

margin used in SOP should be those followed by the organization

[pic][pic] Refer students to Handout 4.1: Sample Guideline for Writing

Procedure Part of SOP, for further reading

o Quality Control and Quality Assurance

▪ Quality control activities are designed to allow self

verification of quality and consistency of work

▪ This part should describe preparation of appropriate quality

control procedures (self checks such as calibration, recounting, re-

identification) and QC materials (such as blanks, performance

evaluation sample) that are required to demonstrate successful

performance of the method

▪ Specific criteria, frequency and limits for each should be

included

o Reference(s)

▪ Here, a list is provided of all other SOPs (SOP number and title)

referred in this procedure

▪ A list of any other document (e.g. guidelines, scientific

literature, user manuals) are also listed here

▪ If no reference is used, then “not applicable” is written here

o Abbreviation(s)

▪ Here, a list of all abbreviations and/or acronyms in the

procedure shall be mentioned with detailed explanations

▪ Abbreviations used in the text of the SOP are defined here

▪ Examples: QA –Quality Assurance

o Flow chart(s)

▪ In this part, a flow chart of steps involved is mentioned with

clear decision stages

o Annexure(s)

▪ These are the formats used for recordings

▪ They all bear a unique format number for better control and

identification

▪ A list of annexure(s) is provided along with annexure number

and title

o Revision History

▪ Every SOP must contain a revision history in order to track the

changes made in the SOP from time to time

▪ This history contains the details of all the previous revisions

performed for a particular SOP

[pic] Refer students to Handout 4.2: Sample Format for Writing SOP,

for further reading

• General format for administrative or programmatic SOP include;

o Title page, table of contents, definitions, purpose, Scope, summary

of procedure, Personnel qualification/responsibilities, quality

assurance and quality control, records management, and references

STEP 6: Writing SOPs (20 minutes)

• SOP should be written in a concise, step-by-step, easy-to-read format

• Information presented should be unambiguous and not overly complicated

i.e. in a simple and clear language

• Effective writing of SOP should consider the following;

o Use of short sentences

▪ Long sentences are harder to understand and tend to include more

than one step

▪ Several short sentences are easier to understand

o Imperative writing

▪ Use of imperative instead of passive voice because imperatives in

form of command are easier to understand

▪ Example;

• Passive:

o The weight of each excipient should recorded in the batch

manufacturing record

• Imperative:

o Record the weight of each excipient in the batch

manufacturing record

o Concise

▪ Few words as possible should be used when writing SOP

▪ Short, direct sentences should be used so that readers can

quickly understand and memorize the steps

|Activity: Small Group Discussion (10 minutes) |

| |

|DIVIDE s |

|tudents into small manageable groups |

| |

|ASK students to discuss on the following question |

|Identify SOPs in the compounding laboratory of your school |

| |

|ALLOW students to discuss for 10 minutes |

| |

|ALLOW few groups to present and the rest to add points not mentioned |

| |

|CLARIFY and SUMMARIZE by using the contents below |

• SOPs in compounding laboratory;

o SOP for cleaning the compounding laboratory

o SOP for storage of raw materials in compounding laboratory

o SOP for using a weighing balance

o SOPs for using a heating facilities (e.g. water bath, hot plate,

Bunsen burner)

o SOPs for disposal of wastes from compounding activities

o SOP for labelling of finished product

o SOP for packaging of finished product

STEP 7: Key Points (5 minutes)

• Standard Operating Procedure (SOP) is a set of written instructions that

document a routine or repetitive activity which is followed by employees

in an organization

• The purpose of a SOP is to carry out the operations correctly and always

in the same manner

• SOPs are part of cGMP and Good Documentation Practices (GDP) and

therefore guide any process, procedure or activity being performed in the

pharmaceutical plant

STEP 8: Evaluation (5 minutes)

• What is SOP?

• What is the importance of SOP in pharmaceutical production?

• Mention two types of SOPs?

STEP 9: Preparation of an SOP (5 minutes)

|Activity: Take home Assignment (240 minutes) |

| |

|DIVIDE students in groups or individual. |

| |

|ASK the students to work on the following assignment |

| |

|Prepare an SOP for cleaning the compounding laboratory |

| |

|ALLOCATE time for students to do the assignment and submit |

| |

|REFER students to recommended references |

References

Escope, Adriene, (1997). Nimble documentation, the practical guide for

World class organization, Milwaukee, Wisconsin, American Society for

Quality, Quality Press

Garner, Willa Y and Mureen S. Barge, Editors, “Good Laboratory Practices.

An agrochemical perspective” ACS Symposium Series 369, American

Chemical Society

Schmidt, O. (ed) (2000) Pharmaceutical Quality systems, Interpharm Press,

Colorado.

Shayne C et al. (2008), Pharmaceutical Manufacturing Handbook: Production

and processes, John Wiley & Sons

|[pic] |Handout 4.1: Sample Format for Writing SOP |

• All Standard Operating Procedures shall be written in a certain format

specified in the mother SOP (SOP on SOPs)

|STANDARD OPERATING PROCEDURE |

|Title: |Copy no.: |

|Department: |Page no.: |

|SOP No.: |Supersedes: |

| |Effective date: |

1. Purpose

2. Scope

3. Responsibility

4. Procedure

5. Revision

6. Abbreviations

7. Annexures

|[pic] |Handout 4.2: Sample Guideline for Writing Procedure Part of |

| |SOP |

• All Standard Operating Procedures shall be written in English language

• Language shall be clear, sequential, and unambiguous

• Where required, SOP shall be additionally prepared in vernacular language

for easy understanding. Content of such SOPs shall be verified and

certified for accuracy with the current approved English version. In

other words, where necessary the SOP shall be translated into the local

languages; however all such translated versions shall have the same

reference number of its original English version

• All SOPs shall be printed on “Letter” size white paper in black in “Times

New Roman” regular font style of size “12” unless specified. The font

size and font style is optional

• General alignment for paragraphs shall always be kept as “Justified”.

Line spacing between two lines shall be maintained as “5 Lines

• Military standard system shall be followed for numbering of heads and

subheads

• Signature of the procedure shall be done with Blue/black ball point pen

only. All pages shall have a border of the setting “Box” 1pt from both

top and bottom and 4pt from left and right, from the text

• The header and footer content shall be common in all pages of the

procedure excluding the formats and annexures.

• Details of header are;

• Title -A proper title that is assigned to represent the core operation

that it carries e.g. if the SOP is being prepared for operation of

cleaning a tablet press, then the title can be written as “Cleaning of

Tablet Press”

• Location -Shows the location where the procedure is prepared

• Department -In this place the name of the department preparing the

procedure is written

• Page number shall be assigned

• Effective date

o Here, the date at which the procedure becomes effective is written.

E.g. is the SOP is prepared and approved on 10th December, 2018, the

effective date shall be assigned 3-10 days from the date of approval

o The period is important to allow time for training of staff/personnel

who will follow the SOP

• Next review date

o The date of next mandatory review is set and written here. If the

review period is three years, then the SOP on cleaning tablet press

will be reviewed on 9th December, 2021.

• SOP number

o Every SOP shall be assigned a number for identification and

reference

o Numbering system varies from one company to another

o Example of a numbering system: TPC/QA/18/001-02 where

▪ TPC denotes Tablet Press Cleaning

▪ QA denotes Quality Assurance Department (name of the department)

▪ 18 denotes the year, 2018

▪ 001 denotes sequential numbering for the SOP’s prepared in the

year

▪ 02 denotes the revision number of the document

• Details of the footer are;

o The footer contains two parts;

o Part A: Signatories

▪ Prepared By:

• name and signature of the person in the department preparing the

SOP who authorizes the document, and the date on which the

document is signed

▪ Checked By:

• name and signature of the person who exhaustively verifies the

content of the SOP after it is prepared and signed

▪ Approved By:

• name and signature of the person who approves the document

including the date of approval

• Part B: Format Numbering

o This is important for identification and control of different formats

used in the company

o The font size of the number is set to 10 and positioned at the bottom

right corner of the document

o For example, the format number may be TPC/QA/18/001/F 02-01, where

o TPC denotes Tablet Press Cleaning

o QA denotes Quality Assurance Department (name of the department)

o 18 denotes the year, 2018

o 001 denotes sequential numbering for the SOP’s prepared in the year

o F denotes Format

o 02 denotes format number

o 01 denotes version number

o If the format is made for the first time, the format revision number

(shown in bold) is TPC/QA/18/001/F 02-00,and if it is revised once

then it becomes TPC/QA/18/001/F 02-02

Session 5: SOP on SOPs (SOP on Standard Operating Procedures)

Total Session Time: 120 minutes

Pre-requisites

• None

Learning Tasks

By the end of this session students are expected to be able to:

• Define SOP of SOPs

• Explain the components of SOP of SOPs

• Develop an SOP of SOPs

Resources Needed:

• Flip charts, marker pens, and masking tape

• Black/white board and chalk/whiteboard markers

• LCD projector and computer

• Handout 5.1: Format for SOP of SOPs

SESSION OVERVIEW

SESSION CONTENTS

STEP 1: Presentation of Session Title and Learning Tasks (5 minutes)

READ or ASK students to read the learning tasks and clarify

ASK students if they have any questions before continuing

STEP 2: SOP of SOPs (5 minutes)

• In order to write Standard Operating Procedure, another Standard

Operating Procedure is needed to standardize and guide the process

• The SOP that guides how other SOPs in the organization should be prepared

is known as an SOP of SOPs or a mother SOP

STEP 3: Components of SOP of SOPs (10 minutes)

• Components of the SOP of SOPs;

o Purpose

▪ The purpose of SOP of SOPs is to describe procedures for

preparation, review and approval of standard operating procedures

in pharmaceutical production

o Scope

▪ This part of the SOP of SOPs describes the way the SOP of SOPs

applies to all SOPs

o Responsibility

▪ This part identifies people (Executive/QA officers or other

designated persons) responsible for preparation, revision,

periodical review and approval of the SOP of SOPs

▪ Persons responsible for the preparation, revision and

periodic review of the SOP of SOPS

▪ Person(s) responsible for review and training of the SOP of

SOPs

▪ Person(s) responsible for approval of the mother SOP

o Procedure

▪ This part should,

▪ Specify the format of all SOPs in the organization

▪ Specify paging and placement of company logo on SOPs

▪ Specify header, content and footer of the SOPs

▪ Specify font style, font size and line spacing in all SOPs

▪ Specify numbering system (and description of characters used

in the numbering system) for the SOPs

▪ Specify placement of dates (supersedes, approval date,

effective date and review date) for SOPs

▪ Specify the signatories of various SOPs in the organization

(i.e. prepared by, reviewed by, approved by)

▪ Specify the content of SOPs

▪ Purpose, scope, responsibility, procedure, revision,

abbreviations, annexures, header, footer, as described in

session 7)

o Revision

▪ Describes revision of SOPs

▪ Provides a revision log showing revision number, effective date

and reason for the revision of each SOP revised

o Abbreviations

▪ Should show abbreviations or acronyms used in the mother SOP and

their expanded form

o Annexure

▪ Provides a list of all the annexure used in the mother SOP (e.g.

SOPs format, list of codes)

STEP 5: Developing an SOP of SOPs (90 minutes)

[pic][pic] Refer students to Handout 5.1: Format for SOP of SOPs

|Activity: Small Group Assignment (60 minutes) |

| |

|DIVIDE students in manageable groups |

| |

|ASK the students to work on the following assignment |

| |

|Prepare an SOP of SOPs for a Compounding Laboratory in your school |

| |

|ALLOCATE time for students to do the assignment and presentation |

| |

|REFER students to recommended references |

STEP 6: Key Points (5 minutes)

• SOP on SOPs is the standard operating procedure for preparation of all

SOPs in an organization

• It guides the process of preparing SOPs in all departments of an

organization

• SOP of SOPs is also known as the mother SOP

STEP 7: Evaluation (5 minutes)

• What is an SOP?

• What is SOP of SOPs?

• Mention the components of an SOP of SOPs

• Who is responsible for preparing the SOP of SOPs in a pharmaceutical

manufacturing company?

References

Escope, Adriene, (1997). Nimble documentation, the practical guide for

World class organization, Milwaukee, Wisconsin, American Society for

Quality, Quality Press

Garner, Willa Y and Mureen S. Barge, Editors, “Good Laboratory Practices.

An agrochemical perspective” ACS Symposium Series 369, American

Chemical Society

Schmidt, O. (ed) (2000) Pharmaceutical Quality systems, Interpharm Press,

Colorado.

Shayne C et al (2008), Pharmaceutical Manufacturing Handbook: Production

and processes, John Wiley & Sons

|[pic] |Handout 5.1: General Format for SOP of SOPs |

| SOP ON STANDARD OPERATING PROCEDURES |

|Title: |Copy no.: |

|Organization/Company: |Page no.: |

|SOP of SOPs No.: |Supersedes: |

| |Effective date: |

8. Purpose

9. Scope

10. Responsibility

11. Procedure

12. Revision

13. Abbreviations

14. Annexures

Session 6: Validation of Pharmaceutical Raw Materials

Total Session Time: 120 minutes

Pre-requisites

• None

Learning Tasks

By the end of this session students are expected to be able to:

• Define pharmaceutical raw materials

• Explain the validation process for pharmaceutical raw materials

• Explain the approaches and importance of raw materials testing

• List tests and equipments used for testing quality of raw materials

Resources Needed:

• Flip charts, marker pens, and masking tape

• Black/white board and chalk/whiteboard markers

• LCD projector and computer

SESSION OVERVIEW

SESSION CONTENTS

STEP 1: Presentation of Session Title and Learning Tasks (5 minutes)

READ or ASK students to read the learning tasks and clarify

ASK students if they have any questions before continuing

STEP 2: Definition of Raw Materials (15 minutes)

• Pharmaceutical raw materials are the starting materials in the

manufacturing of a finished pharmaceutical product

• Raw materials are used in the manufacturing of a finished bulk (even

though it may not be present in the final product e.g. certain solvents

etc.) and are consumed by person using the product

• Pharmaceutical raw materials include the active drug and the inactive

substances (the excipients)

STEP 3: Validation of Pharmaceutical Raw Materials (40 minutes)

• Pharmaceutical raw materials must be validated for quality attributes

(identity, safety, potency, purity, stability and efficacy)

• Validation of pharmaceutical raw materials

o It is a process of demonstrating through documented evidence that the

raw materials will consistently produce a product or result that meets

predetermined specifications and quality attributes in the final

product

• Steps required in validation of raw materials are;

o Preparing a list of all raw materials needed to prepare a product

batch

▪ Should include all materials used in production and testing

including active ingredients and excipients

o Identification of suppliers for each raw materials

▪ Purchase specifications for raw materials for pharmaceutical

manufacturing should be established and used in order to ensure

acquisition of quality raw materials and hence quality finished

products

▪ Mode of purchasing should be specified e.g. by inspection, by

sample, by description brand or by grading

▪ Visiting the suppliers’ warehouse to inspect storage of raw

materials (how quality is maintained) especially for a new supplier

o Obtaining samples and supplier’s certificates of analysis

▪ To determine characteristics of raw materials

▪ Certificates of analysis and samples show the extent of variation

between different lots from the same supplier and the variation

between suppliers

o Establishing specifications for each raw material

▪ The list of parameters show acceptable measurable range of

activity for compendial raw materials and non compendial raw

materials

o Establishing optimum storage conditions

▪ Raw materials must handled and stored under prescribed condition

in order to protect their stability over stated shelf-life

• Primary objective in storage of raw materials once accepted is

to protect their quality and prevent loss through spoilage or

theft

• External containers must be cleaned before storage

• Quantity must be verified

• Storage as per quarantine status of the materials

o Received, sampled, approved, rejected

o Space should be defined for each item or type of item

▪ Chemistry of each raw material should be reviewed and aspects

concerning hygroscopic nature, photosensitivity, sensitivity to

temperatures, ability to support microbial growth, reactivity with

container or closure system and oxidizing capacity are checked

o Establishing sampling procedures

▪ Visual inspection on receipt of the raw materials (based on

detection of physical damage to package, lids or seals; proper

labelling)may not enough to ascertain quality of raw materials

▪ Raw materials must be sampled for laboratory testing

▪ In order to conduct test for raw materials, documentation of raw

material sampling (SOP) must be developed

▪ Documentation of sampling include general requirements for any

raw materials received in the plant;

▪ Quantity of raw material received and number of containers to

sample (sample size)

▪ Sampling responsibility (who should collect the samples)

▪ Sampling formula used

▪ Method of sampling e.g. top, middle, bottom

• Individual raw materials may have their own sampling

requirements based on their stability and/or intended use

o Establishing test procedures for raw materials

▪ Before manufacturing begins, all raw materials must be tested

(for safety, purity, identity and quality)

▪ A test procedure must be established for each specification

▪ For raw materials that are compendia, test procedures are denoted

along with their respective specifications

▪ For raw materials that are not listed in official compendia,

methods are developed for their testing (through modification of

compendia methods that exist for similar compounds or methods

published in literature)

▪ Extent of raw material testing is determined by the manufacturer

STEP 4: Approaches and Importance of Raw Materials Testing (20 minutes)

• Before finished pharmaceutical dosage forms are produced, the identity,

purity and quality of raw materials must be established with the use of

suitable test methods

• Several approaches are used by manufacturers to raw materials testing in

order to comply with national and international standards and regulations

o One such approach by manufacturing company is performing an initial

detailed vendor audit followed by an annual qualification consisting

of full pharmacopoeial monograph testing on three lots of materials.

If the qualification lots test successfully, then subsequent material

shipments will require only monograph identification testing

o Another approach is when a company performs full monograph testing for

each lot of supplied raw material

• It is important to test raw materials for quality;

o Raw materials testing ensures that the raw materials used in

pharmaceutical products are suitable for their intended use

o Testing of raw materials prevents costly production cost and delays

STEP 5: Tests and Equipments for Raw Materials Validation (30 minutes)

• Raw materials analysis requires a wide range of analytical chemistry

expertise

• The most common tests performed in raw materials laboratory include;

o Titrations

o Loss on drying

o Karl Fischer moisture determination

o Heavy metals limit tests

o Infrared spectrophotometry

• Full monograph testing often requires as many as seven different

analytical techniques

o For instance, a full USP monograph testing for methylparaben requires

eight different tests using six analytical techniques ranging from

infrared absorption to gas chromatography

• To perform basic monograph testing, the laboratory must contain a wide

spectrum of instrumentation. Most commonly specified instruments include;

o pH meter, balances, gas chromatographs, high performance liquid

chromatographs (HPLCs), infrared spectrophotometers, ultra

violet/visible (UV- Vis) range spectrophotometers, Karl Fischer

moisture titrators, general titration apparatus, vacuum ovens, melting-

point apparatus, thin-layer chromatography, polarimeters,

refractometers, viscometers and muffle furnaces

• Because of the heavy investment in instruments for raw material testing,

come companies outsource their raw materials testing instead of investing

heavily in equipment

STEP 6: Key Points (5 minutes)

• Pharmaceutical raw materials are the starting materials in the

manufacturing of a finished pharmaceutical product

• Pharmaceutical raw materials include the active drug and excipients

• Validation of raw materials is a process of demonstrating through

documented evidence that the raw materials will consistently produce a

product or result that meets predetermined specifications and quality

attributes in the final product

• Quality attributes of pharmaceutical raw materials that must be validated

are identity, safety, potency, purity, stability and efficacy

• The most common tests performed in raw materials laboratory include ,

titratios, loss on drying (LOD), Karl Fischer moisture determination,

heavy metals limit tests and infrared spectrophotometry

STEP 7: Evaluation (5 minutes)

• What is validation of raw materials?

• What is the importance of testing raw materials?

• Who is responsible for validation of pharmaceutical raw materials?

References

Aulton M.E., & Kevin M.G., Eds: (2013) Pharmaceutics: The design and

manufacture of medicines, (4th ed.) Churchill Livingstone

Berry, I.R and Daniel Harpaz, Validation of active pharmaceutical

ingredients

Gennaro, R. A, et.al (eds) 1995 Remington: The Science and Practice of

Pharmacy, Volume I & II, 19th (ed.): Mack Publishing Company, Easton,

Pennsylvania 18042

Lund, W. Editor (1994). The Pharmaceutical Codex, Principles and Practice

of Pharmaceutics (12th ed.): The Pharmaceutical Press, London

Polderman, J (1990). Introduction to Pharmaceutical Production: Novib, The

Hague

Schmidt, O. (ed) 2000 Pharmaceutical Quality systems, Interpharm Press,

Colorado.

Shayne C et al (2008), Pharmaceutical Manufacturing Handbook: Production

and processes, John Wiley & Sons

Watson, D. G (1999) Pharmaceutical Analysis: A Textbook for Pharmacy

Students and Pharmaceutical Chemists: Churchill Livingstone,

Edinburgh.

Session 7: Dispensing of Pharmaceutical Materials

Total Session Time: 120 minutes

Pre-requisites

• None

Learning Tasks

By the end of this session students are expected to be able to:

• Dispensing of raw materials

• Describe dispensing area for raw materials

• List equipment used in dispensing of raw materials

• Explain the dispensing of raw materials

Resources Needed:

• Flip charts, marker pens, and masking tape

• Black/white board and chalk/whiteboard markers

• LCD projector and computer

SESSION OVERVIEW

SESSION CONTENTS

STEP 1: Presentation of Session Title and Learning Tasks (5 minutes)

READ or ASK students to read the learning tasks and clarify

ASK students if they have any questions before continuing

STEP 2: Dispensing and Dispensing Area (20 minutes)

• Dispensing of raw materials is the process whereby raw materials required

for production are identified, weighed or measured and transferred to the

production area

• Every pharmaceutical manufacturing plant must have an area in which raw

materials are weighed and transferred in clean containers to the

production area

• The area where dispensing takes place is known by various names including

weighing bay, weighing area, weighing room, central weigh, pharmacy or

dispensing room

• Features of a weighing room include;

o Unidirectional flow of materials and personnel

o Segregation between hazardous and non-hazardous materials

o Separation of storage and manufacturing items and space

• The weighing room is the entry point to manufacturing and the transition

point for materials coming from the warehouse and entering processing

areas

• The dispensing areas is commonly comprised of;

o Weighing area

▪ Where actual weighing or measuring of raw materials is done

o Raw material staging area

▪ When weighing is complete, there may still be material left in

the containers received from the client

▪ Large quantities are usually returned to the warehouse, but small

quantities, especially of those materials that will be used again

soon, can be stored on pallets or on shelving in raw material

staging areas (materials requiring special storage conditions not

provided by the raw material staging area are returned to their

appropriate storage locations in the warehouse)

o Work-in-process

STEP 3: Dispensing Equipments (20 minutes)

|Activity: Buzzing (5 minutes) |

| |

|ASK students to pair up and buzz on the following question for 2 |

|minutes |

| |

|Which equipments are used in dispensing of raw materials? |

| |

|ALLOW few pairs to respond and let other pairs to add on points not |

|mentioned |

| |

|WRITE their response on the flip chart/board |

| |

|CLARIFY and SUMMARIZE by using the content below |

• Dispensing equipment include the following;

o Scales

▪ Size of scale used is determined by capacity of materials to be

weighed

▪ Example is a pit-mounted floor scale

o Pippetes

o Calibrated measuring containers

o Fume cabinets

o Labels/printers and related instrumentation

• All equipment must be calibrated and maintained regularly to minimize

errors

o Routine testing must be carried out for all the balances being used in

the facility

• All dispensing equipment must be documented properly

• There should be SOP for using each equipment

STEP 4: Preparation for Dispensing Raw Materials (25 minutes)

• Before any dispensing activity is done, the warehouse, in-process quality

control and production personnel must ensure that ;

o The dispensing area and dispensing equipment are cleaned

o Differential pressure, temperature and relative humidity of the

dispensing area are within the specified limits

o Documents related to previous products are removed from dispensing

area

o All the log books of the respective areas are updated

o Approved materials are to be dispensed

o The reverse laminar flow (RLAF) is switched on 15 minutes before

dispensing activity starts

• Production personnel is responsible for calculating the quantity of

active pharmaceutical ingredients (APIs) and excipients (and adjustments

according to standard batch size, if applicable) as outlined in the Batch

Manufacturing Record (BMR)

o The calculations are verified by in-process quality control personnel

• Personnel enter the dispensing area through the personnel airlock with

proper gowning

• Dispensing is only done in controlled conditions under reverse laminar

air flow

STEP 5: Dispensing Process for Pharmaceutical Raw Materials (40 minutes)

|Activity: Small Group Discussion (10 minutes) |

| |

|DIVIDE students into small manageable groups |

| |

|ASK students to discuss on the following question |

|Explain the dispensing procedures for raw materials? |

| |

|ALLOW students to discuss for 10 minutes |

| |

|ALLOW few groups to present and the rest to add points not mentioned|

| |

|CLARIFY and SUMMARIZE by using the contents below |

o Receipt of “Dispensing of Raw Material Sheet”

▪ The Batch Manufacturing Record (BMR) contains a list of raw

materials to be dispensed known as Dispensing of Raw Material sheet

▪ All raw materials are dispensed as per quantities mentioned in

the “dispensing of raw material” sheet of the BMR

o Verification of Availability

▪ Warehouse personnel verifies the availability of the approval

status of required raw materials

▪ A raw materials stock card of respective raw material is used to

facilitate the verification process

o Dispensing the raw material

▪ After verification of availability, warehouse personnel dispenses

the raw material

▪ All raw material are dispensed as per First Expiry First Out

(FEFO) followed by First In First Out (FIFO) system

▪ Sterile raw materials are dispensed while in their intact

packs

▪ Dispensed raw materials are transferred from approved raw

material storage area to the raw material dispensing area one by

one through the material entry air lock

▪ Inactive ingredients (excipients) are dispensed before the

active ingredients except colours and flavours are dispensed

last

▪ Dispensing of additional raw materials

▪ Additional raw materials are dispensed and issued to the

production department under the following circumstances;

• on line rejection

• spillage and wastage of material during transit or production

activity

o production department must raise a requisition for the additional

requirement of material duly authorized by head of quality assurance

after investigating the additional requirement for raw material

▪ Loose packs of raw materials (remaining after dispensing) are

cleaned, sealed, labelled “loose” and transferred through the

material entry air lock one by one back to their respective storage

areas

o Documentation of dispensed raw material

▪ Warehouse personnel then document the dispensed raw material

appropriately

▪ The warehouse fills the BMR sheet and stock cards as required

▪ Batch number, assay, % of moisture content, manufacturing

date, expiry date, quantity dispensed

▪ If additional materials have been dispensed, the details of

additional materials issued are recorded in material stock card

and supplementary slip for raw materials and attached to the BMR

o Transfer of raw materials

▪ Dispensed raw materials are transferred to the raw material

dispensed quarantine area through the airlock and kept on clean

pallets

o Cleaning the dispensing area and dispensing equipment

▪ After completion of dispensing activity, dispensing equipment and

the dispensing area are cleaned thoroughly according to cleaning

procedures

▪ Cleaning activity is recorded in appropriate records

STEP 6: Key Points (5 minutes)

• Dispensing of raw materials is the process whereby raw materials required

for production are identified, weighed or measured and transferred to the

production area

• Every pharmaceutical manufacturing plant must have an area in which raw

materials are weighed and transferred in clean containers to the

production area

• The area where dispensing takes place is known by various names including

weighing bay, weighing area, weighing room, central weigh, pharmacy or

dispensing room

• The main equipment used in the dispensing of raw materials is the scale

• Before raw materials are dispensed, the dispensing area and equipment

must be cleaned

STEP 7: Evaluation (5 minutes)

• What is dispensing of raw materials?

• List the equipment used in dispensing of raw materials

• What guides the dispensing process for raw materials?

References

Aulton M.E (ed) (1988) Pharmaceutics: The science of dosage form design.

Churchill Livingstone, Edinburgh

Aulton M.E & Kevin M.G, Eds: (2013) Pharmaceutics: The design and

manufacture of medicines, (4th ed.) Churchill Livingstone

Hugo and Russell (2011), Pharmaceutical Microbiology (8th ed.) Willey-

Blackwel publications

Gennaro, R. A, et.al (eds) 1995 Remington: The Science and Practice of

Pharmacy, Volume I & II, (19th ed.) Mack Publishing Company, Easton,

Pennsylvania 18042

Liebsch, B et al. (1988): Tanzania Pharmaceutical Handbook, Dar es Salaam

University Press.

Lund, W. Editor (1994). The Pharmaceutical Codex, Principles and Practice

of Pharmaceutics 12th Edition: The Pharmaceutical Press, London

Polderman, J. (1990) Introduction to Pharmaceutical Production: Novib, The

Hague

Rawlins E.A, Editor: 1977 Bentley’s Textbook of Pharmaceutics, (8th ed.).

Baillie're Tindall. London Kamm, G. and Kohler, B. Editors: 1995

Manual for Decentralized Infusion Production, Infusion Unit Project

Tanzania

Schmidt, O. (ed) 2000 Pharmaceutical Quality systems, Interpharm Press,

Colorado.

Shayne C et al. (2008), Pharmaceutical Manufacturing Handbook: Production

and processes, John Wiley & Sons

Watson, D. G (1999) Pharmaceutical Analysis: A Textbook for Pharmacy

Students and Pharmaceutical Chemists: Churchill Livingstone,

Edinburgh.

Session 8: Pharmaceutical Powders

Total Session Time: 120 minutes

Pre-requisites

• None

Learning Tasks

By the end of this session students are expected to be able to:

• Define powders

• Explain the production of powders

• Classify powders

• List uses of powders in pharmacy

• List advantages and disadvantages of powders

Resources Needed:

• Flip charts, marker pens, and masking tape

• Black/white board and chalk/whiteboard markers

• LCD projector and computer

SESSION OVERVIEW

| | |g | |

SESSION CONTENTS

STEP 1: Presentation of Session Title and Learning Tasks (5 minutes)

READ or ASK students to read the learning tasks and clarify

ASK students if they have any questions before continuing

STEP 2: Introduction to Powders (15 minutes)

|Activity: Brainstorming (5 minutes) |

| |

|ASK students to brainstorm on the following question: |

| |

|What is a pharmaceutical powder? |

| |

|ALLOW few students to respond? |

| |

|WRITE their responses on the flip chart/ board |

| |

|CLARIFY Al,0.++23.2+0000.nd SUMMARISE by using the content below |

• A pharmaceutical powder is a mixture of finely divided drug and /or

chemicals in dry form intended for internal or external use.

• Powders are intended to be used as;

o Dosage forms e.g. dusting powders

o Starting materials for other dosage forms e.g. tablets and capsules

▪ They determine behavior of dosage forms during manufacturing and

in the finished dosage form

▪ Particle size, density and porosity are important characteristic

of powders

• These affect the ability of powders to flow (flowability)

▪ Flowability may be measured by using the angle of repose

• Powders as dosage forms can be classified according to;

o Number of constituents

▪ Simple powders i.e. powders containing only one ingredient

▪ Compound powders i.e. powders containing two or more substances

mixed together

o Mode of application

▪ Powders for internal use

▪ Powders for external use

o Packaging

▪ Bulk powders

▪ Divided powders

STEP 3: Production of Powders (10 minutes)

• Molecular aggregation

o Precipitation

▪ Through super-saturation of solutions

o Crystallization

▪ Through super cooling of solutions

o Spray-drying

▪ Atomization of solution followed by evaporation of solvent

• Particle size reduction

o By use of equipment such as course crushers, grinders, and mills

STEP 4: Preparation and Mixing of Powders (30 minutes)

• Preparation of powder dosage forms

o Preparation of powders involves

o Particle size reduction (all ingredients) to the same range in order

to prevent demixing or segregation

➢ Trituration (using mortar and pestle)

➢ Pulverization by intervention (for gummy or materials difficult

to grind)

➢ Levigation

o Sieving

o Weighing of each ingredient

o Mixing

o Packaging

• Mixing of Powders

o Mixing is as an operation in which two or more components in a

separate or roughly mixed condition are treated so that each particle

lies as nearly as possible in contact with a particle of each of the

other ingredients

o For mixing to occur the individual particles must be redistributed

repeatedly within the bulk, either by tumbling, shearing, scooping,

kneading or impaction.

o Powders are mixed to obtain homogeneity. Equipment used for mixing are

known as mixers

o For small scale mixing e.g. in compounding, equipments used for mixing

are;

▪ mortar and pestle

▪ spatula and tile or paper

▪ sieving equipment (sieving)

o For large scale mixing e.g. in industrial production, large mixers

including

➢ tumbler mixers,

➢ shear mixers,

➢ ribbon mixers,

➢ impact mixers etc are employed

▪ Characteristics of an ideal mixer

• Capable of producing complete blend in reasonable time without damaging

the product

• Dust-tight

• Requiring low maintenance and energy

• Discharged and cleaned easily (All these properties cannot be found in a

single mixer)

o Methods used in mixing powders

▪ Spatulation

▪ Trituration (for both comminution and mixing)

▪ Geometric dilution

▪ Sifting

▪ Tumbling

• Types of powder mixtures

o Free flowing mixtures

o Cohesive mixtures

o Ordered mixtures

o Packaging of Powders

▪ Packed depending on use;

▪ Bulk powders

▪ Divided powders

STEP 5: Bulk and Divided Powders (30 minutes)

Bulk powders

• Bulk powders are limited to non potent drugs

• They are packed into suitable bulk containers to facilitate dosing (e.g.

wide mouth jar, perforated or sifter top cans and aerosol containers)

• Examples for powders commonly dispensed in a bulk form

o Powders used in a dry form e.g. dusting powders, insufflations,

dentifrices

o Powders to be dissolved in water before use e.g. antacid powders,

douche powders

o Powders for reconstitution e.g. oral antibiotic powders, powders for

injection (powders for injection may also be supplied as divided

powders)

• Bulk powders are classified into bulk powders for internal use and bulk

powders for external use

o Bulk Powders for Internal Use

▪ Contain several doses

▪ Dispensed in bulk

▪ Bulk powders for (oral) internal use are generally supplied as

finely divided powders or effervescent granules

• The finely divided powders are intended to be suspended or dissolved in

water or mixed with soft foods, e.g., applesauce, prior to administration

▪ They include; antacid powders, oral antibiotic powders, laxative

powders

o Oral Powders

▪ These generally are supplied as finely divided powders or

effervescent granules

▪ Granules are aggregates of powdered materials as a dosage form or for

making tablets or capsules (because of better flowability of granules

compared to powders)

o Oral powders are finely divided powders or effervescent granules

intended to be suspended or dissolved in water or mixed with soft

foods, e.g. applesauce, prior to administration

• Contain sodium bicarbonate and either citric acid, tartaric acid or

sodium biphosphate in addition to the active ingredients

• On solution in water, carbon dioxide is released as a result of the acid-

base reaction

• The effervescence from the release of the carbon dioxide serves to mask

the taste of salty or bitter medications.

• The completed product must be dispensed in tightly closed glass

containers to protect it against the humidity of the air

Examples of oral powders are antacids and laxative powders

o Bulk Powders for External Use

▪ Supply non potent drugs

▪ Powders dispensed in cardboard, plastic or glass containers, also

in sifter top containers

Classes of Bulk powders for External Uses

• Dusting powders

▪ They are used for external application on the skin and applied in a

very fine state of subdivision to avoid local irritation

▪ Dusting powders contain two or more ingredients one of which must be

either starch, kaolin or talc are used in the formulation

o Talc and kaolin are commonly used because they are chemically inert

o Dusting powders are applied to various parts of the body as

lubricants, protective, absorbents, antiseptics, anti-pruritics, anti-

bromhidrosis agents, astringents and antiperspirants

Characteristics of Dusting Powders

• Homogenous and very fine

• Free from irritation

• Flow easily

• Good covering capacity

• Good absorptive and adsorptive capacity

• Spread uniformly over body surface

• Cling to skin surface after application

• Protect skin from irritation caused by friction, moisture and chemical

irritants

Types of Dusting Powders

• Medical dusting powders

o They are for superficial skin conditions and for antiseptic, anti-

pruritic, astringent, antiperspirant, absorbent, protective and

lubricant purposes e.g. zinc and salicylic acid dusting powder,

clotrimazole dusting powder, starch and talk dusting powder

• Surgical Dusting Powders

o These are sterile powders used in body cavities for treatment of major

wounds such as burn wounds and umbilical cords in infants.

• Insufflations

o They are medicated finely divided powders for application into body

cavities (ears, nose, throat, vagina) by means of a device known as

“insufflators” or powder blower

o Produce local effect e.g. when applied into ears or systemic effect

e.g. when inhaled into the lungs and absorbed

o They are packaged in

o Insufflators (blowers) –for non potent drugs as it is difficult to

obtain uniform doses

o Pressurized aerosols –for potent drugs where the dose is adjusted

applied through a metered valve. Pressurized aerosols are also used

for administration of micronized powders

• Snuffs

o Snuffs are finely divided solid dosage forms of medicament that are

inhaled into the nostrils for antiseptic, bronchodilator, decongestion

actions

• Douche Powders

o These are powders that are completely soluble

o They are dissolved in water before they are used as antiseptics or

cleansing agents for body cavities e.g. vaginal use

• Triturates

o Powder triturates are dilutions of potent medications prepared by

mixing them well with a suitable diluent in a definite proportion by

weight .E.g. atropine sulfate in a lactose diluent

• Dentifrices

o These are dental cleansing powders

o They are powder prepared for use with the help of a tooth brush for

cleansing surfaces of the tooth

o They are available in forms of fine powders and pastes

o The powders contain

o a suitable detergent or soap

o mild abrasive substance e.g. calcium sulphate, magnesium carbonate,

sodium carbonate in fine powder;

o binder

o opacifiers

o humectants

o colouring agent

o sweetening agent e.g. saccharin sodium

o suitable flavour e.g. peppermint, clove oil

• Divided powders

o Divided powders are similar formulations to bulk powders but doses are

individually weighed and separately wrapped (packaged)

o Divided powders are dispensed in the form of individual doses and

generally are dispensed in papers, properly folded

o Traditionally in papers (unsatisfactory for most products, especially

if the ingredients are hygroscopic, volatile or deliquescent)

o Modern packaging materials of foil and plastic laminates have replaced

paper wrapping

o They also may be dispensed in metal foil, small heat-sealed plastic

bags or other containers

• Preparation of divided powders

o After weighing, comminuting and mixing the ingredients, the powders

must be divided accurately into the prescribed number of doses

o In order to achieve accuracy consistent with the other steps in the

preparation, each dose should be weighed individually and transferred

to a powder paper

o Following completion of this step, the powder papers are folded

• Divided powders include

o Packets

o Cachets

o Powders for injection (may be bulk or divided powder)

o Oral (Effervescent) powders or granules (may be bulk or divided)

▪ Packed in separate packages

▪ They are intended to be suspended or dissolved in water or mixed

with soft food

▪ The liquid formed or the food mix is consumed just after the

reaction (effervescence)

▪ Examples include antacids and laxative powders

STEP 6: Advantages and Disadvantages of Powders (20 minutes)

|Activity: Small Group Discussion (10 minutes) |

| |

|DIVIDE students into small manageable groups |

| |

|ASK students to discuss on the following question |

|What are advantages and disadvantages of powders? |

| |

|ALLOW students to discuss for 15 minutes |

| |

|ALLOW few groups to present and the rest to add points not mentioned |

| |

|CLARIFY and SUMMARIZE by using the contents below |

• Advantages of Powders

o More stable than liquid dosage forms

o Rapid dissolution and absorption

o Offer rapid onset of action

o Easy to carry

o Flexibility of compounding/manufacturing

o Convenient for children and elderly

o Available for internal and external use

• Disadvantages of Powders

o Difficult to measure doses (leading to inaccurate dosing)

o Not suitable for bitter and nauseating drugs

o Not suitable for corrosive oral drugs

o Difficult to mask unpleasant organoleptic properties (taste, odour)

o Time consuming in dispensing

o Not suitable for hygroscopic drugs

o Not suitable for deliquescent drugs

o Volatile drugs difficult to dispense

STEP 7: Key Points (5 minutes)

• A pharmaceutical powder is a mixture of finely divided drug and /or

chemicals in dry form

• Powders are used as dosage forms or as starting materials for production

of other dosage forms

• Powders may classified into simple powders, compound powders, bulk

powders, divided powders, powders for external use or powders for

internal use

• Powder mix may be free flowing, cohesive or ordered mixtures

• Bulk powders involves packaging of non potent powders in bulk

• Bulk powders for external use include dusting powders, dentifrices,

insufflations, snuffs, douche powders and triturates

• Bulk powders for internal use include oral powders

• Divided powders are powders packaged in individual correctly weighed

doses. Potent drug powders are packed as divided powders.

• Divided powders include packets, cachets, powder for injection and oral

powders

STEP 8: Evaluation (5 minutes)

• What are the advantages of powders over other dosage forms?

• What is an insufflator?

• What is levigation?

• Explain the process of pulverization by intervention

References

Aulton M.E & Kevin M.G, Eds: (2013) Pharmaceutics: The design and

manufacture of medicines, (4th ed.) Churchill Livingstone

Gennaro, R. A, et.al (eds)( 1995) Remington: The Science and Practice of

Pharmacy, Volume I & II, (19th ed.) Mack Publishing Company, Easton,

Pennsylvania 18042

Liebsch, B et al. (1988): Tanzania Pharmaceutical Handbook, Dar es Salaam

University Press.

Lund, W. Editor (1994). The Pharmaceutical Codex, Principles and Practice

of Pharmaceutics 12th Edition: The Pharmaceutical Press, London

Polderman, J (1990) Introduction to Pharmaceutical Production: Novib, The

Hague

Rawlins E.A, Editor: (1977) Bentley’s Textbook of Pharmaceutics, (8th

ed.). Baillie're Tindall

Schmidt, O.(2000) Pharmaceutical Quality systems, Interpharm Press,

Colorado.

Shayne C et al. (2008), Pharmaceutical Manufacturing Handbook: Production

and processes, John Wiley & Sons

Watson, D. G., (1999) Pharmaceutical Analysis: A Textbook for Pharmacy

Students and Pharmaceutical Chemists: Churchill Livingstone, Edinburgh

Session 9: Mixing of Pharmaceutical Powders

Total Session Time: 120 minutes

Pre-requisites

• None

Learning Tasks

By the end of this session students are expected to be able to:

• Define mixing

• Explain the importance of mixing in pharmacy

• Explain type of powder mixtures

• Explain the mixing and de-mixing of powders

• Explain mixing techniques

• List types of mixers

• Explain the selection and working of mixing equipments (mixers)

Resources Needed:

• Flip charts, marker pens, and masking tape

• Black/white board and chalk/whiteboard markers

• LCD projector and computer

SESSION OVERVIEW

SESSION CONTENTS

STEP 1: Presentation of Session Title and Learning Tasks (5 minutes)

READ or ASK students to read the learning tasks and clarify

ASK students if they have any questions before continuing

STEP 2: Definition (15 minutes)

• Majority of active ingredients and adjuvant (excipients) used for the

manufacture of pharmaceutical dosage forms constitute in the powder form

o Hence handling and processing of powders is central to pharmaceutical

operations

• Mixing and blending of bulk solids occurs frequently in pharmaceutical

manufacturing

• The term mixing and blending are often used interchangeably

• Mixing

o Mixing is defined as a process of thoroughly combining different

materials to achieve a homogenous product

▪ In most cases the mixture is a combination of dissimilar material

e.g. a drug and a diluents although at times, a chemically

homogenous material is mixed to uniformly distribute its large

range of particle sizes

o Mixing of powder is a shuffling type unit operation process involving

both large and small particle groups and even individual particles

o Mixing is an energy consuming process which produces a random

distribution of particles

o Optimum mixing is a prerequisite for manufacturing of solid dosage

forms which involve powder mixing and it has a critical contribution

in achieving uniformity of content

STEP 3: Reasons for Mixing (10 minutes)

|Activity: Brainstorming (5 minutes) |

| |

|ASK students to brainstorm on the following question: |

| |

|What are the reasons for mixing powders? |

| |

|ALLOW few students to respond? |

| |

|WRITE their responses on the flip chart/ board |

| |

|CLARIFY and SUMMARISE by using the content below |

• Mixing is done for the following reasons;

o To ensure an even distribution of the active component(s)

o To ensure an even appearance of the dosage form

o To ensure that the dosage form releases the drug at the correct site

and at the desired rate

o To ensure colour uniformity since powders differs in colour

STEP 4: Types of Powder Mixtures (20 minutes)

• Free flowing mixtures

o Free flowing powders have desirable features like minimal need of

lubricant and effective contact with die cavity

o They suffer from a serious drawback of segregation of individual

components in post mixing processing

o The particles can move smoothly and independently in a particular

direction due to the inter-particulate forces

o The free flowing powders need to be handled and stored in a proper

manner by packing the products in polythene bags and applying vacuum,

before sealing.

• Cohesive mixtures

o The cohesive mixture exhibits “stick-slip” characteristics and the

components are not free flowing, the individual particles are

repeatedly broken down and allowed to redistribute within the system

to ensure a satisfactorily mixed product. The scale of segregation is

less, but the intensity of segregation will be more due to the

retaining of structure by the small agglomerates throughout the mixing

process

o Some of the parameters contributing to the formation of cohesive

mixtures are moisture, electrostatic charges, Van der waals forces and

solid bridges between the particles

• Ordered mixtures

o If one of the constituents of the powder mix is added to a fine,

micronized form then on mixing the larger particles may adsorb some of

these smaller particles to active sites on their surface where they

are held tenaciously

o Ordered mixtures are formed by mechanical, adhesion or coating forces

such that the ordered unit will be the smallest possible sample of the

mix and will be of near identical compositions to all other ordered

units in the mix

STEP 5: Mechanisms of Mixing and De-mixing of Powders (30 minutes)

• Diffusion

o Diffusion blending is characterised by the random motion of solid

particles i.e. diffusive movement of individual particles

(Micromixing)

o It occurs where the particles are distributed over a freshly

developed interface

o It is a slow blending mechanism

o This type of mixing is achieved by tumbler mixers

• Convection

o Mixing by convection is characterised by random motion of solid

particles whereby blending groups of particles (a large portion of the

powder bed) are rapidly moved from one position to another due to the

action of a rotating agitator (Macromixing)

o The movement of solid particles through the mixer is either by a force

action from a paddle or by gentle tumbling under rotational effects

o The blending of solids in ribbon blenders and paddle mixer is mainly a

result of convective mixing

• Shear

o Shear mixing is achieved by the removal of force of attraction between

the powder particles

o Shear blending as the development of slip planes or shearing strains

within a bed of material

o Shear mixing reduces the scale of segregation

o Blenders with high speed chopper blades and intensifiers are examples

of shear blending equipments

• Segregation of Powders (De-mixing)

o All powder mixture have variable tendency to separate during the

processing, which can result in poor quality product

o Segregation is an undesirable separation of the different components

of a powder mix or blend

o Reasons responsible for de-mixing are;

▪ difference in particle size of various constituents

▪ density differences of various constituents

▪ drug-excipient interaction

▪ degree of agglomeration

o The three main mechanisms for segregation of powders are:

▪ Percolation

▪ In a packed bed of powder, gravity causes small particles to

move into the voids between larger particles, due to

relatively larger differences in particle size

▪ Vibration

▪ Upon vibrating of a bed of powder, smaller particles will

gradually move under the bigger ones and thus lead to a

separation of the differently sized particles

▪ Transportation

▪ During transportation of powders, the particles will be

constantly accelerated and decelerated, due to differences in

trajectories of particles within different masses and /or

sizes these particles will be separated during transportation

▪ This also happen when powders are poured on a heap. The

heavier particles will roll to the outside of the heap while

the smaller concentrate in the centre of the powder heap

▪ The shape of the particle also plays an important role

during this type of segregation process

▪ Special precautions must be taken during handling of these

powders by reducing the transportation velocity or minimizing

the falling height to prevent segregation

STEP 6: Mixing Techniques and Equipments (30 minutes)

• Mixing Techniques

o Trituration

▪ This technique is used both to reduce the particle size

(comminution) and mixing the powder

▪ It involves the use of mortar and pestle

▪ A glass mortar-pestle may be preferred for chemicals

▪ This is technique is used for small scale mixing

o Spatulation

▪ Spatulation is a technique of mixing powders by movement of a

spatula throughout the powders on the sheet of paper

▪ This is technique is used for small scale mixing

o Sifting

▪ In this technique the powder is mixed by passing through sifters

▪ This process result in a light fluffy product

▪ It is also suitable for small scale mixing

o Geometric dilution

▪ This method is used when potent substances (drugs) are mixed with

large amounts of diluents

▪ E.g. 100 mg of a potent drug mixed in 900 mg of lactose

(diluents)

o Geometrically, this will be;

▪ 100 mg of the potent drug + 100 mg of lactose = 200 mg of the

mixture

▪ 200 mg of mixture + 200 mg of lactose = 400 mg of mixture

▪ 400 mg of mixture + 400 mg of lactose = 800 mg of mixture

▪ 800 mg of mixture + remaining lactose = 1000 mg of mixture

o Tumbling

▪ In this technique, the powder is mixed in a large container

rotated by an electric motor (uses a tumble blender)

▪ The tumble blender is a mainstay in the pharmaceutical industry

because of its positive features of close quality control (for

batch operation), effective convective and diffusive mechanisms of

blending and gentle mixing for friable particles

• Factors which affect mixing process

o Particle size

o Shape of the particles

o Density

o Electrostatic forces

o Limits of blend

o Segregation mechanisms

• Analysis to Validate Adequacy of Mixing

o During powder mixing process, it is important to sample and validate

the adequacy of mixing as a requirement of Good Manufacturing

Practices

o Uniformity of powder blend need formal documentation in a

pharmaceutical manufacturing

o Samples are extracted from a batch or continuous blender to ensure

that the mix meets critical specifications of mixing

o A sample thief (thief sampling) is commonly used to collect powder

sample from a blender or container such as a drum or a bin

▪ A thief is a metal rod with recessed cavities capable of

receiving powder after being inserted into a powder bed

o Other methods of obtain powder sample can be employed e.g. stratified

(nested) sampling

• Mixing Equipments

o Mixing is achieved by use of mixers. Mixers are of various types and

capacities

o Mixers are classified into two main types;

▪ Batch Mixers

▪ Continuous Mixers

Batch Mixers

• These are of three types

o Tumbling mixers

▪ Without mixing blades e.g. Cube Blenders, Double Cone Blenders, V-

cone Blenders

▪ With mixing blades e.g. V-cone mixers, Double cone mixers

Static Mixers

• E.g. Sigma Blade Blender, Ribbon Mixer, Planetary Motion Blender

Air Mixers

• E.g. Fluidized bed mixer

Continuous Mixers

▪ Barrel type

▪ Zig-zag type

o An ideal mixer should,

▪ be capable of producing complete blend in reasonable time without

damaging the product

▪ be dust-tight

▪ require low maintenance

▪ require low energy

▪ be easily discharged and cleaned

o These properties cannot be found in a single mixer and hence selection

of a suitable mixer depends on the following main factors;

➢ Powder characteristics of the constituent of the mixture

➢ Quality requirement of the product

➢ Process requirement and limitations

o Other factors to consider in selecting a mixer are;

➢ Flexibility to cope with variable batch size

➢ Transportability of the mixer between operations like loading,

mixing, packaging

➢ Access to sampling (of powers being mixed)

➢ Frequency of cleaning

➢ Nature of the mixing surface

o Effectiveness of a mixer depends on;

➢ Powders to be mixed

➢ Time of mixing

➢ Number of rotations of the mixer

o Generally, selection of mixers can follow the following approach;

▪ For free flowing powders

▪ With no segregation problem -Tumbler mixers (Silo mixers)

▪ With segregation problems-Orbiting screw mixers, ribbon mixers

▪ For cohesive powders-Shear mixers (extruders, cyclomix)

▪ Impact mixers (Lodige type mixers, Henschel mixers)

STEP 7: Key Points (5 minutes)

• Powder mixing is a shuffling, energy consuming type unit operation

process involving both large and small particle groups and even

individual particles

• Optimum mixing is a prerequisite for manufacturing of solid dosage forms

which involve powder mixing and it has a critical contribution in

achieving uniformity of content

• Powders are mixed in order to obtain homogeneity

• There three types of powder mixtures namely free flowing mixtures,

cohesive mixtures and ordered mixtures

• Mixing of powders occurs by diffusion, convection and by shear mechanisms

• During mixing process, samples should taken to analyse adequacy of mixing

• Mixing is achieved by use of mixers, which are of various types and

capacities

• Main classes of mixers are batch mixers and continuous mixers

STEP 8: Evaluation (5 minutes)

• What is mixing?

• What is the importance of mixing in pharmacy?

• Mention the mechanisms of mixing powders?

• Name the types of powder mixtures

References

Aulton M.E., & Kevin M.G., Eds: (2013) Pharmaceutics: The design and

manufacture of medicines, (4th ed.) Churchill Livingstone

Hugo and Russell (2011), Pharmaceutical Microbiology (8th ed.) Willey-

Blackwel publications

Gennaro, R. A, et al. (Eds) (1995) Remington: The Science and Practice of

Pharmacy, Volume I & II, (19th ed.): Mack Publishing Company, Easton,

Pennsylvania 18042

Liebsch, B et al (1988). Tanzania Pharmaceutical Handbook, Dar es Salaam

University Press.

Lund, W. Editor (1994). The Pharmaceutical Codex, Principles and Practice

of Pharmaceutics (12th ed.) The Pharmaceutical Press, London

Polderman, J. (1990) Introduction to Pharmaceutical Production: Novib, The

Hague

Rawlins E.A, Editor: (1977) Bentley’s Textbook of Pharmaceutics, (8th ed.)

Baillie're Tindall. London Kamm, G. and Kohler, B. Editors: (1995)

Manual for Decentralized Infusion Production, Infusion Unit Project

Tanzania

Robert EOC, Powders, Remington: the science and practice of pharmacy, vol 2

Schmidt, O. (ed.) 2000 Pharmaceutical Quality systems, Interpharm Press,

Colorado.

Shayne C et al. (2008), Pharmaceutical Manufacturing Handbook: Production

and processes, John Wiley & Sons

Watson, D. G (1999) Pharmaceutical Analysis: A Textbook for Pharmacy

Students and Pharmaceutical Chemists: Churchill Livingstone,

Edinburgh.

Session 10: Introduction to Capsules

Total Session Time: 120 minutes

Pre-requisites

• None

Learning Tasks

By the end of this session students are expected to be able to:

• Define capsules

• Classify capsules

• Explain modified release capsules

• List advantages and disadvantages of capsules

Resources Needed:

• Flip charts, marker pens, and masking tape

• Black/white board and chalk/whiteboard markers

• LCD projector and computer

SESSION OVERVIEW

SESSION CONTENTS

STEP 1: Presentation of Session Title and Learning Tasks (5 minutes)

READ or ASK students to read the learning tasks and clarify

ASK students if they have any questions before continuing

STEP 2: Definitions (15 minutes)

• Capsules are solid unit dosage forms with hard or soft shells of various

shapes and capacities containing a single dose of a drug substance

• The term capsule is derived from the Latin word “capsula”, meaning a

small container.

• The first capsule prepared from gelatin was a one-piece capsule patented

in France by Mothes and Du Blanc in 1834

• Capsules are intended to be swallowed whole; however, some soft gelatin

capsules are intended for rectal or vaginal insertion as suppositories.

• Capsules consists of two main parts, the shell (commonly but exclusively

made up of gelatin) and the fill material (the Active pharmaceutical

ingredient(s) and the excipients)

o The capsule shell may also be made up of plant materials e.g. vegicaps

• Capsules are a common form of dosage for oral administration of

pharmaceutical and nutraceutical products

• Branding and dosage information may be printed on the outer surface of

the capsule

• Medication or ingredients inside the capsule (the fill content) may be

in form of solid, liquid or paste depending on the active pharmaceutical

ingredient (API) or, in the case of nutraceutical, on the form of the

main nutrient (e.g. liquid fish oil)

STEP 3: Classification of Capsules (25 minutes)

• Capsules are classified as either hard or soft, depending on the nature

of the shell

o Hard shell capsules

▪ Hard gelatine capsules consist of a hard gelatine capsule shell

encasing solid fill material

▪ Hard gelatin capsules are also known as dry-filled capsules or

two pieces capsules

▪ Hard gelatin capsules consist of two parts known as capsule body

(longer part) and the capsule cap (the shorter part)

▪ The drug substance placed in the body and the caps are slided

over it, hence enclosing the drug substance

▪ The caps and body pieces of the capsule shell are supplied

unlocked to be filled with the appropriate drug or nutraceutical

ingredients

o Soft shell gelatine capsules

▪ Soft gelatin capsules, also called soft gels, are thicker than

hard shell gelatin capsules

▪ They are softer and hence easier to swallow

▪ They are made up of one piece and hemetically sealed

▪ They are softer due to addition of plasticizers (glycerin or

sorbitol) in the gelatin

▪ The shell is usually made up of gelatin like in the hard shell

gelatin capsule but softer and contain more water (generally

between 6% and 13% by weight) and preservatives

▪ Soft gels can be filled with liquid (solution, suspension etc),

semi solid or rarely solid materials which can be dissolved or

suspended in water to form a paste mixture

▪ In other case the capsule may simply be filled with granules or

powder

▪ Instead of gelatine, seaweed extract and gluten free starch are

used in making up the soft shell (providing animal free product,

suitable for strict vegetarians)

▪ The shell can be clear or coloured and there is a wide range

of shapes, sizes and colours available

▪ They are suitable for vegetarians or people who do not prefer

animal products

▪ They have low shell odour

STEP 4: Modified Release Capsules (30 minutes)

• Both hard or soft gel capsules can be chemically modified to control the

release of the active pharmaceutical ingredient (s)

• Delivery of the active ingredient from the capsule shell is usually

effected by disintegration of the shell and disintegration of the fill

content upon opening of the shell

• The release of the active pharmaceutical ingredient(s) may be modified by

various methods including;

o Coating the capsule shell with a material through which the drug

diffuses

o Coating the capsule shell with a slowly dissolving coat that slowly

releases the drug over time

o Employing a system utilizing a semipermeable membrane that blocks the

drug from diffusing out through the membrane, but where the water on

the exterior of the membrane can diffuse into the formulation,

allowing the drug to be released through channels within the membrane

o Designing the capsule shell to resist disintegration by the stomach

acid until it reaches the intestinal fluid where at a higher pH it

breaks down and releases the active ingredients i.e. enterically

coated capsules

STEP 5: Advantages and Disadvantages of Gelatin Capsules (35 minutes)

|Activity: Small Group Discussion (10 minutes) |

| |

|DIVIDE students into small manageable groups |

| |

|ASK students to discuss on the following question |

|What are the advantages and disadvantages of capsule dosage forms? |

| |

|ALLOW students to discuss for 10 minutes |

| |

|ALLOW few groups to present and the rest to add points not mentioned |

| |

|CLARIFY and SUMMARIZE by using the contents below |

• Advantages of Capsules;

o They are quickly and conveniently filled

o They mask odour and taste of drug substances with objectionable odour

and taste

o They are attractive in appearance

o It is easy to change and dose and combination of drug according to

patient requirement

o They are economical

o They are easy to handle and carry

o They are easy to identify

o Easy to administer

o Easy to package and ship at lower

o Do not break easily

o Shells can be opacified with titanium dioxide or coloured to protect

from light

o Shells are physiologically inert

• Disadvantages of capsules

o Hygroscopic drugs are not suitable for filling into capsules

▪ They absorb water moisture present in capsule shell and make the

shells very brittle ultimately leading to crumbling of the capsules

into pieces

o Concentrated solution requiring previous dilution are unsuitable for

capsules because if administered as such, they will lead to irritation

in the gastrointestinal tract (stomach)

o Gelatin is susceptible to microbial degradation

▪ They require care to be observe during the manufacturing,

packaging, storing and distribution of capsules

o Shell odour especially gelatin capsules

STEP 6: Key Points (5 minutes)

• Capsules are solid unit dosage forms with hard or soft shells of various

shapes ad capacities containing a single dose of a drug substance

• The fill contents for capsule may be liquid, semisolid or rarely solid

• There are two main types of capsules, hard shell and soft shell capsules

• Both hard or soft gel capsules can be chemically modified to control the

release of the active pharmaceutical ingredient (s) e.g. enterically

coated capsules resist gastric acid and open after reaching the alkali

milieu of the small intestine

STEP 7: Evaluation (5 minutes)

• What is a capsule?

• What are the major types of capsule?

• What is the difference between capsule shell and capsule fill content?

• What is the major component of capsule shell?

• What are factors affecting release of medicament(s) from capsule shell?

References

Aulton M.E and Kevin M.G, Eds: (2013) Pharmaceutics: The design and

manufacture of medicines, (4th ed.) Churchill Livingstone

Hugo and Russell (2011), Pharmaceutical Microbiology (8th ed.) , Willey-

Blackwel publications

Gennaro, R. A, et.al (Eds) 1995 Remington: The Science and Practice of

Pharmacy, Volume I & II, (19th ed.): Mack Publishing Company, Easton,

Pennsylvania 18042

Liebsch, B et al (1988): Tanzania Pharmaceutical Handbook, Dar es Salaam

University Press.

Lund, W. Editor (1994). The Pharmaceutical Codex, Principles and Practice

of Pharmaceutics (12th ed.): The Pharmaceutical Press, London

Polderman, J. (1990) Introduction to Pharmaceutical Production: Novib, The

Hague

Rawlins E.A, Editor: 1977 Bentley’s Textbook of Pharmaceutics, (8th ed.)

Baillie're Tindall. London Kamm, G. and Kohler, B. Editors: 1995

Manual for Decentralized Infusion Production, Infusion Unit Project

Tanzania

Schmidt, O. (Ed) 2000 Pharmaceutical Quality systems, Interpharm Press,

Colorado.

Shayne C et al. (2008), Pharmaceutical Manufacturing Handbook: Production

and processes, John Wiley & Sons

Watson, D. G (1999) Pharmaceutical Analysis: A Textbook for Pharmacy

Students and Pharmaceutical Chemists: Churchill Livingstone,

Edinburgh.

Session 11: Gelatin Capsule Shells

Total Session Time: 120 minutes

Pre-requisites

• None

Learning Tasks

By the end of this session students are expected to be able to:

• Define gelatin

• Outline the composition of hard gelatin capsule shells

• Outline the production of hard gelatin capsule shells

• Define size and specification of hard shell capsules

Resources Needed:

• Flip charts, marker pens, and masking tape

• Black/white board and chalk/whiteboard markers

• LCD projector and computer

SESSION OVERVIEW

SESSION CONTENTS

STEP 1: Presentation of Session Title and Learning Tasks (5 minutes)

READ or ASK students to read the learning tasks and clarify

ASK students if they have any questions before continuing

STEP 2: Definitions (15 minutes)

• Hard gelatin shell capsules are hard, flexible edible enclosures intended

for encapsulation of drug materials in solid form

• Hard shell capsules are almost exclusive made up of gelatin

• Gelatin is the major component of capsule shells for the following

reasons;

➢ It is non toxic

➢ Readily soluble in biological fluids at body temperature

➢ It is a good film forming material

• The hard gelatine capsule shells contain less plasticizers and that makes

them hard

• They are made up of two shells

o The capsule body, which is longer and in which the contents are filled

o The capsule cap, which is shorter and fits tightly over the open end

of the capsule body

STEP 3: Composition of Hard Gelatin Capsule Shells (30 minutes)

• The raw materials for the capsule shells are the same for both hard and

soft gelatine capsules

• Higher plasticizer content is used when making soft gelatine capsules (to

make them soft)

• The basic hard gelatin capsule shells are made from mixtures of gelatin,

sugar and water

o They are essentially tasteless

• Gelatine

o Gelatine is heterogeneous product derived by hydrolytic extraction of

animal collagen

o According to the USP NF, gelatin is a product obtained by hydrolysis

of collagen derived from the skin, white connective tissue and bones

of animals

o The hydrolysis may be catalyzed by addition of strong acid or base

o Gelatin derived from acid-catalyzed hydrolysis is known as Type A

gelatin and gelatine obtained by hydrolysis catalyzed by bases is

known as Type B gelatin

o It is the main component for both hard and soft shell capsules

o Bloom Strength

▪ Bloom strength is a measure of the ability of a given weight of

gelatin to set up in water under controlled conditions and is a

function of the molecular weight of the gelatin molecules, the

concentration of the gelatin in the gel, and the pH of the gel

▪ It is a measure of the resultant gel’s resistance to compression

and is reported in bloom-grams or simply grams

▪ Bloom strength increases when the gelatin concentration in the

gel increases, when the average molecular weight of the gelatin

increases, and when the pH of the gel approaches neutrality (from

either direction)

▪ Bloom strength also can have an effect on the clarity and colour

of the liquid-ﬁlled capsules

▪ Gelatin with bloom strengths ranging from 50 to 300 is available;

most gelatin used in the manufacture of liquid-ﬁlled capsules have

bloom strength of approximately 150–200 for soft gels and 220–280

for hard gels

▪ Gelatin are usually mixed to obtain gelatin of required bloom

strength

• The perfect hard gelatin capsules should have the following

specifications;

➢ Gel strength of 200-300 Bloom depending on the gelatin type (A or B)

➢ Viscosity (at 60 ͦC at 6-23 % w/w) of 44-60 mPa depending on the

gelatin type

➢ pH of 4.5-6.5

➢ Aerobic Plate Count <1000/grams

• Plasticizers

o These are materials that make the walls of the shell softer and

flexible

• E.g. Glycerol and sorbitol

• Colouring agents

o Are added to improve appearance of the capsule shells

o Soluble dyes and insoluble pigments are commonly used

• Opaquants

o Opaquants are materials used to make the capsule opaque e.g. to

protect against light

• Preservatives

o Preservatives are added to prevent microbial growth as gelatin is

susceptible to microbial attack

• Water

o Solvent (moisture content is controlled)

STEP 4: Production of Hard Gelatin Capsule Shells (35 minutes)

Production of hard shell gelatine capsules involves the following

processes;

• Dipping

o Pairs of stainless steel pins (metal moulds) with different diameters

at room temperature are dipped into hot gelatin solution to

simultaneously form the caps and bodies

o The hot gelatin solution gels to form a film around the metal moulds

o The dipping solution is maintained at a temperature of about 50 ͦ C in

a heated, jacketed dipping pan

• Spinning

o The pins are then rotated to distribute the gelatin over the pins

uniformly and avoid the formation of a bead at the capsule ends

• Drying

o The gelatin film is dried by a blast of cool air to form a hard shell

o The pins are moved through a series of air drying kilns to remove

water

• Stripping

o A series of bronze jaws strip the cap and body portions of the

capsules from the pins

• Trimming and Joining

o The stripped cap and body portions are trimmed to the required length

by stationary knives and removed from the moulds

o The cap and body portions are finally joined together to form the

capsule shell

• Polishing

o The finished product (joined capsule shells) are dusted and polished

to acquire the final elegancy

o The finished hard shells may be imprinted with a logo or letters e.g.

monograms of manufacturers, which enhances identification of the

product

STEP 5: Size and Specification of Hard Shell Capsules (30 minutes)

• Capsule Shell Size

o Hard gelatin capsule shells are available in various sizes for both

human and veterinary uses

o For human use the hard gelatin capsule shell sizes are from the

largest to the smallest;

▪ 000, 00, 0, 1, 2, 3, 4 and 5

▪ The largest and the smallest shells are rarely used in human

products

o Generally hard gelatin capsule shells are used to encapsulate between

65 mg to 1 gram

• Capsule Shape

o Capsule shell produced by one company may differ from shells produced

by another company by altering the shape of the capsule end (which is

usually round)

▪ e.g. capsules from Eli Lilly (Pulvules®) have the body shell with

a tapered end and the round shaped cap

▪ Capsules from GlaxoSmith Kline have both ends highly tapered

• Security Features

o In order to protect the capsule from accidental opening or tempering,

reliable closing of the filled capsules can be achieve by producing

capsule shells with locking grooves or indentations

o The grooves fit into each other for tight closing and prevent

accidental separation (or splitting) of the capsules or tempering

▪ The grooves protect opening after filling

o Some capsules are made tamper-proof and leak proof by sealing the

joint between the two capsule parts with a gelatin or polymer band

o Other capsule shells are made temper evident by wetting the contact

area between the body and the cap with a mixture of water and ethanol

and then thermally bonded at 40–45 °C

▪ Any attempt to separate a sealed capsule will destroy the capsule

STEP 6: Key Points (5 minutes)

• Hard shell capsules are almost exclusive made up of gelatin

• According to the USP, NF, gelatin is a product obtained by hydrolysis of

collagen derived from the skin, white connective tissue and bones of

animals

• Gelatin is the major component of capsule shells because it is non toxic,

readily soluble in biological fluids at body temperature and it is a good

film forming material

• Hard gelatin capsule shells are made up of the body and a shorter cap

which tightly fits over the body

• The shell is composed of gelatin, plasticizers, preservatives, opaquants,

colouring agents and water

• Production of hard gelatin shells involves dipping, spinning, drying,

stripping, trimming, joining and polishing. Finished shells may also be

imprinted for enhanced identification

• The capsule shells can be produced with security features to protect

filled capsules from accidental opening or tempering

STEP 7: Evaluation (5 minutes)

• What is a hard gelatin capsule shell?

• What are the parts of a hard gelatin capsule shell?

• What are the various sizes of hard gelatin capsule shells for human use?

• Explain how the hard gelatin capsule shells are protected from accidental

opening or tempering

References

Aulton M.E & Kevin M.G, (Eds): (2013) Pharmaceutics: The design and

manufacture of medicines, 4th (ed.) Churchill Livingstone

Hugo and Russell (2011), Pharmaceutical Microbiology (8th ed.), Willey-

Blackwel publications

Gennaro, R. A, et al. (Eds) (1995) Remington: The Science and Practice of

Pharmacy, Volume I & II, (19th ed.) Mack Publishing Company, Easton,

Pennsylvania 18042

Liebsch, B et al (1988): Tanzania Pharmaceutical Handbook, Dar es Salaam

University Press.

Lund, W. Editor (1994). The Pharmaceutical Codex, Principles and Practice

of Pharmaceutics (12th ed.): The Pharmaceutical Press, London

Polderman, J (1990) Introduction to Pharmaceutical Production: Novib, The

Hague

Rawlins E.A, Editor: (1977) Bentley’s Textbook of Pharmaceutics, 8th Ed.

Baillie're Tindall. London Kamm, G. and Kohler, B. Editors: (1995)

Manual for Decentralized Infusion Production, Infusion Unit Project

Tanzania

Schmidt, O. (Eds) 2000 Pharmaceutical Quality systems, Interpharm Press,

Colorado.

Shayne C et al (2008), Pharmaceutical Manufacturing Handbook: Production

and processes, John Wiley & Sons

USP 31–NF 26. Rockville, MD: US Pharmacopeial Convention; 2008:1139

Watson, D. G (1999) Pharmaceutical Analysis: A Textbook for Pharmacy

Students and Pharmaceutical Chemists: Churchill Livingstone,

Edinburgh.

Session 12: Formulation of Capsule Content

Total Session Time: 120 minutes

Pre-requisites

• None

Learning Tasks

By the end of this session students are expected to be able to:

• Define formulation

• Outline preparation of fill materials for encapsulation

• Selection of capsule size

• Explain the determination of capsule fill weight and volume

Resources Needed:

• Flip charts, marker pens, and masking tape

• Black/white board and chalk/whiteboard markers

• LCD projector and computer

SESSION OVERVIEW

SESSION CONTENTS

STEP 1: Presentation of Session Title and Learning Tasks (5 minutes)

READ or ASK students to read the learning tasks and clarify

ASK students if they have any questions before continuing

STEP 2: Formulation (15 minutes)

|Activity: Brainstorming (5 minutes) |

| |

|ASK students to brainstorm on the following question: |

| |

|What is formulation? |

| |

|ALLOW few students to respond? |

| |

|WRITE their responses on the flip chart/ board |

| |

|CLARIFY and SUMMARISE by using the content below |

• Formulation is the process of determining types and quantities of

excipients to be mixed with the active ingredient (the drug) to produce a

final medicinal product

• The word formulation is also used to mean a dosage form

• In large scale or small scale preparation of filled hard gelatin capsules

is divided into the following general steps;

➢ Developing and preparing formulation

➢ Selection of size of capsules

➢ Filling the capsule shell

➢ Capsule sealing

➢ Cleaning and polishing the filled capsules

• Developing and preparing formulation involves determination of processes,

types and quantities of ingredients that will be used in forming a

mixture (fill material) to be filled into the capsule shells (in the hard

or soft gelatin capsules)

• Formulation of capsule fill materials employs two major groups of

ingredients, the active ingredients and the excipients

o The active pharmaceutical ingredients (API)

▪ The amount and type of active ingredients influence capsule size

and nature and amount of excipients to used in the formulation

▪ Active ingredients tend to make up to the high percentage of the

contents of a capsule compared to tablets

o The excipients

▪ Type and amount of excipient mixed with API depends on the type

of capsules to be produced (i.e. hard gelatin capsules or soft

gelatin capsules) and the nature of the fill materials i.e. solids

(powders, granules, pellets, tablets, small capsules), semi solids

and liquids (neat liquids, solutions and suspension)

• Pharmaceutical processes involved during formulation of capsule fill

material may include milling/comminution, blending/mixing, granulation,

pelletization and micronization

• Size of the capsule to be produced must be considered during formulation

of the fill material

STEP 3: Preparation of Fill Materials for Encapsulation (45 minutes)

Preparation of Dry Powders

• Dry powders are filled into hard gelatin capsules. Formulation and

preparation of these powders include processes and different substances

which promote the release of drug constituents from the hard gelatin

capsules

o Milling

▪ In order to achieve uniform drug distribution throughout a powder

mix, it is advantageous that the density and particle size of the

drug and non-drug components are similar. This is achieved by

particle size reduction (milling)

o Diluents

▪ Generally, hard gelatin capsules are used to encapsulate between

65 mg and 1 gram of powdered materials (drug and diluents required)

▪ If the dose of the drug in a single dose is smaller than 65 mg to

produce the proper fill, lactose, microcrystalline cellulose, and

pre-gelatinized starch are common diluents used in capsule filling

▪ If the amount of drug is larger enough to fill a capsule

completely, a diluents may not be required

▪ Diluents are present in the greatest concentration of all

excipients

o Lubricants

▪ They are added to prevent adhesion and facilitate the flow of

powder in capsule filling machine e.g. Magnesium stearate and talc

o Glidants

▪ The powder mixture or granules must be free-flowing to allow

passage from the hopper by the addition of a glidant such as 1%

silicon dioxide

▪ Lubricants and glidant are used to improve the filling properties

o Wetting agents

▪ These are agents added to facilitate wetting (improve water

penetration) of the drug substance by gastrointestinal fluid to

enhance dissolution and overcome the problem associated with water

insoluble lubricants such as magnesium stearate which can delay

the dissolution of the drug and its absorption

▪ Sodium lauryl sulphate is a common wetting agent used in

capsules

o Disintegrants

▪ Produce disruption of the powder mass when the capsule is in

contact with body fluids e.g. crospovidone, sodium and starch

• Preparation of Granules and Pellets

o Granules and pellets are packed in capsules instead of powders to

produce modified release patterns

o Granules are produced by granulation process and are more irregular

than pellets which are spherical and produced by microencapsulation

technique

• Preparation of Tablets and Capsules

o Tablets and small capsules may be encapsulated in hard gelatin

capsules

o Tablets and capsules can be encapsulated in order to produce special

release forms or to separate incompatible ingredients

o Small tablets are made and placed inside capsules following addition

of small quantity of the powder and filling completed

o Additionally, for separation of one ingredient from another in the

formulation, a small capsule (e.g. number 5) is filled with powder of

one ingredient and placed into a larger capsule with the remaining of

ingredients in the formulation

• Preparation of Semisolids

o Can be used for both liquid and solid active ingredients

o Mixtures for filling need to be liquid only when filled and should

semisolid after being inside the capsules

o The materials to be filled must be either thermosoftening or

thixotropic in nature to be liquefied by heating or shearing forces

using heated hopper with a stirrer and revert to solid state within

the capsule shell

o This type is used when;

▪ Potent drugs are being encapsulated to improve uniformity of

filling

▪ Toxic drugs are being encapsulated to reduce contamination with

filling powders and improve safe handling

• Preparation of Liquids

o Liquids are generally filled into soft gelatin capsules and in some

instances into hard gelatin capsules

o Gelatin capsules are not suitable for encapsulation of aqueous liquids

(water softens the gelatin and produce distortion of the capsules)

o Non aqueous liquids such as fixed oils or volatile oils that do not

interfere with the stability of the gelatin shells may be filled in

gelatin capsules

o The liquids may be pure, or solution of solids in liquids, miscible

liquids or suspension of solid drugs in a carrier

o The suspension are prepared in the general techniques for preparation

of suspension with suitable suspending agents

o After filling the liquids into the capsules, the shells are sealed to

retain the liquids

STEP 4: Selection of Capsule Size (15 minutes)

• Capsules vary in shapes and sizes.

• Determination of capsule size is important during formulation of the fill

materials because the amount of excipients to be included is dependent

upon the size or capacity of the capsule to be selected

• For hard gelatin capsules range from 000 (the largest) to 5 (the

smallest)

o Factors considered when selecting capsule size are;

▪ Amount of fill material to be encapsulated

▪ Density and compressibility of the fill material

o The final determination may largely be the result of trial and error

• For soft gelatin capsules, size of the capsule depends on the amount of

fill material encapsulated and the filling methods e.g. size of the mould

• The fill materials (solids, liquids and semisolids) must be prepared

prior to filling into the capsules

STEP 5: Determination of Capsule Fill Weight and Volume (25 minutes)

• Because empty gelatin capsules are manufactured in various sizes, varying

in length, in diameter and capacity

o The fill contents must be formulated in such a way that one dose is

contained in the volume represented by a given capsule size

• Capsule fill weight is determined by the following relation;

o Capsule fill weight = Tapped bulk density of formulation x Capsule

volume

• Selection of capsule size is done when the product is being developed or

in extemporaneous compounding of prescription

STEP 5: Key Points (5 minutes)

• Developing and preparing formulation involves determination of processes,

types and quantities of ingredients that will be used in forming fill

material to be filled into the hard or soft gelatin capsules

• Formulation of capsule fill materials employs the active ingredients and

excipients

• During formulation, pharmaceutical processes to be used in mixing the

ingredients to obtain a fill mix are also identified

• Determination of capsule size is important during formulation of the fill

materials because the amount of excipients to be included is dependent

upon the size or capacity of the capsule to be selected

• The fill contents must be formulated in such a way that one dose is

contained in the volume represented by a given capsule size

STEP 6: Evaluation (5 minutes)

• What is capsule formulation?

• How are various fill materials for encapsulation formulated?

• How is capsule size determined?

References

Aulton M.E & Kevin M.G, (Eds): (2013) Pharmaceutics: The design and

manufacture of medicines, (4th ed.)Churchill Livingstone

Hugo and Russell (2011), Pharmaceutical Microbiology (8th ed.) , Willey-

Blackwel publications

Gennaro, R. A, et al. (Eds) (1995) Remington: The Science and Practice of

Pharmacy, Volume I & II, (19th ed.): Mack Publishing Company, Easton,

Pennsylvania 18042

Liebsch, B et al. (1988): Tanzania Pharmaceutical Handbook, Dar es Salaam

University Press.

Lund, W. Editor (1994). The Pharmaceutical Codex, Principles and Practice

of Pharmaceutics (12th ed.): The Pharmaceutical Press, London

Polderman, J. (1990) Introduction to Pharmaceutical Production: Novib, The

Hague

Rawlins E.A, Editor: (1977) Bentley’s Textbook of Pharmaceutics, (8th ed.)

Baillie're Tindall. London Kamm, G. and Kohler, B. Editors: (1995)

Manual for Decentralized Infusion Production, Infusion Unit Project

Tanzania

Schmidt, O. (ed) (2000) Pharmaceutical Quality systems, Interpharm Press,

Colorado.

Shayne C et al. (2008), Pharmaceutical Manufacturing Handbook: Production

and processes, John Wiley & Sons

Watson, D. G (1999) Pharmaceutical Analysis: A Textbook for Pharmacy

Students and Pharmaceutical Chemists: Churchill Livingstone,

Edinburgh.

Session 13: Filling Hard Gelatin Capsules

Total Session Time: 120 minutes

Pre-requisites

• None

Learning Tasks

By the end of this session students are expected to be able to:

• Explain the general process for hard gelatin capsule filling

• Explain the methods for hard gelatin capsule filling

• List types of hard gelatin capsule filling machines

• Explain working of hard gelatin capsule filling machines

• Explain the sealing of hard gelatin capsules

• Explain the process of cleaning hard gelatin capsules after manufacturing

• List common problems encountered during hard gelatin capsule production

Resources Needed:

• Flip charts, marker pens, and masking tape

• Black/white board and chalk/whiteboard markers

• LCD projector and computer

SESSION OVERVIEW

SESSION CONTENTS

STEP 1: Presentation of Session Title and Learning Tasks (5 minutes)

READ or ASK students to read the learning tasks and clarify

ASK students if they have any questions before continuing

STEP 2: General Filling Process (10 minutes)

• Filling of hard gelatin capsule shells involves a working process with

the following steps;

o Rectification (orientation of the empty capsule shells in same

direction)

o Separation of caps from the body

o Filling the bodies (bench-scale filling or industrial-scale filling)

▪ E.g. Auger filling principle (flat blade auger or crew auger)

o Scraping the excess powder

o Replacing the caps

o Sealing the capsules

o Cleaning the outside of the filled capsules

STEP 3: Filling Methods (35 minutes)

• Powders and granules can be filled by direct or indirect methods

o Direct Filling Methods

▪ The Punch Method

▪ This method is used for small scale filling e.g. filling a

small number of capsules in a pharmacy

▪ The powder is placed on a clean paper or porcelain plate and

formed into a cake

▪ The empty capsule body is punched vertically into the powder

cake repeatedly until filled

▪ Feston Capsule Filling

▪ This methods employs a hand operated capsule filling machine

▪ With this method, about 200-2000 capsules can be produced per

hour

▪ Empty capsules are placed on a loader tray which is placed on

top of the filler unit of the machine

▪ The loader inserts the capsules into the filling unit and is

removed and the top plate is lifted to separate the caps from

the bodies

▪ The powder is placed on the unit and the capsule bodies are

filled

▪ The top plate is returned to the unit and the caps placed on

filled capsule bodies

o Indirect Filling Methods

▪ Auger-filling Principle (dependent dosing system)

▪ Employs rotating augers mounted in the hopper and allow a

constant flow of powder or granules to the capsules at a

constant rate (flat bed auger or screw auger)

▪ Amount of powder fed into the body of the capsules depends on

the time the capsule body spends under the hopper outlet and

auger speed

o Slower rotation of the auger increases fill weight

o It is a semi-automated operation

o The powder is filled by volume (the capsule body measures the

powder or granules)

o Requires the powder to have good flow properties

▪ Vibration-filling Principle

▪ A perforated resin plate is positioned in the powder and

connected to a vibrator

▪ The powder blend is fluidized by vibration of the plate and

assists the powder to flow into the bodies through the holes in

the resin plate

▪ This is also known as vibration-assisted filling

▪ Piston Tamp Principle (independent dosing system)

▪ In this method, pistons or taming pins lightly compress the

individual doses of powders into plugs (also called slugs) and

eject the plugs into empty capsule bodies

▪ Dosator

▪ Consists of cylindrical dosing tube fitted with movable

piston

▪ Position of the piston is preset to a particular height to

define volume of the capsule

▪ Powder enters the open end of dosator and is slightly

compressed against the piston into a plug

▪ The capsules are filled based on weight

▪ Dosing disc

o Filling is done on the basis of weight

o A solid stop brass plate slides down the dosing disc to close

the hole

o Five sets of pistons compress the powder into cavities to

form plugs

• Filling of pellets into hard gelatin capsules may be accomplished

through;

o Double slide method

▪ Pellets flow from pellet magazine to dosing chambers

▪ Dosing slide is closed to separate dosing chamber and pellet

magazine

▪ Outlet slides open

o Vacuum-assisted method

▪ Dosing tube enters pellet bed

▪ With the help of vacuum, the pellets are sucked into the dosing

tube

▪ Excel pellets are scraped off the end of the dosing tube

▪ Dosing tube is lowered and pellets released into capsule body

• Filling of tablets into hard gelatin capsule shells

o Dosing slide which can accommodate exactly one tablet moves under the

tablet feeder

o Slider moves over the capsule body where the tablet simply drops into

o If properly filled, the pin dropped into the capsule body will have

limited movements, the horizontal bare connected to the in touches a

sensor

o If not properly filled, the horizontal bar will switch the sensor

indicating incorrect filling

o Empty capsules can be detected and eliminated from the product

• Filling Semisolid Mass in Hard Gelatin Capsules

o If the material to be placed into hard gelatin capsules is a

semisolid, it can be encapsulated by either forming a pipe or pouring

a melt

• Filling Liquids in Hard Gelatin Capsules

o Liquids can be prepared in hard gelatin capsules if the gelatin is not

soluble in the liquid to be encapsulated

▪ E.g. alcoholic solutions and fixed and volatile oils

▪ Solubility of gelatin in the liquid may be determined by

experimentation

o The liquid is measured using a pipette (micropipette) or a calibrated

dropper and dropped into the body taking care not to touch the opening

o The gelatin caps are moistened at the open ends by touching them on a

moist towel or in warm water to soften the gelatin at the opening of

the caps

o The cap is then placed over the body containing the liquid with a

slight twist and the softened edge of the cap forms a seal with the

body to prevent leakage

▪ The capsules are observed for leakage before packaging them

STEP 4: Capsules Filling Machines (25 minutes)

• The process of encapsulation of hard gelatin capsules may be done using

manual, semi-automatic and automatic capsule filling machines

• Filling Solids in Hard Gelatin Capsules

o Manual/Hand Operated Capsule Filling Machines

▪ The machine are made up of a bed with 200-300 holes, a pin plate

with 200 or 300 pins corresponding to the number of holes in the

bed, a capsule loading tray, a powder try, a lever, a handle and a

sealing plate with rubber top

▪ All parts of the machines are made up of stainless steel

▪ The machines are generally supplied with additional loading

trays, beds, and pin plates with various diameters of holes so as

to fill the desired size of the capsules

▪ These machines are very simple to operate, can be easily

dismantled and reassembled

▪ Operation

▪ The empty capsules are filled into the loading tray which is

then placed over the bed

▪ By opening the handle, the bodies of the capsules are locked

and caps separated in the loading tray itself which is then

removed by operating the liver

▪ The weighed amount of the drug to be filled in the capsules is

placed in powder tray already kept in position over the bed

▪ The powder is spread with the help of a powder spreader so as

to fill the bodies of the capsules uniformly

▪ Excess powder is collected on the platform of the powder tray

▪ The pin plate is lowered and moved downward to press the

powder in the bodies

▪ The powder tray is removed and the caps holding tray is placed

in position

▪ The caps are pressed with the help of the plate with rubber

top and the lever is operated to unlock the cap and the body of

the capsule shells

▪ The loading tray is removed and filled capsules in a tray

▪ With 200-hole machine, about 5,000 capsules can be filled per

hour and with 300 hole-machines 7,500 capsules can be filled per

hour.

o Semi-automatic and Automatic Capsule Filling Machines

▪ On large-scale manufacturing various types of semiautomatic and

automatic machines are used

▪ They operate on the same principle as manual filling, namely the

caps are removed, powder filled in the bodies, caps replaced and

filled capsules are ejected out

▪ With automatic capsule filling machines powders or granulated

products can be filled into hard gelatin capsules

▪ With accessory equipment, pellets or tablets along with powders

can be filled into the capsules

▪ Examples of automatic capsule filling machines;

▪ Farmatic, capacity 40,000-160,000 capsules per hour, dosator

type feeding units

▪ Hofliger and Karg, fills pellets, tablets and thixotropic

liquids, follows auger principle

▪ Osaka, high capacity, continuous motion, follows vibratory

filling principle, capacity up to 400,000 capsules per hour

o Capsule Filling Devices

▪ A number of different manually operated capsule filling devices

are commercially available for filling up to 50 or 100 capsules at

a time

▪ The method of using these machines requires a careful

determination of the capsule formulation

▪ The powder is blended properly and the empty gelatin capsules are

placed into the device and oriented so that the cap is on top

▪ The machine is worked to separate the base from the cap and the

portion of the machine holding the caps is removed and set aside

▪ The capsule bases are allowed to “drop” into place so that the

tops are flush with the working surface

▪ The powder mix is careful, uniformly and evenly spread over the

working surface with the aid of a plastic spatula

▪ The powder is evenly filled into the capsule bases or the machine

can be “tapped” to spread the powder and drop it down into the

capsule bases

▪ A small device consisting of several “pegs” on a handle can be

used to tamp the powder into the capsule bases gently and evenly

▪ Any remaining powder is spread evenly over and into the capsule

bases and tamped

▪ The procedures are repeated until all of the powder is in the

capsules

▪ The capsule caps are then fitted over the machine, fixed in

place, and the filled capsules removed, dusted using a clean cloth,

and packaged

• Industrial scale Hard Gelatin Filling

o Machines developed for industrial use automatically separate the caps

from the empty capsules and fill the bodies

o The machines for industrial -scale filling of hard gelatin capsules

come in many shapes and sizes, varying from semi- to fully automatic

and ranging in output from 5000 to 15000 per hour

o Automatic machines can be either continuous in motion, like a rotary

tablet press, or intermittent, where the machine stops to perform a

function and then indexes round to the next position to repeat the

operation on a further set of capsules

STEP 5: Sealing the Capsules (15 minutes)

• Capsule sealing is done by the following methods;

o Tamper evident capsules by sealing the joint between the two capsule

parts (head and the body)

o Distinctive looking capsules by sealing them with coloured band of

gelatin. If removed, the band cannot be restored without expert

sealing with gelatine

o Through a heat welding process that fuses the capsule cap to the ring

around the capsule where the head welded (e.g. Weld’s gelatin seal)

o Capsules may also be sealed through a heat welding process that fuses

the head to the body

o Light coating the inner surface of the cap with a warm gelatin

solution immediately prior to placement on the filled capsule body

STEP 6: Cleansing and Polishing Process (10 minutes)

• Small amount of powder may adhere to the outside of capsules after

filling

• It is imperative that every precaution to minimize traces of moisture or

body oils on capsules be taken to reduce powders sticking to the surface,

which would create disagreeable appearance and taste

• Cleaning capsules is difficult if they have become moist or sticky

• The capsules should be handled so that they retain their dryness and

shiny appearance.

• Use of gloves provides a more hygienic environment and helps preserve the

dry, shiny capsule appearance

• On a small scale, capsules may be cleaned individually or in small

numbers by rubbing them with a clean gauze or cloth (cloth dusting)

• On large scale, many capsule filling machines are affixed with a cleaning

vacuum that removes any extraneous material from the capsules as they

exit the equipment.

o Industrial cleaning and polishing of filled hard capsules can be done

e.g. by the Accela-cota apparatus

STEP 7: Common Problems during Manufacturing of Capsules (10 minutes

• Filling of deliquescent/ hygroscopic powder

o Remedy

▪ Addition of adsorbent e.g. magnesium carbonate/light magnesium

oxide

• Filling of eutectic mixture

o Remedy

▪ Use of adsorbent e.g. Magnesium carbonate, kaolin

• Small dose of drug

o Remedy

▪ Addition of inert powders (fillers)

• Incompatibilities of materials

o Remedy

▪ Use of two capsules –small in large

• Lack of adhesiveness difficult to fill by punch method

o Remedy

▪ Moistened with alcohol, granules reduced to powders

STEP 9: Key Points (5 minutes)

• Filling of hard gelatin capsule shells involves rectification

(orientation of the empty capsule shells in same direction), separation

of caps from the body, filling the bodies (bench-scale filling or

industrial-scale filling), scraping the excess powder, replacing the

caps, sealing the capsules, cleaning the outside of the filled capsules

• Powders and granules can be filled by direct or indirect methods

• Machines developed for industrial use automatically separate the caps

from the empty capsules and fill the bodies

STEP 10: Evaluation (5 minutes)

• Mention the steps involved in filling of hard gelatin capsule shell

• What are the common problems encountered in capsule manufacturing?

• What is the importance of capsule sealing?

References

Aulton M.E & Kevin M.G, (Eds): (2013) Pharmaceutics: The design and

manufacture of medicines, (4th ed.) Churchill Livingstone

Hugo and Russell (2011), Pharmaceutical Microbiology (8th ed.) , Willey-

Blackwel publications

Gennaro, R. A, et al. (eds) (1995) Remington: The Science and Practice of

Pharmacy, Volume I & II, (19th ed.): Mack Publishing Company, Easton,

Pennsylvania 18042

Liebsch, B et al (1988): Tanzania Pharmaceutical Handbook, Dar es Salaam

University Press.

Lund, W. Editor (1994). The Pharmaceutical Codex, Principles and Practice

of Pharmaceutics (12th ed.): The Pharmaceutical Press, London

Polderman, J (1990) Introduction to Pharmaceutical Production: Novib, The

Hague

Rawlins E.A, Editor: (1977) Bentley’s Textbook of Pharmaceutics, (8th ed.)

Baillie're Tindall. London Kamm, G. and Kohler, B. Editors: (1995)

Manual for Decentralized Infusion Production, Infusion Unit Project

Tanzania

Schmidt, O. (ed) (2000) Pharmaceutical Quality systems, Interpharm Press,

Colorado.

Shayne C et al. (2008), Pharmaceutical Manufacturing Handbook: Production

and processes, John Wiley & Sons

Watson, D. G (1999) Pharmaceutical Analysis: A Textbook for Pharmacy

Students and Pharmaceutical Chemists: Churchill Livingstone,

Edinburgh.

Session 14: Soft Gelatin Capsules

Total Session Time: 120 minutes

Pre-requisites

• None

Learning Tasks

By the end of this session students are expected to be able to:

• Define soft gelatin capsules

• Explain the composition of soft gelatin shell

• List the advantages and disadvantages of soft gelatin capsules

• Explain the formulation of fill materials for soft gelatin capsules

• Explain the filling process for soft gelatin capsules

• Explain packaging of soft gelatin capsules

• Differentiate soft gelatin capsules from hard gelatin capsules

Resources Needed:

• Flip charts, marker pens, and masking tape

• Black/white board and chalk/whiteboard markers

• LCD projector and computer

SESSION OVERVIEW

SESSION CONTENTS

STEP 1: Presentation of Session Title and Learning Tasks (5 minutes)

READ or ASK students to read the learning tasks and clarify

ASK students if they have any questions before continuing

STEP 2: Definition and Shell Composition (20 minutes)

• Soft gelatin capsules (softgels) are one piece, hermetically sealed, soft

gelatin shells containing a liquid, a suspension or a semisolid

• They are also known as soft elastic capsules (SEC)

• Soft gelatin capsules are available in round, oval, oblong and tube

shapes

• Soft gelatine capsules are mainly used for oral, vaginal and rectal

administration

• Typical soft gels are made up of gelatin, plasticizer, preservatives and

materials that impart the desired appearance (colorants and/or

opacifiers), and sometimes flavours

o Plasticizers

▪ They are materials added to make the softgel shell elastic and

pliable, usually accounting for 20-30%

▪ The most common plasticizer used in softgels is glycerol,

although sorbitol and propylene glycol are used frequently often in

combination with glycerol

▪ The amount and choice of the plasticizer contribute to the

hardness of the final product and may even affect its dissolution

or disintegration characteristics, as well as its physical and

chemical stability

▪ Plasticizers are selected on the basis of their compatibility

with the fill formulation, ease of processing, and the desired

properties of the final soft gel, including hardness, appearance,

handling characteristics and physical stability

▪ One of the most important aspect of soft gel formulation is to

ensure that there is minimum interaction or migration between the

liquid fill matrix and the soft gel shell

▪ The choice of plasticizer type and concentration is important in

ensuring optimum compatibility of the shell with the liquid fill

matrix

o Water

▪ The other essential component of the soft gel shell is water.

Water usually accounts for 30-40 % of the wet gel formulation and

its presence is important to ensure proper processing during gel

preparation and softgel encapsulation

▪ Following encapsulation, excess water is removed from the

softgels through controlled drying

▪ In dry gels the equilibrium water content is typically in the

range 5-8% w/w, which represents the proportion of water that is

bound to the gelatin in the soft gel shell.

▪ This level of water is important for good physical stability,

because in harsh storage conditions softgels will become either too

soft and fuse together, or too hard and brittled

o Colorants/opacifiers

▪ Colorants (soluble dyes, or insoluble pigments or lakes) and

opacifiers are typically used in the wet gel formulation

▪ Colorants can be either synthetic or natural, and are used to

impart the desired shell colour for product identification

▪ An opacifier, usually titanium dioxide may be added to produce an

opaque shell when the fill formulation is a suspension, or to

prevent photo degradation of light-sensitive fill ingredients

▪ Titanium dioxide can either be used alone to produce a white

opaque shell or in combination with pigments to produce a coloured

opaque shell

o Chelating agents

▪ Iron is always present in raw gelatin, excess iron should be

removed

▪ Addition of chelating agent prevents reaction of iron with other

materials e.g. colours

o Preservatives

▪ They are added to prevent from microbial attack e.g. fungi growth

▪ This is important because gelatin is susceptible to microbial

attack

▪ Preservatives include methyl paraben

STEP 3: Advantages and Disadvantages of Soft Gelatin Capsules (10 minutes)

• Advantages of soft gelatin capsules

o Improved bioavailability (drug is presented in a solubilised form)

o Enhanced drug stability

o Liquids can be encapsulated (non aqueous liquids)

o Easier to swallow and taste can improve compliance

o Convenient to carry

o Can be enteric coated for delayed release

o Popular for pharmaceutical, cosmetics and nutritional products

• Disadvantages of soft gelatin capsules

o Require special manufacturing equipment

o Stability concerns with highly water soluble compounds and compounds

susceptible to hydrolysis

o Efflorescent materials cannot be encapsulated

o Deliquescent materials cannot be encapsulated as they will cause

hardening or brittled capsules

o Limited choice of excipients/carriers compatible with gelatin

STEP 4: Formulation of Fill Materials (30 minutes)

• In soft gelatin capsules, the outer shell surrounds a liquid or semi-

solid centre (inner fill)

o Soft gelatin capsules are suitable for liquids and semisolids

• An active ingredient can be incorporated into the outer shell, the inner

fill, or both

• Formulation of the soft gel capsules therefore involves liquid rather

than powder as in hard shell capsules

• Materials are generally formulated to produce the smallest possible

capsule consistent with maximum stability, therapeutic effectiveness and

manufacture efficiency

• Many drug compounds cannot be encapsulated into the soft gelatine

capsules because of their solubility in water and thus their ability to

dissolve the gelatin wall

o E.g. emulsions cannot be filled into these shells because they contain

water which will affect the gelatin

o Aqueous compounds that are minor constituents of a formula or are

combined with a type of carrier (liquid or solid) that reduces their

effect on the shell can be filled into soft gelatin capsules

o The fill content (or inner fills) for the soft gelatin shells are only

non-aqueous materials

o The pH of the liquids filled into soft gelatin capsules can be between

2.5 to 7.5

• There are three primary types of inner fill materials:

o Neat substances

▪ Oily liquids are filled into the capsules

▪ E.g. cod liver oil capsules

o Solution fills

▪ An active solid drug is dissolved in a solvent or carrier

▪ Solvents include oils and polyethylene glycol

o Suspension fills

▪ An active solid drug is dispersed in a carrier

▪ Can accommodate up to 30% solids before viscosity and filling

become a problem

▪ Suspensions can be heated up to 35ºC to decrease viscosity during

the filling process

▪ Suspended solids must be smaller and made homogeneous before

filling to prevent clogging during filling

▪ Suspension is used for solids that are not sufficiently soluble

in liquids or in combinations of liquids

▪ The capsulation of suspensions is the basis for the existence of

a large group of products

▪ The design of suspension type formulations and the choice of the

suspending medium are directed toward producing the smallest size

capsule having maximum production capacity consistent with maximum

physical and ingredient stability and therapeutic efficacy

▪ The formulation of suspensions for capsulation follows the basic

concepts of suspension technology

▪ Formulation techniques, however, can vary depending on the drug

substance, the desired flow characteristics, the physical or

ingredient stability problems, or the biopharmaceutical properties

desired

▪ Examples of suspension fills include drugs suspended in the

following carriers;

▪ Oily soy bean mixtures

o Soybean Oil with beeswax (4-10% w/w) and lecithin (2-4% w/w)

o The lecithin improves material flow, and imparts some

lubrication during filling

o Enough beeswax is added to get a good suspension, but avoid

creating a non-dispersible plug

▪ Polyethylene glycol

o PEG 800 -1000 for semi-solid fills

o PEG 10,000 -100,000 for solid fills

o A mixtures of the above is also employed (Heat up to 35ºC to

make fluid enough for filling)

▪ Optional Ingredients that can be added in the suspension fill:

o Surfactant: sorbitan derivatives such as polysorbate 80 or

lecithin

o For hydrophobic drugs dissolved or dispersed in an oily

matrix, a surfactant of HLB 10 will increase the

dispersibility of the product in aqueous fluids and also may

improve bioavailability

STEP 5: Filling Process for Soft Gelatin Capsules (20 minutes)

• Soft gelatin capsules are usually formed, filled and sealed in one

operation

• Soft gelatin capsules are mainly manufactured by the following methods

(plate process, rotary die process and Globex methods)

o Plate-process Method

▪ A warm sheet of gelatin is placed over a die plate containing

numerous die pockets

▪ Then a vacuum is applied to draw the sheet into the die pockets

▪ Then the pockets (now lined with gelatin) are filled with the

fill liquid or paste

▪ Another gelatin sheet is placed over the filled pockets and

sandwiched under a die press, and the capsules are formed

o Rotary-die Method

▪ This methods uses a rotary die press with two hoppers and two

rotating dies

▪ In this machine the soft gelatin capsules are prepared and filled

immediately with a liquid medicament i.e. formation of the shell

and filling are performed in a single operation

▪ The gelatin liquid mix (for the soft shell) is placed in one

hopper and the liquid medicament is placed in the other hopper

▪ The two rotating dies rotate in opposite directions, and when the

fluid gelatin mixture enters the machine from the hopper, two

continuous gelatin ribbons are formed in half gelatin shells

▪ Measured quantity of the medicament (metered fill) is injected

between the ribbons precisely at the moment that the dies form

pockets of the gelatin ribbons

▪ The two halves of the capsules are sealed together by heat and

pressure of the rotating dies

▪ As the die roll rotate, the convergence of the matching die

pockets seals and cuts out the filled capsules

▪ The capsules are washed with organic solvents and pre-dried

o Globex Method

▪ This method takes advantage of the phenomenon of drop formation

▪ The apparatus used consists of two concentric tubes, through the

inner tube flows the medicament (the fill liquid) and, through the

surrounding outer tube, the gelatin solution (shell forming

solution)

▪ Shell forming solution is pumped through the outer capillary of

the concentric double capillary

▪ The medicament issues from the tube surrounded by gelatin and

forming a spherical drop

▪ This is ensured by allowing the drop to form in cooling bath of

liquid paraffin of about 4°C, in which the gelatin is insoluble

▪ Cooling bath ensures immediate sol-gel transformation, hence

formation of flexible yet firm robust outer film

▪ Soft capsules are collected, washed with organic solvent to

remove residues of cooling liquid, and gently dried at a relative

humidity of 20% in infrared tunnels

▪ The advantage of this method is the production of seamless

capsules which are tamper-evident and free of contamination or

entrapped air

STEP 6: Packaging of Soft Gelatin Capsules (10 minutes)

• Packaging is the science, art and technology of enclosing or protecting

products

• Some of the characteristics of packaging materials include;

➢ Should protect the capsules from environmental conditions

➢ Non-reactive with the product

➢ Not impart taste or odour to the capsules

➢ Nontoxic

➢ Meet applicable tamper resistance requirements

• The capsules are packaged in well closed containers and stored at

temperature not exceeding 30 C

o Glass containers

o Plastic containers

• Capsules are individually protected by enclosing in strip and blister

packaging

o Strip packaging involves hermetically sealing the capsules within the

strip of aluminium or plastic film

▪ A press on the blister forces the capsule through the backing

strip

o Capsules have longer shelf life in unopened glass bottles than in

strip pack and vice versa

STEP 7: Difference between Hard and Soft Gelatin Capsules (15 minutes)

|Hard shell gelatin capsules |Soft shell gelatin capsules |

|Two pieces i.e. short cap and large|One piece, hermetically sealed |

|body | |

|Cylindrical in shape |Round, oval and tube like shapes |

|Powders, pellets, tablets are |Non aqueous liquids and semisolid|

|encapsulated | |

|Gelatin in hard form (less |Gelatin is soft (more |

|plasticizers) |plasticizers) |

|Capsules are sealed after they are |Filling and sealing of the soft |

|filled to ensure that the |gelatin capsules are done in a |

|medicaments may not come out of the |combined operation |

|capsule due to rough handling | |

|Different specific sizes are |No specific size are available |

|available | |

STEP 8: Key Points (5 minutes)

• Soft gelatin capsules (softgels) are one piece, hermetically sealed, soft

gelatin shells containing a liquid, a suspension or a semisolid

• Typical soft gels are made up of gelatin, plasticizer, preservatives and

materials that impart the desired appearance (colorants and/or

opacifiers), and sometimes flavours

• Materials are generally formulated to produce the smallest possible

capsule consistent with maximum stability, therapeutic effectiveness and

manufacture efficiency

• Soft gelatin capsules can be manufactured by plate process, rotary die

process and Globex methods

• The capsules are packaged in well closed containers and stored in a cool

place

STEP 9: Evaluation (5 minutes)

• What is a soft gelatin capsule?

• How do softgels differ from hard gelatin capsules?

• List ingredients used to make the soft gelatin shell

References

Aulton M.E & Kevin M.G, (Eds): (2013) Pharmaceutics: The design and

manufacture of medicines, (4th ed.) Churchill Livingstone.

Hugo and Russell (2011), Pharmaceutical Microbiology (8th ed.), Willey-

Blackwel publications

Gennaro, R. A, et al. (Eds) (1995) Remington: The Science and Practice of

Pharmacy, Volume I & II, (19th ed.): Mack Publishing Company, Easton,

Pennsylvania 18042

Liebsch, B et al. (1988): Tanzania Pharmaceutical Handbook, Dar es Salaam

University Press.

Lund, W. Editor (1994). The Pharmaceutical Codex, Principles and Practice

of Pharmaceutics (12th ed.): The Pharmaceutical Press, London

Polderman, J. (1990) Introduction to Pharmaceutical Production: Novib, The

Hague

Rawlins E.A, Editor: 1977 Bentley’s Textbook of Pharmaceutics, (8th ed).

Baillie're Tindall. London Kamm, G. and Kohler, B. Editors: 1995

Manual for Decentralized Infusion Production, Infusion Unit Project

Tanzania

Schmidt, O. (ed) 2000 Pharmaceutical Quality systems, Interpharm Press,

Colorado.

Shayne C et al (2008), Pharmaceutical Manufacturing Handbook: Production

and processes, John Wiley & Sons

Watson, D. G (1999) Pharmaceutical Analysis: A Textbook for Pharmacy

Students and Pharmaceutical Chemists: Churchill Livingstone,

Edinburgh.

Session 15: Introduction to Tablets

Total Session Time: 120 minutes

Pre-requisites

• None

Learning Tasks

By the end of this session students are expected to be able to:

• Define tablets

• List characteristics of tablets

• Classify tablets

• List advantages and disadvantages of tablets

• List unit processes in tablet manufacturing

Resources Needed:

• Flip charts, marker pens, and masking tape

• Black/white board and chalk/whiteboard markers

• LCD projector and computer

SESSION OVERVIEW

SESSION CONTENTS

STEP 1: Presentation of Session Title and Learning Tasks (5 minutes)

READ or ASK students to read the learning tasks and clarify

ASK students if they have any questions before continuing

STEP 2: Definitions (10 minutes)

|Activity: Buzzing (5 minutes) |

| |

|ASK students to pair up and buzz on the following question for 2 |

|minutes |

| |

|What is a tablet? |

| |

|ALLOW few pairs to respond and let other pairs to add on points not |

|mentioned |

| |

|WRITE their response on the flip chart/board |

| |

|CLARIFY and SUMMARIZE by using the content below |

• Tablets are defined as compressed or moulded unit solid dosage forms

containing one or more medicaments with or without excipients

• Tablets are prepared by compressing drugs or mixture of drugs with or

without diluents

• Tablets differ in

➢ size,

➢ shape,

➢ weight,

➢ hardness,

➢ thickness,

➢ disintegration and

➢ dissolution

• characters depending on the amount of medicinal substance and intended

mode of administration

• Tablets are the most popular dosage forms

• Most medicines are available in tablet form except where it is difficult

to formulate or administer

STEP 3: Characteristics of Tablets (20 minutes)

• General characteristics of tablets include the following;

o A tablet should have elegant product identity while free of defects

like chips, cracks, discoloration, and contamination

o Should have sufficient strength to withstand mechanical shock during

its production packaging, shipping and dispensing

o Should have the chemical and physical stability to maintain its

physical attributes over time

o The tablet must be able to release the medicinal agents in a

predictable and reproducible manner

o Must have a chemical stability over time so as not to follow

alteration of the medicinal agents

o Should be uniform in size, weight, and appearance

STEP 4: Classification of Tablets (50 minutes)

• Tablets can be classified according to the way they are made or mode of

administration

• Based on how they are made, tablets are classified into;

o Compressed tablets

▪ Uncoated

▪ Coated

o Moulded tablets

▪ Dispensing tablets

▪ Hypodermic tablets

• Based on mode of administration, tablets are classified into;

o Tablets ingested orally (oral tablets)

▪ Compressed tablets (CT) e.g. paracetamol tablets

▪ Multiple compressed tablets or press coated tablets

▪ Repeat action tablets

▪ Delayed release tablets e.g. enterically coated bisacodyl tablets

▪ Sugar coated tablets e.g. multivitamin tablets

▪ Film coated tablets e.g. metronidazole tablets

▪ Chewable tablets e.g. antacid tablets

o Tablets used in the oral cavity

▪ Buccal tablets

▪ Sublingual tablets

▪ Troches

▪ Lozenges

▪ Dental cones

o Tablets administered by other routes

▪ Implantation tablets (implants)

▪ Vaginal tablets e.g. clotrimazole tablets

o Tablets to prepare solution

▪ Effervescent tablets e.g. aspirin tablets

▪ Dispensing tablets e.g. enzyme tablets

▪ Hypodermic tablets

▪ Tablet triturates

STEP 5: Advantages and Disadvantages of Tablets (15 minutes)

|Activity: Small Group Discussion (10 minutes) |

| |

|DIVIDE students into small manageable groups |

| |

|ASK students to discuss on the following question |

|What are the advantages and disadvantages of tablets? |

| |

|ALLOW students to discuss for 10 minutes |

| |

|ALLOW few groups to present and the rest to add points not mentioned |

| |

|CLARIFY and SUMMARIZE by using the contents below |

• The advantages of tablets over other dosage forms include;

o They are unit dosage forms and offer the greatest capabilities of all

oral dosage forms for the greatest dose precision and the least

content variability

o Cost is lowest of all oral dosage forms

o Lighter and compact

o Easiest to package and strip

o Cheapest to package and strip

o Easier to swallow

o Easy to produce sustainable release product by enteric coating

o Objectionable odour and bitter taste can be masked

o Suitable for large scale production

o Greatest chemical and microbiological stability over all oral dosage

forms

o Product identification is easy and rapid

▪ By embossing and or monogramming punch face

• Disadvantages of tablets include;

o Difficult to swallow in case of children and unconscious patients

o Some drugs resist compression due to amorphous nature and low density

characters

▪ Drugs with poor wetting slow dissolution properties and hence are

poorly absorbed from the gastrointestinal tract (hence low

bioavailability)

▪ Bitter tasting drugs or drugs with objectionable odour or

sensitive to oxygen may require encapsulation or coating, hence

increased cost

STEP 6: Unit Processes in Tablet Manufacturing (10 minutes)

• Formulation of a tablet is governed by a number of factors:

o The chemical and physical properties of active ingredient involved and

route of administration.

o The manufacturing process to be employed.

o The method by which the tablet is to be used, i.e. swallowed whole,

chewed, dissolved in water, etc. These three factors are inter-

related.

• The preparation of tablets can be divided into:-

o Dry methods which includes:-

• Direct compression, and

• Dry granulation or Precompression method (Slugging and roller

compaction)

o Wet methods which includes:-

▪ Wet granulation.

▪ Fluidized bed granulation.

• Production of tablets involves the following unit processes;

o Weighing and Measuring

o Mixing

o Granulation

o Drying

o sieving

o Compression

o Coating

o Packaging [pic]

[pic]

STEP 7: Key Points (5 minutes)

• Tablets are the most popular dosage forms

• Tablets are defined as compressed or moulded unit solid dosage forms

containing one or more medicaments with or without excipients

• Tablets vary in size, shape, weight, hardness, thickness, disintegration

and dissolution characters

• Tablets can be classified into tablets ingested orally, tablets used in

the oral cavity, tablets administered by other routes, tablets to prepare

solution

• A tablet should have elegant product identity while free of defects like

chips, cracks, discoloration, and contamination

STEP 8: Evaluation (5 minutes)

• What is a tablet?

• Mention four characteristics of tablets

• What is an effervescent tablet?

References

Aulton M.E & Kevin M.G, Eds: (2013) Pharmaceutics: The design and

manufacture of medicines, (4th ed.) Churchill Livingstone

Hugo and Russell (2011), Pharmaceutical Microbiology (8th ed.), Willey-

Blackwel publications

Gennaro, R. A, et al. (Eds) (1995) Remington: The Science and Practice of

Pharmacy, Volume I & II, (19th ed.): Mack Publishing Company, Easton,

Pennsylvania 18042

Liebsch, B et al (1988): Tanzania Pharmaceutical Handbook, Dar es Salaam

University Press.

Lund, W. Editor (1994). The Pharmaceutical Codex, Principles and Practice

of Pharmaceutics (12th ed.): The Pharmaceutical Press, London

Polderman, J (1990). Introduction to Pharmaceutical Production: Novib, The

Hague

Rawlins E.A, Editor: (1977) Bentley’s Textbook of Pharmaceutics, 8th Ed.

Baillie're Tindall. London Kamm, G. and Kohler, B. Editors: (1995)

Manual for Decentralized Infusion Production, Infusion Unit Project

Tanzania

Schmidt, O. (ed) (2000) Pharmaceutical Quality systems, Interpharm Press,

Colorado.

Shayne C et al (2008), Pharmaceutical Manufacturing Handbook: Production

and processes, John Wiley & Sons

Watson, D. G (1999) Pharmaceutical Analysis: A Textbook for Pharmacy

Students and Pharmaceutical Chemists: Churchill Livingstone,

Edinburgh.

Session 16: Formulation of Tablets

Total Session Time: 120 minutes

Pre-requisites

• None

Learning Tasks

By the end of this session students are expected to be able to:

• Define formulation

• Explain main ingredients used in tablet production

• Classify excipients used in tablet production

• List characteristics of excipients used in tablet production

• Explain role of excipients used in tablet production

Resources Needed:

• Flip charts, marker pens, and masking tape

• Black/white board and chalk/whiteboard markers

• LCD projector and computer

SESSION OVERVIEW

SESSION CONTENTS

STEP 1: Presentation of Session Title and Learning Tasks (5 minutes)

READ or ASK students to read the learning tasks and clarify

ASK students if they have any questions before continuing

STEP 1: Formulation of Tablets (30 minutes)

• Tablet formulation is the process in which the active pharmaceutical

ingredient(s) (APIs) and excipients are combined to produce a tablet

o The type and amounts of each ingredient i.e. the medicament(s) and the

excipients are known prior to manufacturing process

o Formulation must ensure that the dosage form formed is stable

acceptable to the patient who will use it

o In formulation the variety of ingredients used (including the drug

itself) must be compatible with each other

o Therefore it is very important to do a lot of formulation studies in

order to detect the point of compatibility

o Formulation studies must focus on other factors like particle size,

polymorphism, pH and solubility, in order to check whether these

factors will effect on bioavailability of the drug or not

o Oral formulations such as tablets and capsules must be formulated in

such as way to ensure that they release the drug(s) in a constant and

predictable manner

o A formula for tablet production

o A formally authorized Master Formula Record or Master Production

Record should exist for each product and batch size to be manufactured

▪ This document specifies the starting materials with their

quantities and packaging materials, together with a description of

the procedures and precautions required to produce a specific

quantity of a finished product as well as the processing

instructions including the in-process controls

STEP 2: Ingredients Used in Tablet Production (25 minutes)

• Tablets are composed of two main groups of ingredients;

o Active Pharmaceutical Ingredients (APIs)

▪ This is the medicament part of the tablet e.g. paracetamol,

diclofenac, amoxicillin etc.

▪ The function of API in tables is to produce pharmacological

action upon administration of the tablet

o Excipients/Pharmaceutical aids

▪ Excipients or additives are inert materials for the purpose of

improving the quality of the tablets or facilitating

manufacturing process

|Activity: Small Group Discussion ( 10 minutes) |

| |

|DIVIDE students into small manageable groups |

| |

|ASK students to discuss on the following question |

|What are the functions of excipients in tablets? |

| |

|ALLOW students to discuss for 10 minutes |

| |

|ALLOW few groups to present and the rest to add points not mentioned |

| |

|CLARIFY and SUMMARIZE by using the contents below |

• General functions of excipients are;

o Impart weight, accuracy and volume

o Ensure accuracy of the dose

o Improve solubility

o Increase stability

o Enhance bioavailability

o Modify drug release pattern

o Assist product identification

o Increase patient acceptability

o Facilitate dosage form design

STEP 5: Classification, Properties and Roles of Excipients (50 minutes)

• Classes of excipients used in the manufacture of tablets include;

o Diluents/filler/bulking agents

o Binders and adhesives

o Disintegrants

o Lubricants and glidants

o Colouring agents

o Flavouring agents

o Sweetening agents

o Adsorbent

• Diluents/filler/bulking agent

o They are fillers and make required bulk when the drug(s) is/are not

adequate to make the bulk

o They also help improve cohesion and permit use of direct compression

manufacturing or to promote flow

o Some commonly used diluents are Microcrystalline cellulose, Mannitol,

Dextrose, Sorbitol, Lactose anhydrous and Starch

o Diluents should have the following properties;

▪ Must be non toxic

▪ Must be commercially available in accepted grades

▪ Cost must be low

▪ Must be physiologically inert

▪ Must be physically and chemically stable by themselves and in

combination with the drug(s)

▪ Must be free from all microbial contamination

▪ They should not alter the bioavailability of drug

▪ They must be colour compatible

• Binders

o They are materials added to form granules or to form cohesive compacts

for directly compressed tablets

o Binders are classified into two groups

▪ Solution binders

▪ Are dissolved in solvent before being added e.g. cellulose,

gelatin

▪ Dry binders

▪ These are added to the powder blend e.g. polyethylene glycol

(PEG)

o Some commonly used binders are acacia, tragacanth, cellulose

derivatives (methyl cellulose, hydroxymethyl cellulose, hydroxyproply

cellulose), gelatine, glucose, polyvinyl pyrolidone (PVP), starch,

sodium alginate, sorbitol

• Disintegrants

o Are materials added in tablet formulation to facilitate its breaking

down when it contacts water in the gastrointestinal tract

o They are added before granulation and before compression

o Some commonly used disintegrants include starch; starch derivatives

(e.g. primogel); clays e.g. veegum, bentonite; cellulose; cellulose

derivatives e.g. sodium carboxymethyl cellulose; alginate and

polyvinyl pyrolidone cross-linked

o Super disintegrants

▪ Swell up to ten times their volume within 30 seconds of

contacting water

▪ Examples of super disintegrants include crosscarmellose (cross-

linked cellulose), crospovidone, sodium starch glycolate

• Lubricants and Glidants

o Lubricants

▪ Are substances added to reduce or prevent friction, heat and wear

when introduced as a film between solid surfaces

▪ Lubricants prevent adhesion of tablet materials to the surface of

dies and punches thereby reducing interparticle friction

▪ improve the rate of flow of granules or powder materials

▪ Commonly used lubricants are; stearic acid, stearic acid salt

(e.g. magenisum stearate), talc, polyethylene glycol (PEG),

surfactants

o Glidants

▪ Reduce friction between particles or granules and hence promote

flow

▪ Commonly used glidants are; corn starch, talc, silica derivatives

e.g. colloidal silica

• Colouring agents

o These are colours and dyes used for;

▪ Masking of off colour drugs

▪ Tablet identification

▪ Production of more elegant tablets where they impart a

distinctive appearance to the tablets

▪ Colouring agents can be natural or synthetic

o All colouring agents must be approved and certified by competent

authority e.g. TFDA

o These excipients are added in solution or in dry form

o Two classes of colouring agents are used in tablet production

▪ FD and C colours (colouring agents for foods, drugs and

cosmetics)

▪ D and C colours (colouring agents for drugs and cosmetics)

o Commonly colouring agents used in tablet production are white, sunset

yellow, tartrazine, fast green, brilliant blue, erythrosine and indigo

carmine

o Ideal characteristics of colouring agents

▪ Should be nontoxic

▪ Should not have physiological activity

▪ Should be free from harmful impurities

▪ Should have high colouring (tinctorial) power so that only small

quantities are used

▪ Should be unaffected by light, tropical temperatures, hydrolysis

and microorganisms i.e. stable on storage

▪ Should be compatible with the drugs and other excipients

▪ Should be readily soluble in water

▪ Should be free from objectionable odour or taste

▪ They should be approved and certified for use in foods, drugs and

cosmetics i.e. FD and C colouring agents

o Flavouring agents

▪ These are normally added to chewable tablets

▪ They are used to increase patient acceptance

▪ Flavour oils are used

▪ Clove oil, citric acid, rose oil, orange oil etc.

o Sweetening agents

▪ There are materials added to increase palatability

▪ They are commonly used in chewable tablets

▪ They may be natural or synthetic

▪ Commonly used sweetening agents are; saccharine (artificial)

–sweeter than sugar, has one disadvantage –bitter after taste and

carcinogenic; aspartame (artificial) –not stable in presence of

moisture

STEP 4: Key Points (5 minutes)

• Tablet formulation is the process in which the active pharmaceutical

ingredient(s) (APIs) and excipients are combined to produce a tablet

• Formulation process must ensure that the dosage form formed is stable

acceptable to the patient who will use it

• Major ingredients used in production of tablets are the active

pharmaceutical ingredient(s) and the excipients

• Excipients used in tablet manufacturing are diluents, binders and

adhesives, disintegrants, lubricants and glidants, colouring agents,

flavouring agents and sweetening agents

STEP 5: Evaluation (5 minutes)

• What is the role of glidants in tablet manufacturing?

• Who prepares the formula for tablet manufacturing?

• What are the general roles of excipients in tablet production?

References

Aulton M.E & Kevin M.G, Eds: (2013) Pharmaceutics: The design and

manufacture of medicines, (4th ed.) Churchill Livingstone

Handbook of pharmaceutical excipients, Edition sixth, Edited by Raymond

Crow, Paul J Shekey and Marian E. Quinn, Publisher –Pharmaceutical

Press

Hugo and Russell (2011), Pharmaceutical Microbiology (8th ed.), Willey-

Blackwel publications

Gennaro, R. A, et al. (Eds) (1995) Remington: The Science and Practice of

Pharmacy, Volume I & II, (19th ed.): Mack Publishing Company, Easton,

Pennsylvania 18042

Liebsch, B et al (1988): Tanzania Pharmaceutical Handbook, Dar es Salaam

University Press.

Lund, W. Editor (1994). The Pharmaceutical Codex, Principles and Practice

of Pharmaceutics (12th ed.): The Pharmaceutical Press, London

Polderman, J (1990) Introduction to Pharmaceutical Production: Novib, The

Hague

Rawlins E.A, Editor: (1977) Bentley’s Textbook of Pharmaceutics, (8th ed.)

Baillie're Tindall. London Kamm, G. and Kohler, B. Editors: (1995)

Manual for Decentralized Infusion Production, Infusion Unit Project

Tanzania

Schmidt, O. (ed) (2000) Pharmaceutical Quality systems, Interpharm Press,

Colorado.

Shayne C et al (2008), Pharmaceutical Manufacturing Handbook: Production

and processes, John Wiley & Sons

Watson, D. G (1999) Pharmaceutical Analysis: A Textbook for Pharmacy

Students and Pharmaceutical Chemists: Churchill Livingstone,

Edinburgh.

Session 17: Granulation

Total Session Time: 120 minutes

Pre-requisites

• None

Learning Tasks

By the end of this session students are expected to be able to:

• Define granulation

• List the reasons for granulation

• Explain the types of granulation

• Explain the process of granulation

Resources Needed:

• Flip charts, marker pens, and masking tape

• Black/white board and chalk/whiteboard markers

SESSION OVERVIEW

SESSION CONTENTS

STEP 1: Presentation of Session Title and Learning Tasks (5 minutes)

READ or ASK students to read the learning tasks and clarify

ASK students if they have any questions before continuing

STEP 2: Introduction to Granulation (15 minutes)

Granulation has been defined as “any process whereby small particles are

gathered into larger, permanent masses in which the original particles can

still be identified

• Granulation is a process whereby small (powder) particles are gathered

into large permanent masses (granules) in which the original particles

can still be identified

• It is a process whereby primary powder particles are made to adhere to

form larger, multiparticle entities called granules

• In granulation process, powder particles are collected together by

creating bonds between them through compression or by using a binding

agent

• Pharmaceutical granules for tablets or capsule production typically have

a size range between 0.2 and 0.5 mm depending on their use

• Ability to produce reproducible tablets, batch to batch, lot to lot, is

directly related to the ability to produce reproducible granulation

• Uses of granules;

o As dosage form

▪ Where they are packed as bulk granules or divided granules

o As intermediate product in preparation tablets

▪ Granules have excellent compressability

STEP 3: Importance of Granulation (25 minutes)

• Granulation is important for various reasons including;

o To prevent segregation of the constituents of powder mix

▪ Segregation is caused by difference is particle size or density

of components of the powder mix

▪ The small and/or denser particles concentrate at the base of a

container with the larger and/or less denser particles above them

▪ An ideal granulation process will contain all the particles in

the mix (smaller or larger and denser or less denser) in the

correct proportion in each granule, and thus segregation of

ingredients will not occur

o To improve flow properties of the mix

▪ Because of small size, irregular shape or surface

characteristics, many powders are cohesive and do not flow well

▪ Poor flow will result in weight variation in the final product

due variable fill of tablet dies or capsule shells, etc

▪ Granules are larger and flow is improved

o To improve compaction characteristics of powder mix

▪ Granules are easier to compress than powders. Some powers are

difficult to compact even after inclusion of compactable adhesives

o To reduce hazards of toxic dust powders

▪ Powders produce dust during handling, and when toxic powders are

being handled it is hazardous to the personnel

▪ Production of non friable granules with suitable strength

eliminate the problem of dust production

o To reduce the hazard of hygroscopic powders adhesion

▪ Materials that are slightly hygroscopic may adhere to form cake

if stored as powder

▪ Granulation reduces this problem because granules can absorb

moisture while retaining their flowability due to their larger size

o To improve storage

▪ Granules are more convenient to store or ship as they occupy

less volume per unit weight (granules are denser than powders)

STEP 4: Granulation Methods (50 minutes)

• There are two main methods for granulation

o Wet granulation, which uses liquid in the process

o Dry granulation, which does not use any liquid

o Granulation by crystallization is a rarely used method in granulation

which exploits the presence of crystallization water in the active

materials

• During granulation process, a number of different excipients are added in

addition to the drug (Diluents, disintegrants, adhesives/binders)

• Equipment for granulation process are known as granulators

o Different types of granulators are employed depending on the process

• Wet granulation

o It is the most commonly used method

o Wet granulation involves wet massing of a mix of dry primary powder

particles using a granulating ﬂuid

o It involves the formation of granules by aggregating primary powder

particle by using a solution (liquid) containing binding agents

dissolved in a solvent. The liquid may also be used without adding

binding agent

▪ This liquid or the solution of binding agent is known as

granulation fluid

▪ Granulating fluid contains a solvent which must be volatile so

that it can be removed by drying, and be non-toxic

▪ Solvents commonly used in wet granulation are water, ethanol and

isopropanol either alone or in combination

• Organic solvents are used when water-sensitive drugs are

processed

• Water is used when water-stable drugs are processed.

▪ Advantages of water include non flammability and economical

▪ Disadvantages of using water include

▪ Water may affect stability of the drug e.g. causing

hydrolysis

▪ Needs longer drying time than volatile solvents

o Granulation fluid ensures particles adhere together once the granule

is formed and dried

o Steps in wet granulation

➢ Dry mixing (of powder particles)

➢ Wet mixing (addition of granulating fluid) to form a wet mass

➢ Squeezing the wet mass through a sieve to produce wet ribbons

➢ Drying the ribbons

➢ Milling to produce granules of suitable size

o Wet granulation uses a variety of granulators

▪ Shear granulators

• Powders are mixed in a separate operation using suitable mixers

▪ Planetary mixer is used for a wet massing of the powders i.e.

to form the wet mass

▪ Powders are fed into the mixer followed by granulating fluid

▪ Then the wet mass is transferred to the share granulator such

as oscillating granulator where the rotor bars of the granulator

oscillate and force the moist mass through a sieve screen to

form granules which are collected on trays and transferred to

drying oven or fluidized bed drier

▪ Advantage of shear granulation process

o Not very sensitive to change in characteristics of granule

ingredients e.g. surface area variations

o The end point of massing process can be determined by

examination

▪ Disadvantages of shear granulation

o Long duration

o Need several pieces of equipment e.g. mixers, granulator,

drier

o High material loss due to transfers stages

• High speed mixer/Rapid Mix Granulator (RMG)

o Have stainless steel mixing bowl containing a three-bladed

main impeller which revolves in horizontal plane and a three-

bladed auxiliary chopper (breaker blade) which revolve either

in the vertical or horizontal plane

o Unmixed powders are placed in the bowl and mixed by the

rotating impeller for a few minutes

o Granulating fluid is then added through a pot in the lid of

the granulator while the impeller is turning

▪ the granulating fluid is mixed into the powders by the

impeller

▪ The chopper is switched on once the granules have been formed

o The granular product is discharged through a wire mesh which

break up any large aggregates into the bowl of a fluidized

bed drier

o Advantages of high speed mixer/granulators

▪ Mixing and granulation are performed in one piece of

equipment with a few minutes

▪ No transfers of materials required

o Disadvantages of high speed mixer/granulators

▪ Process needs to be controlled with care as granulation

process is so fast

▪ Usable granules can be quickly transformed into an

unusable, over massed system hence a suitable monitoring

system is required to monitor when granules of desired

properties are attained

▪ The process is sensitive to variation in raw materials

• Fluidized bed granulators

o Powder particles are fluidized in a stream of air

o Granulation fluid is pumped from a reservoir and sprayed from a nozzle

onto the bed of powders

o Heated and filtered air is blown through the bed of unmixed powders to

fluidize the particles and mix them

o The fluid causes the primary particles to adhere when droplets and

powders collide

o Exhaust filters prevent escape of materials from the granulation

chamber

o The filters are periodically agitated to reintroduce the collected

materials into the fluidized bed

o Sufficient fluid is sprayed to produce granules of required size

o The wet granules are then dried in the heated fluidizing air stream

▪ Advantages of fluidized bed granulation

• All processes are carried out in one equipment

• Saves labour costs, transfer losses and time

• The process can be automated

▪ Disadvantages of fluidized bed granulation

• The equipment is expensive

• Optimization of parameters affecting granulation needs extensive

development work

• Spray drier granulators

o Granular product is made from a solution or a suspension rather than

initially dry powder particles

o Resulting granules are free-flowing hollow spheres and the

distribution of the binder in such granules results in good compaction

properties

o Spray drying can covert hard elastic materials into more ductile ones

o Primary advantage of this process is short drying time and minimal

exposure to heat due to short residence time in the drying chamber

▪ Spheronizers/pelletizers

o Employed when dense, spherical pellets are needed. These are difficult

to produce by other (previous described) equipments

o The process involves;

▪ Separation of wet massing

▪ Extrusion of this mass into rod-shaped granules

▪ Spheronization to round off these rods into spherical particles

(pellets)

• This is done by using a spheronizer Consists of a bowl with

fixed side walls and rapidly rotating bottom plate or disc

▪ Drying to achieve desired final moisture content

▪ Screening to achieve desired narrow size distribution of pellets

• Advantages of this process

o Uniform sized spherical particles are made

o Used primary to make multiparticulates for controlled release

products

o Achieves ideal flow behaviour and disability

o Produce compact structures

o Products produced are of low hygroscopicity

▪ Rotor granulators

o Powders are added and wetted with granulating fluid e.g. from a spray

followed by mixing with the rapid rotating base of the granulator

o The rotating base and stationary wall of the granulator cause the mass

to break into isolated spherical pellets

▪ The process involves

• Addition of powder into the granulator

• Spraying the granulating fluid

• Rolling of the wet mix

• Drying of the formed spheres (pellets)

• Dry Granulation

o Primary powder particles are aggregated under high pressure without

use of liquid

▪ Large aggregates are then comminuted and screened to granules of

suitable size

Methods used in dry granulation;

• Slugging (double compression)

o Involves the use of heavy duty presses called Sluggers to form large,

flat tablets (large compacts) known as slugs

o Slugging involves the following steps;

➢ Preparing the formula

➢ Milling

➢ Mixing of the ingredients (all ingredients and half of the

lubricant)

➢ Slugging (compressing the mix in slugger, which consists of large

die large punches)

➢ Grinding the slugs by dry granulator or homogenizer to convert

slug into granules

• Roller compaction

o Whereby powder particles are squeezed between rollers to produce a

sheet of material (large tablet mass) by using Roller compactors

o Roller compaction involves

▪ Two rolls rotate against each other, to increase the density of

powder by pressing it between the rollers and get a thin wide sheet

or ribbon equivalent to the slug produced by slugging

▪ The ribbons or aggregates are then screened to produce uniform

granules

o Generally, dry granulation produces an intermediate product (slugs or

ribbon/sheet)

o This intermediate product is then milled (and screened) into granular

materials using suitable milling equipment/technique

o Advantages of dry granulation

▪ It is more economical than wet granulation

▪ Less space and less equipment are employed

▪ It is less time consuming e.g. no drying process as no liquid is

used

▪ Used for moisture sensitive materials

▪ No migration of colours (mottling) that may occur as in wet

granulation because of presence of moisture

▪ Avoids head-temperature combinations that might cause degradation

of the product

Disadvantages of dry granulation

▪ Slugging required specialized heavy duty machine

▪ Produces more dust which may cause contamination of the product.

▪ Generation of charges of static electricity and lead to reduce

flowability

▪ Decreases the dissolution of insoluble drugs (lipophilic drug)

• Granulation mechanisms

o To form granules, strong bonds must be formed between powder particles

so that they adhere to prevent break down of granules to powder during

handling

o There four primary mechanisms

▪ Adhesion and cohesion forces in the immobile liquid films between

individual primary powder particles

▪ Interfacial forces in mobile liquid films within the granules

▪ Formation of solid bridges after solvent evaporation

▪ Attractive forces between solid particles

STEP 5: Characteristics of granules (15 minutes)

• Process variables, granulating equipment and processing conditions affect

characteristics of granules produced; these characters include;

➢ Particle size and shape

➢ Surface area

➢ Density

➢ Strength and friability (which measure the strength of the

granules)

➢ Flow properties

➢ Compaction

STEP 6: Key Points (5 minutes)

• Granulation is a process whereby primary powder particles are made to

adhere to form larger, multiparticle entities called granules

• In granulation process, powder particles are collected together by

creating bonds between them through compression or by using a binding

agent

• Pharmaceutical granules for tablets or capsule production typically have

a size range between 0.2 and 0.5 mm depending on their use

• Two methods are employed when forming granules; dry granulation and wet

granulation

• Granules are used as dosage form or as intermediate product for tablet

production

STEP 7: Evaluation (5 minutes)

• What is a granule?

• What is granulation?

• What is the difference between dry granulation and wet granulation?

• Why is wet granulation more common than dry granulation?

References

Aulton M.E. & Kevin M.G, Eds: (2013) Pharmaceutics: The design and

manufacture of medicines, (4th ed.) Churchill Livingstone

Hugo and Russell (2011), Pharmaceutical Microbiology (8th ed.), Willey-

Blackwel publications

Gennaro, R. A., et al. (Eds) (1995) Remington: The Science and Practice of

Pharmacy, Volume I & II, (19th ed.): Mack Publishing Company, Easton,

Pennsylvania 18042

Liebsch, B et al (1988): Tanzania Pharmaceutical Handbook, Dar es Salaam

University Press.

Lund, W., Editor (1994). The Pharmaceutical Codex, Principles and Practice

of Pharmaceutics (12th ed.): The Pharmaceutical Press, London

Polderman, J. (1990) Introduction to Pharmaceutical Production: Novib, The

Hague

Rawlins E.A., Editor: (1977) Bentley’s Textbook of Pharmaceutics, (8th

ed.) Baillie're Tindall.

London Kamm, G. and Kohler, B. Editors: (1995) Manual for Decentralized

Infusion Production, Infusion Unit Project Tanzania

Schmidt, O., (ed) (2000) Pharmaceutical Quality systems, Interpharm Press,

Colorado.

Shayne C et al. (2008), Pharmaceutical Manufacturing Handbook: Production

and processes, John Wiley & Sons

Watson, D. G., (1999) Pharmaceutical Analysis: A Textbook for Pharmacy

Students and Pharmaceutical Chemists: Churchill Livingstone,

Edinburgh.

Session 18: Compression

Total Session Time: 120 minutes

Pre-requisites

• None

Learning Tasks

By the end of this session students are expected to be able to:

• Define compression

• Explain the importance of pre-compression mixing

• List equipments used for tablet pressing

• Explain the events during compression

• Explain problems encountered in tablet production

Resources Needed:

• Flip charts, marker pens, and masking tape

• Black/white board and chalk/whiteboard markers

• LCD projector and computer

SESSION OVERVIEW

SESSION CONTENTS

STEP 1: Presentation of Session Title and Learning Tasks (5 minutes)

READ or ASK students to read the learning tasks and clarify

ASK students if they have any questions before continuing

STEP 2: Compression and Pre-Compression Mixing (20 minutes)

• Compression is a unit process in pharmaceutical production in which

granules (obtained from granulation) or powder mix are compressed to form

tablets

• Compression is done after preparation of granules or mixing of

ingredients (in case of direct compression)

o The granules or powder mix are compressed to form tablets

• Compression is accomplished by using equipment called tablet machine or

tablet pres

• Materials to be compressed into tablets must have good flow properties

and compressibility

• During compression, the proximity of particles surface causes bond

formation between particles which provide coherence to the powder i.e.

compact formation

• Powder compression causes compaction and consolidation i.e. the increase

in mechanical strength of material from particle-particle interactions

• Before the granules or powder mix are compressed, pre-compression mixing

is done

o Excipients such as lubricants, glidants, antiadherents and

disintegrants are added in the required proportion onto the surface of

granules or powder particles in the powder mix

o The reason for pre-compression mixing is to improve tablet

manufacturing process e.g. by reducing friction and promoting flow of

materials into the compression machine and improve the pharmaceutical

quality of the tablets e.g. disintegration

• The unit processes in manufacture of tablets are;

o Dispensing (weighing)

o Granulation (wet or dry)

o Drying and sizing

o Lubrication

o Compression

o In-process checking

o Packing

o Final product analysis and release

• In some instances, powder mix is compressed into tablet without passing

through granulation process i.e. direct compression

• The unit processes in the manufacture of tablets are shown in figure 21.1

below;

Figure 21.1: Unit process in tablet manufacturing

[pic]

STEP 3: Equipment Used for Compression (35 minutes)

• After mixing the ingredients, the powder mix or the granules (after pre-

compression mixing) are compressed into tablets by using a machine called

Tablet Press

• There are two types of tablet presses;

o Single punch (single station) tablet press

▪ This is for small scale production of tablets

o Multi-station (rotary) tablet press

▪ This is for large scale production of tablets

• Tablet press

o A tablet press is a high speed machine that squeezes (compresses) the

ingredients (granules or powder mix) into required tablet shape and

size

o Tablet presses can also press the name of the manufacturer, of the

product or other markings into the top of the tablet

o A typical single punch tablet press consists of the following parts;

▪ A hopper shoe

• This is for holding and delivering powder mix or granules into

the compression chamber in the die

▪ A die

• A disc shaped piece of hardened steel with a hole cut up of

through its centre

• The hole in the die is known as a compression chamber

• The functions of the compression chamber;

• To receive materials for compression

• It is where compression takes place

• Provides shape and size to the tablets

▪ A punch (A set of two punches for each die)

• It is a rod-shaped hardened steel that fits into top or bottom

of the die

• For each die, there are two punches (a lower punch –which fits

into the bottom of the die and an upper punch –which fits into

the top of the die)

• The punches press name of the manufacturer, name of the product

or other markings into the top of the tablet during compression

• The function of the upper punch

• To compress the materials in the die chamber (by downward

movement) to form a tablet

• Functions of the lower punch

• Lower punch controls the size of the tablet

• Eject the tablet from the die chamber after it is formed

▪ Ejection regulating screw

• It controls the movement of the lower punch during ejection of

the tablet

▪ Capacity regulating screw

• Adjust lower punch movement to control volume of materials into

the die chamber

• This determines thickness of the tablet

o A typical multi-station or rotary tablet press consists of the

following sections and parts;

▪ Upper cam section

• Consists of the upper compression roller and all adjustment to

the position of upper compression rollers

• The primary components of the upper cam section are;

o Upper punch removal/dwell cam

o Upper punch lowering cam

o Upper pre-compression and main compression rollers section

depth adjustment

o Upper punch pull up-cam

o Cam material of construction

▪ Compression section

• Contains all the components that are exposed to the materials to

be compressed

• It is made up of the following parts

o Material hopper

o Feed frame

o Excess material stripper

o Tablet stripper

o Material recirculation

▪ Lower cam section

• This section is completely sealed from the compression section

• It houses the lower compression rollers, the entire lower cam

track that guide lower punch as the turret rotates

• Parts of the lower cam section includes;

o Fill cam

o Weight regulation cam

o Pre-compression and compression rail

o Ejection rail

▪ Lower mechanical section

• This section houses the main drive motor and the gearbox, the

hydraulic pump, the lubrication pump and signal wire

distribution

• Proper ventilation and cooling of the lower mechanical section

is essential to prevent machine damage and minimize heat

generation

• This section is equipped with cooling system for product that

are sensitive to heat generation e.g. contain low melting point

ingredients that are prone to picking and sticking

STEP 4: The Compression Cycle (25 minutes)

• Compression cycle is a series of events which eventually results in

formation of a tablet

• The events of a compression cycle for a single punch tablet press are;

o Opening of the die (chamber)

▪ To allow the die chamber to be filled

▪ The lower punch moves down in at this phase and upper punch stays

▪ The hopper moves in to fill the die chamber (in multi-station

press the die table moves the die chamber under the hopper)

o Filling of the die with powder mix or granules

▪ This is by gravitational flow of powder mix or granules into the

die chamber

o Compression

▪ The upper punch descents and enter the die and the materials are

compressed until a tablet is formed

▪ During compression (as the upper punch moves downward) the lower

punch remain stationary or moves upward in the die (to a pre-set

level)

▪ After maximum applied force, the upper punch leaves the

compressed mix/granules i.e. the decompression phase

o Ejection

▪ During this phase, the lower punch rises until its tip reaches

the level of the top of the die

▪ The tablet is subsequently removed from the die by the hoper as

it moves in to fill the die chamber (for multi-station presses the

tablet is removed from the die table by a pushing device)

• The working of a multi-station tablet press is based on the compression

of materials between a pair of moving punches within a stationary die

• The events of a compression cycle in a multi-station (rotary) tablet

press are;

o Die filling

o Volume control

o Compression

o Tablet ejection

STEP 5: Problems Occurring in Compression (25 minutes)

• Proper understanding of material compression characteristics and

knowledge of tablet compression equipment (the press) is essential for

efficient troubleshooting of production problem

|Activity: Small Group Discussion (10 minutes) |

| |

|DIVIDE students into small manageable groups |

| |

|ASK students to discuss on the following question |

|List common problems that occur during compression |

| |

|ALLOW students to discuss for 15 minutes |

| |

|ALLOW few groups to present and the rest to add points not mentioned |

| |

|CLARIFY and SUMMARIZE by using the contents below |

• Various tablets problems occur during production;

o Tablet weight variation

▪ Caused by various factors including poor flow, increasing machine

speed

▪ Excessive weight variation should call for examination of the

following;

▪ Condition of the lower punch pull-down cam

▪ Condition and position of excess material stripper

▪ Feeder paddle speed cam

▪ Minimum amount of material recirculation is necessary

o Low hardness

▪ May be due to capping or non-compressibility

▪ In this case the following should be done;

▪ Pre-compression and compression with large diameter roller

▪ Press speed is reduced in order to increase total compression

time

o Punch variation

o Hardness variation

o Poor flow of powder mix or granules

o Tablet jam and chipping

o Picking and sticking

▪ The following should be done to minimize picking and sticking;

▪ Heat of compression

▪ Press speed

▪ Pre-compression force

▪ Tool condition (tooling set comprises of a die and a pair of

punches)

▪ Tablet stripper

o Capping and lamination

STEP 6: Key Points (5 minutes)

• Compression is a unit process in pharmaceutical production in which

granules (obtained from granulation) or powder mix are compressed to form

tablets

• During compression, the proximity of particles surface causes bond

formation between particles which provide coherence

• Tablets may be produced by direct compression that does not involve

formation of granules

• Tablets are produce by compression by an equipment called tablet press

• For small scale production of tablets, a single punch tablet press is

used while multi-station or rotary tablet press is used for industrial

scale production of tablets

• During compression, four events take place namely die opening, die

filling, compression and ejection

• A number of problems may occur during compression and knowledge of the

characteristics of powder mix and granules as well as the knowledge of

tablet press is useful in troubleshooting these problems when they occur

STEP 7: Evaluation (5 minutes)

• What is compression?

• What is consolidation?

• What are the parts of multi-station (rotary) tablet press?

• What are the events occurring in a compression cycle?

References

Aulton M.E & Kevin M.G,( Eds): (2013) Pharmaceutics: The design and

manufacture of medicines, (4th ed.) Churchill Livingstone

Hugo and Russell (2011), Pharmaceutical Microbiology (8th ed.), Willey-

Blackwel publications

Gennaro, R. A. , et.al (Eds) (1995) Remington: The Science and Practice of

Pharmacy, Volume I & II, (19th ed.): Mack Publishing Company, Easton,

Pennsylvania 18042

Liebsch, B et al (1988): Tanzania Pharmaceutical Handbook, Dar es Salaam

University Press.

Lund, W. Editor (1994). The Pharmaceutical Codex, Principles and Practice

of Pharmaceutics (12th ed.): The Pharmaceutical Press, London

Polderman, J. (1990) Introduction to Pharmaceutical Production: Novib, The

Hague

Rawlins E.A, Editor: (1977) Bentley’s Textbook of Pharmaceutics, 8th Ed.

Baillie're Tindall. London Kamm, G. and Kohler, B. Editors: (1995)

Manual for Decentralized Infusion Production, Infusion Unit Project

Tanzania

Schmidt, O. (ed) (2000) Pharmaceutical Quality systems, Interpharm Press,

Colorado.

Shayne C et al. (2008), Pharmaceutical Manufacturing Handbook: Production

and processes, John Wiley & Sons

Watson, D. G (1999) Pharmaceutical Analysis: A Textbook for Pharmacy

Students and Pharmaceutical Chemists: Churchill Livingstone,

Edinburgh.

Session 19: Tablet Coating

Total Session Time: 120 minutes

Pre-requisites

• None

Learning Tasks

By the end of this session students are expected to be able to:

• Define tablet coating

• List reasons for tablet coating

• Explain types of tablet coating

• Explain equipment for tablet coating

Resources Needed:

• Flip charts, marker pens, and masking tape

• Black/white board and chalk/whiteboard markers

• LCD projector and computer

SESSION OVERVIEW

SESSION CONTENTS

STEP 1: Presentation of Session Title and Learning Tasks (5 minutes)

READ or ASK students to read the learning tasks and clarify

ASK students if they have any questions before continuing

STEP 2: Meaning of Tablet Coating (10 minutes)

|Activity: Brainstorming (5 minutes) |

| |

|ASK students to brainstorm on the following question: |

| |

|What is tablet coating? |

| |

|ALLOW few students to respond |

| |

|WRITE their responses on the flip chart/ board |

| |

|CLARIFY and SUMMARISE by using the content below |

• Coating is a process by which an essentially dry, outer layer of special

material is applied to the surface of a dosage form in order to confer

specific benefits over uncoated variety

• Tablet coating is the last (optional) critical step in tablet production

cycle and one of the oldest pharmaceutical processes still in existence

STEP 3: Reasons for Tablet Coating (15 minutes)

➢ Coating masks unpleasant odour, taste or colour of the drug

➢ Coating provides physical and chemical protection for the drug

➢ Coating controls the release of drug from the tablet

➢ Coating protects the drug from gastric environment of stomach in case of

acid sensitive drugs

➢ Coating help avoid chemical incompatibility

➢ Coating improves pharmaceutical elegance by using colours and

contrasting printing

STEP 4: Factors Considered in Tablet Coating (10 minutes)

• Tablet properties

o Tablet to be coated must possess the proper physical characteristics

like spherical shape and uniform surface

o Tablets to be coated must be able to tolerate attrition during coating

process i.e. tablets must be resistant to abrasion and chipping

▪ for example, tablet surfaces that are brittle and soften in

presence of heat or affected by coating composition and tend to

become rough in the early stages of coating process are

unacceptable for film coating

• Coating process

o Coating equipment

o Coating parameters

o Facility and ancillary equipment

o Automation of coating process

• Coating composition

o Polymers, colour, plasticizer and solvent

STEP 5: Types of Tablet Coating (35 minutes)

• There three types of tablet coating

o Sugar coating

o Film coating

➢ Non enteric film coating

➢ Enteric film coating

o Other types of coating include compression coating, electrostatic

coating, DIP coating, vacuum film coating, dry coating and laminated

coating

• Sugar Coating

o Sugar coating involves the application of sugar solution with colour

to the tablets for several times to give uniform and elegant film

o Tablets suitable for sugar coating are those;

➢ with deep convex surfaces with thin rounded edges

➢ resistant to breakage, chipping and abrasions (sugar coating

process is long and vigorous)

o Sugar coating involves the following steps;

➢ Sealing

➢ Sub-coating

➢ Syruping (smoothing)

➢ Finishing

➢ Polishing

o Sealing Step

▪ This step prevents penetration of moisture into the tablet core

▪ Over wetting tablets during coating causes moisture to penetrate

the tablet core and lead to softening or disintegration of the

tablet hence affecting physical and chemical stability of the

tablet

▪ Materials used for sealing tablets include shellac (more

effective but lengthens disintegration and dissolution times), zein

(alcohol soluble protein derivative), oleic acid, polyethylene

glycol and alcohol methylene chloride

o Sub-coating Step

▪ Sub coating is applied to form uniform edges and to build up the

tablet size

▪ Sub-coating increases the tablet weight from 50 to 100%

▪ Materials used for sub-coating include gelatin, sugarcane powder,

corn syrup, distilled water, gum acacia

▪ This step involves;

▪ Application of binder solution to the tablets

▪ Dusting of the sub-coating with powders and drying until the

entire tablets have covered and desired thickness is achieved

o Syruping Step

▪ Syruping is done in order to cover the imperfections in the

tablet surface caused during sub-coating step

▪ This step involves;

▪ Application of syrup coating with grossing syrups followed by the

addition of dilute colorants to provide tinted base

▪ Syrup coating constitute colorants, sub-coating powder, calcium

carbonate, cane sugar powder, corn starch, syrup and distilled

water

▪ When the tablets are quit smooth, a syrup solution containing dye

(colouring agent)e is applied until final size and colour are

achieved

▪ Finally a clear syrup coat without dye is applied to the syruped

tablets

o Polishing Step

▪ Polishing is done to obtain the desired lustre to the tablets

▪ Tablets are polished in standard coating pans by application of

carnauba wax (yellow), bees wax (white), paraffin wax or warm

solution of waxes in naphtha or suitable volatile solvents

o Advantages of sugar coating

➢ It prevents unpleasant odour

➢ Gives sweet taste to the tablet by masking any unpleasant or

bitter taste

➢ It is highly elegant and glossed

o Disadvantages of sugar coating

➢ Appreciable increase in size of the tablets

➢ Appreciable increase in weight of the tablets

➢ Tablets cannot be engraved

• Film coating

o Film coating is a process of applying a polymeric solution to tablets

in order to form a thin uniform layer (a film) around the tablet

o Materials used for film coating are classified into;

Non-enteric film formers

▪ They give uniform film with desired mechanical strength

▪ They include Hydroxy propyl methyl cellulose (HPMC), Methyl

hydroxyl ethyl cellulose (HMEC), Ethyl cellulose (EC), Hydroxy

propyl cellulose (HPC), Povidone and acrylate polymers

Enteric film formers

▪ These materials are resistant to gastric acid and they are used

for the following reasons;

▪ to protect acid-labile drugs from gastric fluid e.g. enzymes and

certain antibiotics

▪ to prevent gastric distress or nausea due to irritation from the

drug e.g. sodium salicylate

▪ to deliver drugs intended for local action in the intestines e.g.

intestinal antiseptics

▪ to deliver drugs that are optimally absorbed in the small

intestines to primary absorption site

▪ to proved a delayed-release component for repeat-action tablets

Characteristics of Ideal Enteric Coating Materials

▪ Resistance to gastric fluids

▪ Not susceptible or permeable to intestinal fluids

▪ Compatible with most coating solution components and drug

substances

▪ Stable alone or in coating solution

▪ The film should not change on aging

▪ Should form a continuous film

▪ Should be nontoxic

▪ Should be of low cost

▪ Should be easy to apply without the need of special equipment

▪ Should be readily printed and allow film to be applied to

debussed tablets

▪ Some enteric film formers include cellulose acetate phthalate

(CAP), acrylate polymers, hydroxypropyl methyl cellulose phthalate

(HPMCP), and polyvinyl acetate phthalate (PVAP)

▪ Composition of the solution for film coating

▪ Solvent

▪ For dissolving or disperse the polymers and other additives

to form a coating solution

▪ The solvent should be colourless, tasteless, odourless,

inexpensive, nontoxic, inert, non-flammable and with rapid

drying rate

▪ Examples of solvents are water, ethanol, methylene ethyl

ketone

▪ Plasticizers

▪ they are added to modify the quality of the film (making it

softer, flexible yet strong)

▪ they are of two groups, internal plasticizers and external

plasticizers

▪ level of plasticizers ranges from 1-50% by weight of the

film former

▪ examples plasticizers include castor oil, propylene glycol,

glycerine, surfactants, polysorbate (tween), sorbitan esters

(span), organic acid esters

▪ Colorants

▪ Provide distinct colour and elegance to the tablets

▪ Achieved by proper distribution of suspended colouring

agents in the coating solution

▪ The concentrate of colouring agents in the coating solution

depends on the colour shade (lighter or dark), desired type

of dye and concentration of opaquant extenders

• Colorant used are food, drugs and cosmetic (FD & C) colorants or

drug and cosmetic (D & C) colorants

• They are lakes (dyes precipitated by carriers such as alumina)

and dyes

▪ Opaquant –extenders

• They are very fine inorganic powders used in the coating

solution formulation to provide more pastel colours and increase

film coverage

• They provide white coating or mask the colour of the tablet core

• They include titanium dioxide, silicates e.g. talc, aluminium

silicate; carbonates e.g. magnesium carbonate; sulphates e.g.

calcium sulphate

o Film Defects

▪ Sticking and picking

• Attachment tablets to each other due to over wetting, rapid

drying or tackiness of tablets

• Can be solved by reduce liquid application, control rate of

drying and change of formulations

▪ Roughness

• Formation of rough or gritty surface due to increase in path

length of spray nozzle to tablet bed or rapid drying

• Remedied by decreasing path length and controlling drying rate

▪ Orange peel effect

• Inadequate of spreading coating solution which is caused by

rapid drying, high viscosity of coating solution

• Remedied by decreasing drying rate, decreasing viscosity by

adding solvent

▪ Bridging

• Shrinking or pulling away of film from corners due to over

wetting, less viscous liquids and spread ability problems

• Remedied by decreasing application rate of coating solution,

increasing viscosity and change in formulation

▪ Blistering

• Removal of film due to rapid evaporation of solvent from tablet

core due to rapid evaporation of solvent (high temperature) and

high viscosity of coating solution

• Remedied by decreasing drying temperature, diluting coating

solution

o Advantages of film coating

▪ Causes minimal increase in the size of the tablets

▪ Causes minimal increase in tablet weight

▪ Forms a very thin layer over tablets

▪ Engravings are possible on tablets surface (not possible in sugar

coating)

▪ Provides better mechanical strength to the tablets

▪ The cost is less

STEP 6: Equipment for Tablet Coating (35 minutes)

• Standard Coating Pan

o Also known as conventional pan system

o Consists of a circular metal pan mounted angularly on a stand

o The pan rotates on its horizontal axis by a motor

o Heated air is directed into the pan and on the tablet bed surface and

is exhausted by means of ducts through the front of the pan

o Coating solution is applied to the tablets by ladling or spraying the

material on to the rotating tablet bed

o Spraying system is advantageous over the ladling system

▪ It is faster and provides more even distribution of the coating

solution or suspension than ladling

▪ It reduces drying time between solution application in sugar

coating

▪ It allows continuous application of coating solution in film

coating

▪ In the standard coating pan, drying efficiency is improved by;

• Pellegrini pan

o A baffled pan that diffuses or distributes the drying air

uniformly over the tablet bed surface

• Immersion sword

o A perforated metal sword device immersed in the tablet bed

(in the pan)

o Drying air is introduced through this device and flows upward

from the sword through the tablet be

• Immersion tube system

o A tube immersed in the tablet bed to deliver heated air

o The coating solution is applied with the heated air from the

immersed tube

• Perforated Coating Pan

o Employs a perforated or partially perforated drum

o The drum rotates on its horizontal axis in an enclosed housing

o The coating solution is applied to the surface of the rotating bed of

tablets through spraying nozzles, which are present inside the drum

o Perforated pan coaters are efficient drying system with high coating

capacity

Types of perforated pan system are, Accela-cota system, Hi coater

system, Dria coater pan and the Glatt coater (which is the

largest coater)

▪ Accela-coater and Hi coater systems; -drying air is directed into

the drum, passed through the tablet bed and exhausted through

perforations in the drum

▪ Dria coater pan; -drying air enters through hollow perforated

ribs located on the inside periphery of the drum

• As the coating pan rotates, the ribs dip into the tablet bed and

drying air passes up through.

• Exhaust is from the back of the pan

▪ Glatt coater

• Drying air can be directed from inside the drum through the

tablet bed

• The air is exhausted through an exhaust duct

• Fluidized bed Coater

o In this system, fluidization of tablet mass is achieved in a columnar

chamber by an upward flow of drying air

o The air flow is controlled so that more air enters the centre of the

column causing the tablets to rise in the centre (fluidization)

o The movement of tablets is upward through the centre of the chamber,

then fall toward the chamber wall, finally moving downwards to re-

enter the air stream at the bottom of the chamber

o Coating solution is applied from a spray nozzle which is located at

the bottom of the chamber

o In other models of fluidized bed coater, the coating solution is

sprayed on the top of the cascading tablet bed by nozzles located in

the upper region of the chamber

STEP 7: Key Points (5 minutes)

• Coating is one of the important technique in manufacturing of dosage

forms

• Coating improves the stability, shelf life and release pattern of drugs

from tablets

• Coating of tablets help improve patient compliance

• Tablet coating is the last (optional) critical step in tablet production

cycle and one of the oldest pharmaceutical processes still in existence

• There three main types of tablet coating; sugar coating film coating

(Non enteric or enteric film coating)

• Equipment commonly used for coating include standard coating pan,

perforated coating pan and fluidized bed coater

STEP 8: Evaluation (5 minutes)

• What is tablet coating?

• What is sugar coating?

• What is the difference between film coating and sugar coating?

References

Aulton M.E & Kevin M.G, Eds: (2013) Pharmaceutics: The design and

manufacture of medicines, (4th ed.) Churchill Livingstone

Hugo and Russell (2011), Pharmaceutical Microbiology (8th ed.), Willey-

Blackwel publications

Gennaro, R. A, et al. (Eds) (1995) Remington: The Science and Practice of

Pharmacy, Volume I & II, (19th ed.): Mack Publishing Company, Easton,

Pennsylvania 18042

Liebsch, B et al. (1988): Tanzania Pharmaceutical Handbook, Dar es Salaam

University Press.

Lund, W. Editor (1994). The Pharmaceutical Codex, Principles and Practice

of Pharmaceutics (12th ed.): The Pharmaceutical Press, London

Polderman, J. (1990) Introduction to Pharmaceutical Production: Novib, The

Hague

Rawlins E.A, Editor: (1977) Bentley’s Textbook of Pharmaceutics, (8th ed.)

Baillie're Tindall. London Kamm, G. and Kohler, B. Editors: (1995)

Manual for Decentralized Infusion Production, Infusion Unit Project

Tanzania

Schmidt, O. (Eds) (2000) Pharmaceutical Quality systems, Interpharm Press,

Colorado.

Shayne C et al. (2008), Pharmaceutical Manufacturing Handbook: Production

and processes, John Wiley & Sons

Watson, D. G (1999) Pharmaceutical Analysis: A Textbook for Pharmacy

Students and Pharmaceutical Chemists: Churchill Livingstone,

Edinburgh.

Session 20: Packaging of Tablets and Capsules

Total Session Time: 120 minutes

Pre-requisites

• None

Learning Tasks

By the end of this session students are expected to be able to:

• Define packaging

• List Materials used in Tablet of Packaging

• Explain Types of Packaging Materials for Tablets and Capsules

• Describe Procedures for Packaging of Tablets and Capsules

Resources Needed:

• Flip charts, marker pens, and masking tape

• Black/white board and chalk/whiteboard markers

• LCD projector and computer

SESSION OVERVIEW

SESSION CONTENTS

STEP 1: Presentation of Session Title and Learning Tasks (5 minutes)

READ or ASK students to read the learning tasks and clarify

ASK students if they have any questions before continuing

STEP 2: Introduction to Packaging Materials (25 minutes)

• Packaging is the science, art and technology of enclosing or protecting

a product and providing information about the product for distribution,

storage, sale and use

• Pharmaceutical packaging is defined as the economical means of providing

presentation, protection, identification, information, convenience,

compliance, integrity and stability of the product

• Packaging for pharmaceutical uses may be glass (type I, type II, type III

and type IV), plastic (thermosetting type, thermoplastic type), rubber,

paper/cardboards or metals (aluminium, tin plated steel, stainless steel,

tin and lead)

• Importance of Packaging

o Provision of physical protection to products

o Facilitates use of the product by patient

o Provide dose control

o Identifies the product

o Helps in transmission of information (lebelling)

o Provides integrity of the product

o Provide security to the product

o Packaging promotes the product

▪ Packaging is a bridge between production and marketing

STEP 3: Characteristics of Packaging Materials (25 minutes)

|Activity: Brainstorming (5 minutes) |

| |

|ASK students to brainstorm on the following question: |

| |

|Mention the characteristics of packaging materials? |

| |

|ALLOW few students to respond |

| |

|WRITE their responses on the flip chart/ board |

| |

|CLARIFY and SUMMARISE by using the content below |

• They should protect the product from environmental condition

• Should be nonreactive with the product

• Should not impart taste or odour to the product

• Should be nontoxic

• Should be adoptable to commonly high speed packaging equipment

• Should meet applicable tamper resistance requirements

Requirements of a pharmaceutical packaging are;

o Should allow easy of dispensing

o Should be child resistant but senior friendly

o Should be hemetically sealed

o Modularized machinery

STEP 4: Types of Packaging (40 minutes)

• Packaging materials are grouped into three general classes; primary,

secondary and tertiary packaging materials

• Primary Packaging

o Primary packaging is the material that envelops the product and holds

▪ Primary packaging are in direct contact with the product

▪ Provides the smallest unit of distribution or use

▪ Examples of primary packaging include aerosol spray can, blister

pack and bottles

o Blister Packaging

▪ It is a primary packaging materials used for small consumer goods

▪ Blister packs are commonly used for unit dose packaging for

tablets and capsules

▪ The principal components of pharmaceutical blister packages;

• The forming film (blister)

o It is a pocket inside which the product fits

o This pocket or cavity in the forming film is used to receive

the tablet or the capsule

o Forming film accounts for approximately 80-85% of the blister

pack

o Receives the product in deep drawn pockets

o Backing or Lidding material

▪ It is sticked over the back of the blister and makes up 15-20%

of the package

▪ Provides the base or main structural component upon which the

final blister package is built

▪ The lidding material is sealed onto the support material

• After the tablets have been properly fed to the preformed

support materials, the lidding material is sealed onto the

support material

• Temperature for sealing ranges from 140C to 300 C

▪ Materials used for backing/lidding are;

• Paper

• Paper-aluminium combination

• Aluminium foil

▪ The backing or lidding material can be push-through type,

peelable type (used to provide child resistant packing), pee-push,

tear-open and child resistant options

• Formation of a blister pack

o Thermosoftening

▪ Involves heat softening a sheet of thermoplastic resin and then

vacuum drawing the softened sheet of plastic onto a mould

▪ After cooling the sheet is released from the mould

o Filling

▪ The sheet then proceeds to the filling station for filling

o Sealing

▪ Sealing is then accomplished by lidding it with a heat sealable

backing material

o Advantages of blister packaging;

➢ Ensures product integrity

➢ Ensures product protection

➢ Provides tamper evident packaging

➢ Reduces the possibility of accidental misuse

➢ Enhances patient compliance

o Strip Package

▪ A strip package is formed by feeding two webs of a heat sealable

flexible film through a heated crimping rollers

▪ Strip packaging is used for capsules and tablets

▪ Materials used include;

• Foil laminations (for moisture sensitive products)

• Paper

• Polyethylene

• Cellophane (transparent plastic film formed from processed

cellulose)

▪ Steps involved in the formation of a strip package;

▪ The product is fed into the pocket formed between two heat

sealable flexible films

▪ Sealing is accomplished by heat crimping rollers

▪ The strip is then cut into desired number of packets in

length

o Alu-alu Packaging

▪ Alu-alu packaging means aluminium is used both at the upper and

lower side of the pack

▪ Alu-alu packaging is similar to that of blister packing

▪ But differ from blister packaging in that the forming film is

formed from aluminium foil instead of a plastic material

o Bottle Packaging

▪ Bottles are commonly used for liquid pharmaceuticals as well as

for tablets and capsules

▪ Bottle packaging involves packaging of pharmaceuticals in glass

or plastic bottles

▪ Materials used include;

For the bottle

• Polyethylene

• Polypropylene screw-cap

• Polystyrene

▪ For the mouth seal-Aluminium foil

• Secondary Packaging

o Secondary packaging are used around the primary packaging –are used to

group primary packages together

o Examples of secondary packaging include boxes, cartons

o Primary packaging is not in direct contact with the product

o Secondary packaging include;

➢ Labels and leaflets

➢ Wrapping materials

➢ Bags and sacks

➢ Collapsible and rigid cartons and boxes

➢ Moulded pulpboard containers

➢ Paper liners, linings and laminations

➢ Paper

Used as a flexible wrapper for products or as a closure material

for jars

Most are used with a liner applied either as a laminate or as a

coating

• Tertiary Packaging

o They are used for bulk handling, warehouse storage and transport

o Examples of tertiary packaging include barrel, container, edge

protector

STEP 5: Selection of Packaging Materials (15 minutes)

|Activity: Brainstorming (5 minutes) |

| |

|Ask students to brainstorm on the following question: |

| |

|What are the factors to consider when selection a packaging materials |

|for tablets and capsules? |

| |

|ALLOW few students to respond |

| |

|WRITE their responses on the flip chart/ board |

| |

|CLARIFY and SUMMARISE by using the content below |

• Choice of packaging materials depends on;

➢ The degree of protection required

➢ Compatibility with the dosage form

➢ Customer convenience e.g. size, weight of dosage form

➢ Filling method

➢ Sterilization method to be employed

➢ Cost

STEP 9: Key Points (5 minutes)

• Pharmaceutical packaging is defined as the economical means of providing

presentation, protection, identification, information, convenience,

compliance, integrity and stability of the product

• Requirements of a pharmaceutical packaging include easy of dispensing,

child resistant but senior friendly and hemetically sealed

• Packaging materials are grouped into three general classes; primary,

secondary and tertiary packaging materials

• Primary packaging include blister packaging, strip packaging, alu-alu

packaging and bottle packaging

• Secondary packaging does not directly contact the product e.g. boxes

STEP 10: Evaluation (5 minutes)

• What is packaging?

• What is the importance of packaging?

• List the types of packaging for tablets and capsules

References

Aulton M.E & Kevin M.G, (Eds): (2013) Pharmaceutics: The design and

manufacture of medicines, (4th ed.) Churchill Livingstone

Hugo and Russell (2011), Pharmaceutical Microbiology (8th ed.), Willey-

Blackwel publications

Gennaro, R. A, et.al (Eds) (1995) Remington: The Science and Practice of

Pharmacy, Volume I & II, (19th ed.): Mack Publishing Company, Easton,

Pennsylvania 18042

Liebsch, B et al. (1988): Tanzania Pharmaceutical Handbook, Dar es Salaam

University Press.

Lund, W. Editor (1994). The Pharmaceutical Codex, Principles and Practice

of Pharmaceutics (12th ed.): The Pharmaceutical Press, London

Polderman, J., (1990) Introduction to Pharmaceutical Production: Novib, The

Hague

Rawlins E.A, Editor: (1977) Bentley’s Textbook of Pharmaceutics, (8th ed.)

Baillie're Tindall. London Kamm, G. and Kohler, B. Editors: (1995)

Manual for Decentralized Infusion Production, Infusion Unit Project

Tanzania

Schmidt, O. (ed) (2000) Pharmaceutical Quality systems, Interpharm Press,

Colorado.

Shayne C., et al. (2008), Pharmaceutical Manufacturing Handbook: Production

and processes, John Wiley & Sons

Watson, D. G (1999) Pharmaceutical Analysis: A Textbook for Pharmacy

Students and Pharmaceutical Chemists: Churchill Livingstone,

Edinburgh.

Session 21: Quality Assurance and Quality Control

Total Session Time: 120 minutes

Pre-requisites

• None

Learning Tasks

By the end of this session students are expected to be able to:

• Explain quality assurance in pharmaceutical manufacturing

• Explain quality control in pharmaceutical manufacturing

• Differentiate between quality assurance and quality control

• Explain quality variations in pharmaceutical manufacturing

• Define documentation in pharmaceutical manufacturing

• List documents required for pharmaceutical manufacturing

• Explain the importance of documentation in pharmaceutical manufacturing

Resources Needed:

• Flip charts, marker pens, and masking tape

• Black/white board and chalk/whiteboard markers

• LCD projector and computer

• Handout 21.1: Raw Material Quality Assurance Monograph

SESSION OVERVIEW

SESSION CONTENTS

STEP 1: Presentation of Session Title and Learning Tasks (5 minutes)

READ or ASK students to read the learning tasks and clarify

ASK students if they have any questions before continuing

STEP 2: Quality Assurance in Pharmaceutical Production (20 minutes)

• Quality is the totality of features and characteristics of a medicinal

product and its ability to satisfy stated and/ or implied needs

o Quality begins with research and development

o Quality is designed and built in the product

• Quality assurance (QA) is a wide ranging concept covering all matters

that individually or collectively influence the quality of a product

• QA is a totality of the arrangements to ensure that the drug is

continuously of the right quality for the intended use

• Quality assurance is a part of quality management focused on providing

confidence that quality requirements will be fulfilled

• Quality Assurance incorporates GMP (which incorporates QC) and also

includes product design and development with special focus on process

design

o GMP is a part of QA which ensures that products are consistently

produced and controlled to the quality standards appropriate to their

intended use

o Quality relationships in a pharmaceutical industry is;

Quality Management

Quality Assurance

Good Manufacturing Practice (GMP)

Quality Control

• Elements of Quality Assurance circle in Pharmaceutical Manufacturing;

o Research

o Development

o Prototyping

o Documentation

o Raw materials

o Facilities (buildings)

o Equipment

o Personnel and supervision

o Monitoring, feedback, follow-up

• Features of a good QA system;

o It is a process, not an end point

o It must be independent of financial pressures

o Must ensure that quality policies are followed

o Must have final authority in product acceptance, rejection and release

to public

o Must be an integral part in production

o Must be responsible for day-to-day operations and for longer term goal

settings

• Responsibilities of QA include the following;

o QA department is responsible for ensuring that the quality policies

adopted by the company are followed

o Helps to identify and prepare the necessary SOPs relative to the

control of quality

▪ Ensures that SOPs are prepared, approved, used and updated

o It must determine that the products meet all the applicable

specifications and that it was manufactured according to the internal

standards of GMP

o QA is responsible for quality monitoring or audit function

o QA functions to assess operations continually and to advise and guide

them towards full compliance with all applicable internal and external

regulations

o Ensures that proper documentation is followed

▪ Documents are systematic and well kept

▪ Quality manuals are made and staff trained and motivated to

comply

• Primary functions of QA

o Quality control (analytical testing of products)

o Raw materials control (sampling, inspecting and testing of incoming

raw materials)

o Packaging and labelling components (bottles, foils, labels, measures,

cartons)

o Physical inspection of product and operations at critical intermediate

stages

▪ In-process quality control

▪ Batch review

▪ Batch release

o Management of internal audit system

o Handle customers’ feedback and satisfaction

o Management of deviations, incidents and investigations

o Management of GMP training system

o Management of validation system

STEP 3: Quality Control in Pharmaceutical Production (15 minutes)

• Quality control (QC) is a component of GMP concerned with sampling,

specification and testing, documentation and release procedures which

ensure that the necessary and relevant tests are performed and the

product is released for use only after ascertaining its quality

• QC is a part of quality management focused on fulfilling quality

requirements

• Responsibilities of QC

o QC department is responsible for day-to-day control of quality within

the company

o QC plays major role in selection of qualified vendors from whom raw

materials are purchased

▪ Tests representative samples as required

▪ Audit vendor’s operations to determine suitability of the vendor

and degree of compliance with GMPs prior to being approved

o QC is responsible for analytical testing of incoming raw materials

(e.g. assay, titrations etc)

o QC is responsible for analytical testing and inspection of packaging

components, including labelling (e.g. appearance, spectroscopy, loss

on drying etc)

o QC is responsible for conducting in-process testing when required,

perform environmental monitoring, and inspect operations for

compliance

o QC is responsible for conducting required tests on finished products

or dosage forms (e.g. assay, dissolution, content uniformity etc)

o Environmental areas for manufacturing of various dosage forms are

tested and inspected by QC department

o Generally QC is responsible for efficacy, safety, quality and

compliance in pharmaceutical manufacturing

• Objectives of quality control

o To establish quality standards

o To locate quality deviation

o To evaluate methods and processes

o Quick sale of quality products

o Production of standard quality products

o Improvement of quality

• Steps in Quality Control

➢ Devising the control over raw materials

➢ Fixing standards and specifications

➢ Exercising control over production operation

➢ Locating inspection point

➢ Maintaining quality of equipment

➢ Maintaining records

• Advantages of quality control

o Improves quality of production and reduction in product cost

o Uniformity in the production and supply of standard quality to

consumers

o Offering full return of the price paid the consumers and giving

convenience and satisfaction to customers

o Reduction in spoiled production and rejection from consumers and

dealers

o Promotion of exports due to superior and standard quality production

o Reduction in inspection cost

o Making products popular in markets

STEP 4: Difference between QA and QC (10 minutes)

• The differences between Quality Assurance and Quality Control are

summarised in the table bellow

|Quality Assurance (QA) |Quality Control (QC) |

|A set of activities for ensuring|A set of activities for ensuring |

|quality in the process by which |quality in the products. |

|products are developed | |

|It is a managerial tool |It is a corrective tool |

|Aims to prevent defects (a |Aims to identify defects in |

|proactive process) |finished products (a reactive |

| |process) |

|The goal is to improve |The goal is to identify defects |

|development and test processes |after product is developed and |

|so that defects do not arise |before it is released for use |

|when product is being developed | |

|Prevents quality problems |Activities or techniques are used|

|through planned and systematic |to achieve and maintain product |

|activities including |quality, process and services |

|documentation | |

|Establishes quality management |Finds and eliminates sources of |

|system |quality problems to meet |

| |customers’ requirements |

|It is the responsibility of |It is the responsibility of a |

|everyone in the team involved in|specific team that tests the |

|production of the product |product for defects |

|Verification is an example of QA|Validation is an example of QC |

STEP 5: Quality Variation in Pharmaceutical Production (30 minutes)

• Quality variations occur due to mistake or alterations occurring in the

whole process i.e. from reception of raw materials to the final product

in its package

• General sources of product quality variation during manufacturing are;

o Raw materials

▪ Variations among supplier of the same raw material

▪ Variation among batches from the same supplier

▪ Variation within a batch

o Methods

▪ Wrong procedure

▪ Inadequate procedure

▪ Negligence in procedure

o Machines

▪ Variation of equipment for same process

▪ Differences in adjustment of equipment

▪ Aging of machine and improper care

o Personnel

▪ Improper working conditions

▪ Inadequate training

▪ Lack of interest and emotional upheavals

▪ Dishonesty, fatigue and carelessness

• Control of Quality Variation

o Raw materials control

o Raw materials for pharmaceutical production are classified into two

broad groups;

▪ Active or therapeutic raw materials (Active Pharmaceutical

Ingredients)

▪ Inactive or inert raw materials (excipients)

o To control quality variation contributed by raw materials;

▪ Starts before and just after reception of raw materials

▪ Raw materials (active substances, excipients, packaging

materials, printed labelling materials) are received from suppliers

▪ Therefore, there are should be a adequate established system for

the receipt, testing and storage of all raw materials i.e. a good

raw material specifications must be written in precise terminology,

complete and provide specific details of test methods, type of

instruments and manner of sampling

▪ After physical inspection (for active constituents and

excipients: proper container, labels, lot number, expiry date etc;

for packaging materials: colour of label, weight of label, carton,

damage etc) received materials are kept (properly arranged) in a

definite area

▪ Each raw material must be sampled according to standard sampling

procedures and sent to the quality control laboratory for testing

according to written procedures

▪ QA personnel should keep preservation samples of active raw

material to perform all required tests for the raw material (these

preservation samples are kept for at least 7 years or as otherwise

specified)

▪ If raw material passes quality test it is labelled “Passed” and

is accepted and moved to the release storage area

▪ Accepted raw materials should be rotated such that oldest stock

is used first

▪ If a raw material is substandard it is kept in “rejected Area”

and sent back to the supplier

[pic][pic] Refer students to Handout 21.1: Raw Material Quality

Assurance Monograph for further reading

o Control of manufacturing practices

▪ Important issues to control are

Personnel control

▪ Only properly trained persons should work in the industry

▪ There are should be proper selection and training in all

departments i.e. production, packing, labelling etc.

▪ Continuing education should there e.g. seminars, workshops

▪ All personnel should be properly checked and all processes

monitored by highly trained and experienced persons

▪ There are should be a friendly system of reporting errors or

mistakes so that to avoid serious loss or compromise in quality

Equipment and building control

▪ They should be of suitable design, size, construction and

location

▪ Surfaces of equipment should be non-reactive, non-absorptive, and

non-additive

▪ Equipment should be constructed and fitted in such a way that it

is easy to replace, easy to clean, and easy to operate and empty

▪ Buildings should not allow cross contamination e.g. table and

liquid sections should be separated completely

Control of records

▪ All records must maintained (e.g. Master Formula Record, Batch

production record)

▪ All records must be signed by a competent and responsible person

▪ Must be checked by another competent person and countersigned

▪ Records must be in clear language to avoid misinterpretation

Production procedure control

▪ Manufacturing processes are operated as stipulated in established

rules from reception of raw materials up to delivery of final

product

▪ A master formula of a batch (a complete list of ingredients with

their quantities) is delivered to the production department

▪ It contains all the information of that batch i.e. procedures

and equipment to used and precautions to be taken etc

▪ This formula is taken to the store and all materials for the

batch are weighed/measured and delivered to in-process quality

control laboratory (under the quality control department)

▪ Both quality control and production departments are

responsible for the production procedure control

Packaging control

▪ Control of packaging is completed before manufacturing of a

product

▪ When the product reaches the packaging section, it should be

packed in recommended containers and not otherwise

▪ There are should never be any mistakes in case of labelling and

writing of batch numbers etc

▪ Packaging materials should be used according to the nature and

distribution of the product

Distribution control

▪ Samples of each released batch are kept in records (for future

reference)

▪ Samples kept in records are selected during packaging and are in

the same packs as they are marketed

▪ These samples are kept for years in order to examine or test the

materials for any purpose or necessary demand

STEP 6: Documentation in Pharmaceutical Production (30 minutes)

• Documentation means any written statements or proof of any activity in

pharmaceutical manufacturing

• Purpose of documentation

o Defines specifications and procedures for all materials and methods of

manufacture and control

o Ensures all personnel know what to do and when to do it

o Ensures that authorized persons have all information necessary for

release of products

o Ensures documented evidence, traceability, provide records and audit

trail for investigation

o Ensures availability of data for validation, review and statistical

analysis

• Due to the importance given to documentation in pharmaceutical

manufacturing, Good Documentation Practice (GDP) is required

• GDP is a systematic procedure of preparing, checking, verifying, issuing,

storing and retrieval and review of any document

• GDP is an essential part of QA

• Importance of GDP

o Facilitates compliance with GMP and regulatory authorities

o Define manufacturers’ system of information and control

o Minimize risks of misinterpretation and errors caused by oral or

casually written communications

o Provide unambiguous procedures to be followed to provide confirmation

of performance

o Allow calculations to be checked and approved

o Allow tracing of batch history

o Ensure quality of product

• Attributes of good documentation are accurate, clear, complete,

consistent, indelible(isiyofutika), legible(readable), timely, direct,

authentic(real,original) and authorized

• Documents required in pharmaceutical manufacturing include;

o Site Master File (SMF)

▪ This is a document that provides all information of a

pharmaceutical industry (plant)

• Contents of the SMF are;

• General information

• Information related to the organization, manufacturing

activities, name and address, type of products, description of

employees, external technical support and daily management

system

• Personnel and organization chart

• Qualification, experience and responsibilities of key personnel,

training, health requirements and personnel hygiene clothing

• Premises and equipment

• Description of manufacturing area, nature of construction and

finish, brief description of ventilation, special areas, water

system, maintenance of premises, major production and laboratory

equipments, maintenances of equipments, calibrations and

sanitizations

▪ Documents-Preparations, revision and distribution of

documents

▪ Production-Brief description of production operations,

handling of materials, handling of rejected materials and

products, brief description of general policy of process

validation

▪ Quality management system -Quality Assurance (QA), Quality

Control (QC)

▪ Inspection -Self inspection and self inspection programme

▪ Change control-A document for review, approval and

implementation of any change in validated system, equipment,

process and materials

▪ Protocols-Written plan stating how validation is conducted

and defining acceptance criteria

o Specifications

▪ Describes the requirements with which products or materials used

or obtained during manufacture have to conform

▪ They serve as a basis for quality evaluation

▪ Some specifications include;

• Specifications for raw materials (active substances and

excipients)

• Specifications for primary printed and packing materials

• Specifications for intermediate and semi finished product

• Specifications for finished products

o SOPs

▪ For all processes and operations

▪ Guided by the mother SOP

o Test Methods

▪ Describes the detailed test procedures

o Lists

▪ Contain catalogues of any object such as list of equipments

o Certificates of analysis

▪ An authentic document showing the analytical reports and decision

of acceptance or rejection of products

o Labels

▪ For finished products

o Organograms

▪ Showing administration of the company/organization

o Job description

▪ For each personnel

o Master Formula Record (MFR)

▪ It is defined as a document or a set of documents specifying the

starting materials with their quantities and packaging materials,

together with a description of the procedures and precautions

required to produce a specific quantity of a finished product as

well as the processing instructions including the in-process

controls.

▪ It is a master document for any pharmaceutical product

▪ It is also known as Master Manufacturing Record or Master

Production Record

▪ It is prepared by the research and development team of company

▪ It contains all the information about the manufacturing process

for the product

▪ It is used as a reference standard for preparing Batch

Manufacturing Record (BMR) or Batch Production Record (BPR) by

manufacturing units

▪ A Master Formula is required for each product and batch size to

be manufactured (It ensures consistency in production of each

batch)

Contents of MFR

▪ Product details

• Name, logo and address of the manufacturing company

• Name of product (brand name, generic name), dosage form and

strength

• Product code

• Label claim of all ingredients including excipients

• Product description

• Batch size

• Pack size and packing style

• Shelf life

• Storage conditions

• MFR number and date

• Supersede MFR number and date

• Effective batch number

• Authorization by the production and quality assurance head

▪ Flow chart

• Steps of the manufacturing process to be monitored

• Flow chart of the material movement from dispensing to the final

product stores

▪ Equipment

• A all required equipment and machines required in the

manufacturing process with their capacity

▪ Special instructions

• Precautions, special instructions to follow during manufacturing

process and packing (also included in the BMR)

▪ Calculations

• Calculations steps of all active materials to get 100% of the

active material

• The calculations are done using water or LOD to get 100% potency

▪ Manufacturing process

• All steps in all stages of manufacturing process

• All processes like sifting, milling, lubricating, granulation,

compression and coating should be written in detail including

the process time and yield

• Should also include atmospheric conditions such as temperature,

humidity and storage conditions for every step

▪ Packing process

• A list of all packing materials with their quantities (closures,

containers, labels, packaging)

• Line clearance, reconciliation of printed and unprinted packing

materials should be included in the details

▪ Yield

• Theoretical yield, actual yield and acceptance limit of the

batch

o Batch Production Record (BPR)

▪ It is also known as Batch Manufacturing Record (BMR)

▪ It must be prepared, maintained and controlled for each batch of

a product

▪ Batch production record should have the following information

• Name of product

• Generic name, strength, shelf-life, manufacturing date and

expiry date, batch number, code number)

• A complete list of ingredients

• Full description, codes and quantities issued

• Statement of processing location and equipment

• Method or reference to method used for preparing critical

equipment

• Cleaning, assembling, calibration and sterilizing

• Dates and time of all activities

• Line clearance procedure in every step

• Labelling control and specimen for coding in primary, secondary

and tertiary packing materials

• Deviation records

• Statement of control instructions, sampling and testing

procedure, specifications and precautions followed

• Results of tests performed

• A statement of theoretical yield and reconciliation

• Preparation, issues and uses of documents

o All documents should be carefully and logically specified to prevent

wrong uses

o Information must be clear and easy to understand

o Each document should include;

▪ Company name (and logo)

▪ Purpose and title

▪ Identification number and revision number

▪ Date of authorization

▪ Date of review

▪ Signature of prepared by, checked by and authorized by

▪ Distribution list

▪ Page number

▪ Reason for revision

▪ Abbreviations and references

STEP 7: Key Points (5 minutes)

• ..Quality assurance (QA) is a wide ranging concept covering all matters

that individually or collectively influence the quality of a product. It

is a totality of the arrangements to ensure that the drug is continuously

of the right quality for the intended use

• Quality Assurance incorporates GMP (which incorporates QC) and also

includes product design and development with special focus on process

design

• Quality control (QC) is a component of GMP concerned with sampling,

specification and testing, documentation and release procedures which

ensure that the necessary and relevant tests are performed and the

product is released for use only after ascertaining its quality

• QC is a part of quality management focused on fulfilling quality

requirements

• Quality variations occur due to mistake or alterations occurring in the

whole process i.e. from reception of raw materials to the final product

in its package

• Documentation means any written statements or proof of any activity in

pharmaceutical manufacturing

• Due to the importance given to documentation in pharmaceutical

manufacturing, Good Documentation Practice (GDP) is required

• GDP is a systematic procedure of preparing, checking, verifying, issuing,

storing and retrieval and review of any document

STEP 8: Evaluation (5 minutes)

• What is quality assurance?

• How does quality assurance differ from quality control?

• List documents commonly used in pharmaceutical production

• What is Good Documentation Practice?

• What is Master Formula Record?

• What is Site Master File?

• What is Batch Manufacturing Record?

References

Aulton M.E & Kevin M.G, (Eds): (2013) Pharmaceutics: The design and

manufacture of medicines, (4th ed.) Churchill Livingstone

Hugo and Russell (2011), Pharmaceutical Microbiology (8th ed.), Willey-

Blackwel publications

Gennaro, R. A, et al. (Eds) (1995) Remington: The Science and Practice of

Pharmacy, Volume I & II, (19th ed.): Mack Publishing Company, Easton,

Pennsylvania 18042

Liebsch, B et al (1988): Tanzania Pharmaceutical Handbook, Dar es Salaam

University Press.

Lund, W. Editor (1994). The Pharmaceutical Codex, Principles and Practice

of Pharmaceutics (12th ed.): The Pharmaceutical Press, London

Polderman, J., (1990) Introduction to Pharmaceutical Production: Novib, The

Hague

Rawlins E.A, Editor: (1977) Bentley’s Textbook of Pharmaceutics, 8th Ed.

Baillie're Tindall. London Kamm, G. and Kohler, B. Editors: (1995)

Manual for Decentralized Infusion Production, Infusion Unit Project

Tanzania

Schmidt, O. (ed) (2000) Pharmaceutical Quality systems, Interpharm Press,

Colorado.

Shayne C et al (2008), Pharmaceutical Manufacturing Handbook: Production

and processes, John Wiley & Sons

Watson, D. G., (1999) Pharmaceutical Analysis: A Textbook for Pharmacy

Students and Pharmaceutical Chemists: Churchill Livingstone,

Edinburgh.

|[pic] |Handout 21.1: Raw Material Quality Assurance Monograph |

• Raw Material Name

1. Structural formula, Molecular weight

2. Chemical name(s)

3. Item number

4. Date of issue

5. Date of superseded, if any, or new material

6. Signature of writer

7. Signature of approval

• Samples

1. Safety requirement

2. Sample plan and procedure

3. Sample size and sample container to be used

4. Preservation sample required

• Retest programme

1. Retesting schedule

2. Re-analysis to be performed to ensure identity, strength, quality

and purity

• Specifications (wherever applicable)

1. Description

2. Solubility

3. Identity

a. Specific chemical test such as related alkaloids, organic

nitrogen basis, acid moiety or inorganic salts tests (sulphate,

chloride, phosphate, sodium and potassium tests or other spot

organic and inorganic chemical test as needed

b. Infrared absorption

c. Ultraviolet absorption

d. Melting range

e. Congealing point

f. Boling point or range

g. Thin-layer, paper, liquid or gas chromatography

4. Purity and Quality

a. General completeness of solutions (pH, specific rotation, non-

volatile residue, ash, acid insoluble ash, residual on ignition,

loss on drying, water content, heavy metals (arsenic, lead,

mercury), sulphate, chloride, carbonate, acid value, iodine

value, saponification value)

b. Special quality tests (particle size, crystallinity

characteristics and polymorphic forms)

c. Special purity tests (ferric in ferrous salt, peroxide and

aldehydes in ether and related degradation products

5. Assay, calculated either on non-hydrous or hydrous basis

6. Microbial limits (especially for raw materials from natural

sources)

• Test procedures

1. Compendia tests (USP, BP or NF references

2. Non compendia tests (detailed analytical procedure, weights,

dilutions, extractions, normality, reagents, instrumentation used

and procedure if any, calculations)

• Approved Suppliers

1. List of prime suppliers and other approved alternative suppliers,

if any

Session 22: In-process Quality Control (IPQC)

Total Session Time: 120 minutes

Pre-requisites

• None

Learning Tasks

By the end of this session students are expected to be able to:

• Explain the concept of in-process quality control

• List tests and equipment/apparatus used for in-process quality control of

tablets and capsules

• Explain the consequences of in-process quality control of tablets and

capsules

• List the objectives of in-process quality control

Resources Needed:

• Flip charts, marker pens, and masking tape

• Black/white board and chalk/whiteboard markers

• LCD projector and computer

SESSION OVERVIEW

SESSION CONTENTS

STEP 1: Presentation of Session Title and Learning Tasks (5 minutes)

READ or ASK students to read the learning tasks and clarify

ASK students if they have any questions before continuing

STEP 2: The Concept of In-process Quality Control (25 minutes)

|Activity: Buzzing (5 minutes) |

| |

|ASK students to pair up and buzz on the following question for 2 |

|minutes |

| |

|What is in-process quality control? |

| |

|ALLOW few pairs to respond and let other pairs to add on points not |

|mentioned |

| |

|WRITE their response on the flip chart/board |

| |

|CLARIFY and SUMMARIZE by using the content below |

• In-process quality control is a type of quality control that provides

accurate specific and definite description of procedure to be employed

from the receipt of raw material to the release of the finished product

• In-process quality control performs checks during production in order to

monitor and, if necessary, to adjust the process to ensure that the

product conforms to its specifications

• In-process quality controls are usually performed within the production

area. The performance of such in-process controls should not have any

negative effect on the quality of the product or another product

• Generally, the in-process control procedures are usually rapid and simple

tests or inspections that are performed when the manufacturing of a

product batch is in progress

STEP 3: Objectives of In-process Quality Control (20 minutes)

• Some of the objectives of in-process quality control are;

o To minimize human errors

o To provide accurate, specific and definite description of the

procedure to be employed in manufacturing of a product

o To detect errors if and when they occur

o To pin point responsibility to the personnel involved in the operation

of the entire process

o To ensure that the flow of manufacturing and packing operations

according to established routes and practice is rigidly followed

o To detect abnormality immediately and at the same time indicate action

needed to correct the problem

STEP 4: In-process Quality Control Tests in the Manufacture of Tablets and

Capsules (55 minutes)

• Evaluation of dosage forms (tablets);

o General appearance

▪ Size, shape and texture

▪ Unique identification markings (embossing, engraving or printing)

▪ Organoleptic properties (e.g. colour distribution, taste, odour)

o Content uniformity test

▪ 30 tablets are kept aside (sampled), 10 tablets are assayed, 9

tablets should have percentage limit of 85-115%

▪ If more than 1 tablet has 85-115%, then, 20 tablets are assayed

and not more than 1 tablet should have 75-125%

o Tablet hardness test or tablet crushing strength

▪ Hardness of a tablet is the force required to break a tablet in a

diametric compression test

▪ Hardness testing is a laboratory technique used to test the

breaking point and structural integrity of tablet under conditions

of storage, transportation, and handling before usage (breaking

point of a tablet is based on its shape)

▪ Tablet hardness is tested by using Tablet Hardness Tester e.g.

Monstanto hardness tester, Stokes harness tester, Erweka tester,

Schleuniger or heberlein tester, Strong Cobb tester and Pfizer

hardness tester

▪ Conventional tablet hardness: 2.5 – 5 kg/cm2

▪ Dispersible/chewable tablet hardness: 2.25 -2.5 kg/cm2

▪ Extended release tablets hardness: 5-7.5 kg/cm2

o Friability

▪ Friability is the tendency of tablets to powder chip or fragment.

This affects the elegant appearance of tablets and consumer

acceptance of the tablets

▪ Friability leads to variation in the weight and content of

tablets

▪ Friability is related to hardness of a tablet

▪ Instrument used for friability testing is known as Friabilator

(e.g. Roche friabilator)

▪ Consisting of a plastic chamber that revolves at 25 rpm dropping

the tablets through a distance of 6 inches in the friabilator,

which is then operated for 100 revolutions

▪ From the friabilator, the tablets are reweighed

▪ Loss in weight is determined

▪ Allowable range is 0.5 – 1.0%

o Weight variation

▪ 20 tablets are taken (sampled) and weighed individually

▪ Average weight of the 20 tablets is determined

▪ Weight of individual tablet is compared to the average weight

▪ Not more than 2 of the individual tablet weights deviate from the

average weight by more than the prescribed percentage deviation and

none deviates by more than twice that percentage (e.g. USP limits,

I. P limits)

o Disintegration test

▪ For most tablets, the first important step towards formation of

solution is break down of the tablet into smaller particles or

granules i.e. disintegration

▪ Disintegration test is performed by use of the disintegration

apparatus

▪ The disintegration apparatus is comprised of glasses and a mesh

screen at the bottom and operates at a temperature of 35℃ to 39℃

and speed of 28-32 rpm

▪ Tablets are sampled and placed in the glass and the apparatus is

run for specified period of time

▪ Tablets pass the test if they disintegrate and all particles

past through the screen in the time specified

▪ For uncoated tablets, disintegration time should be 15 minutes

▪ For coated tablets, disintegration time should be 30-60 minutes

▪ For enteric coated tablets, disintegration time should be 60

minutes

▪ Dispersible and soluble tablets should disintegrate in 3 minutes

▪ Effervescent tablets disintegrate in 5 minutes

o Dissolution test

▪ Dissolution is a process by which a solid solute enters into a

liquid and form solution

There are different types of dissolution apparatus

▪ Basket type, paddle type, reciprocating paddle, flow through

cell, paddle over disc, cylinder with membrane, reciprocating

cylinder

▪ Conditions maintained include temperature (36.5℃ to 37.5℃) and

speed (25-150 rpm)

▪ Test done according to compendial monographs or non compendial

o Tablet thickness

▪ May be measured by micrometer or by other device

▪ Tablet thickness should be controlled within a ± 5% variation of

standard value

o -Blister or strip sealing test

▪ To ensures that only intact blisters are realised

• Quality control tests during production of Capsules (Hard shell)

o Content uniformity

▪ 10 capsules are taken and subjected to assay

▪ 9 out of 10 capsules should be in the range of 85-115% and the

10th capsule in the range of 75-125%

▪ If 2 capsules are beyond the prescribed range, then 20 capsules

are assayed. All capsules should be in the range of 75-125%

o Bloom strength

▪ Gelatin is weighed into water to typically create a 6.67%

solution in standard Bloom bottles

▪ The mix is then stirred and kept for 3 hours at room temperature

▪ Bottles are placed in a 65℃ bath for 20 minutes

▪ The bloom jars are allowed to cool for 15 minutes at room

temperature

▪ The bloom jars are then conditioned for 16 hours in 10℃ water

bath

▪ When conducting a gelatin Bloom test, the Bloom jar is centred

with the probe just above the sample surface

▪ The probe penetrates the gelatin to a target depth of 4 mm at a

speed of 0.5 mm/s, and then retracts

▪ The peak force is the gel strength in Grams Bloom

o Weight variation

▪ A total of 20 capsules are individually weighed and standard

deviation from mean is measured

▪ It should not be less than 90% or greater than 110%

o Other tests include;

▪ Assays

▪ Dissolution test

▪ Disintegration time

▪ Moisture content

▪ Iron test

▪ Hardness and flexibility of shell

▪ Loss on drying

• In-process quality control tests during production of Capsules (Soft

shell)

o There are four important test during encapsulation process;

▪ Gel ribbon thickness

▪ Soft gel seal thickness at the time of encapsulation

▪ Fill matrix weight and capsule shell weight

▪ Softgel moisture level and hardness and the end of the drying

stage

STEP 5: Key Points (5 minutes)

• In-process quality control is a type of quality control that provides

accurate specific and definite description of procedure to be employed

from the receipt of raw material to the release of the finished product

• Generally, the in-process control procedures are usually rapid and simple

tests or inspections that are performed when the manufacturing of a

product batch is in progress

• In-process quality testing is achieved by conducting various tests on the

critical stages of the manufacturing process

STEP 6: Evaluation (5 minutes)

• What is in-process quality control?

• How does in-process quality control differ from quality control?

• Lit the in-process quality control test performed during production of

tablets and capsules

References

Aulton M.E & Kevin M.G., (Eds): (2013) Pharmaceutics: The design and

manufacture of medicines, (4th ed.)Churchill Livingstone

Hugo and Russell (2011), Pharmaceutical Microbiology (8th ed.), Willey-

Blackwel publications

Gennaro, R. A, et al. (Eds) (1995) Remington: The Science and Practice of

Pharmacy, Volume I & II, (19th ed.): Mack Publishing Company, Easton,

Pennsylvania 18042

Liebsch, B., et al (1988): Tanzania Pharmaceutical Handbook, Dar es Salaam

University Press.

Lund, W. Editor (1994). The Pharmaceutical Codex, Principles and Practice

of Pharmaceutics (12th ed.): The Pharmaceutical Press, London

Polderman, J., (1990) Introduction to Pharmaceutical Production: Novib, The

Hague

Rawlins E.A, Editor: (1977) Bentley’s Textbook of Pharmaceutics, (8th ed).

Baillie're Tindall. London Kamm, G. and Kohler, B. Editors: (1995)

Manual for Decentralized Infusion Production, Infusion Unit Project

Tanzania

Schmidt, O. (ed) (2000) Pharmaceutical Quality systems, Interpharm Press,

Colorado.

Shayne C et al. (2008), Pharmaceutical Manufacturing Handbook: Production

and processes, John Wiley & Sons

Watson, D. G., (1999) Pharmaceutical Analysis: A Textbook for Pharmacy

Students and Pharmaceutical Chemists: Churchill Livingstone, Edinburgh.

Session 23: GMP for Pharmaceutical Premises

Total Session Time: 120 minutes

Pre-requisites

• None

Learning Tasks

By the end of this session students are expected to be able to:

• Explain the concept of GMP on pharmaceutical premises

• List the general GMP Requirements on Design of Premises

• Explain how pharmaceutical manufacturing premises are maintained

Resources Needed:

• Flip charts, marker pens, and masking tape

• Black/white board and chalk/whiteboard markers

• LCD projector and computer

SESSION OVERVIEW

SESSION CONTENTS

STEP 1: Presentation of Session Title and Learning Tasks (5 minutes)

READ or ASK students to read the learning tasks and clarify

ASK students if they have any questions before continuing

STEP 2: GMP and Manufacturing Premises (20 minutes)

• Good Manufacturing Practices (GMP) are a part of Quality Assurance (QA)

which ensures that products are consistently produced and controlled to

the quality standards appropriate to their intended use

• GMP is designed to minimize the risks involved in any pharmaceutical

production that cannot be eliminated through testing the final product

• GMP covers all aspects of production;

o Raw materials

o Premises

o Equipment

o Personnel

• Principles of GMP are;

o Proper design and construction of premises

o Following written procedures and instructions

o Documentation of work

o Validation of work

o Monitoring facilities and equipment

o Writing SOPs

o Designing, developing and demonstrating job competence

o Protection against contamination

o Controlling components and product related processes

o Conducting planned and periodic audits

• The premise for pharmaceutical production must meet the GMP standards

STEP 3: General GMP Requirements on Location of Premises (25 minutes)

• The land and buildings where the manufacturing operations are located

must contribute towards the quality of the products

• Proper location and design help avoid the risks of contamination,

permitting effective cleaning and maintenance, minimizing the build-up of

dirt and dust and preventing quality defects

• Premises must be located, designed, constructed, adapted and maintained

for production processes to;

➢ Minimize risks of errors and cross-contamination

➢ Permit effective cleaning

➢ Permit effective maintenance

➢ Minimize build-up of dirt and dust

➢ Eliminate any adverse effects on quality

• Principle for the location of pharmaceutical production premise;

o Location must minimize risks of cross-contamination

▪ Not located next to a melting factory with high airborne levels

of yeast

o Location must be in conducive climatic and geographic (e.g. away from

noise, earthquake hazards, flooding, humidity, )

• A site inspection is useful before building commences to ensure that the

area is suitable for the construction of a pharmaceutical factory

STEP 4: General GMP Requirements on Design of Premises (40 minutes)

|Activity: Small Group Discussion (10 minutes) |

| |

|DIVIDE students into small manageable groups |

| |

|ASK students to discuss on the following question |

|What are the GMP requirements on design of premise? |

| |

|ALLOW students to discuss for 10 minutes |

| |

|ALLOW few groups to present and the rest to add points not mentioned |

| |

|CLARIFY and SUMMARIZE by using the contents below |

• Premises should be laid out in such a way as to allow the production to

take place in areas connected in a logical order corresponding to the

sequence of the operations and to the requisite cleanliness levels

• Working and in-process storage space should be adequate to permit orderly

and logical positioning of equipment and materials to minimize risk of

confusion between different pharmaceutical products or their components,

to avoid cross-contamination and to minimize the risk of omission or

wrong application of any of the manufacturing or control steps

• The premise must have good pipe work, light fittings and ventilation

points (air handling system)

• Design of the premise must include the following design features;

o Design of facilities required

▪ Adequate space for future expansion

▪ Zoning laws –to allow anticipated development, restricting

undesirable developments in the vicinity

▪ Availability of water (quality and quantity), power, fuel, sewage

and waste removal

▪ Accessibility to employees, materials and visitors

▪ Environmental issues such as site history (soil, water, and air

quality)

▪ Proximity of undesirable activities likely to cause pollution

▪ Availability of a suitable labour force

▪ Ability to provide adequate security arrangements

▪ Political situation

▪ Government stability, trade policies and taxation, financial

incentives

o Design of Ancillary areas

▪ Rest and refreshment rooms must be separated from manufacturing

and control areas

▪ Facilities for changing and storing clothes and for washing

appropriate to the number of workers

▪ Toilets should not communicate directly with production or

storage areas

▪ Maintenance workshops (should be separated from production area)

▪ Animal houses should be well isolated from other areas with

separate entrance (animal access) and air handling facilities

o Design of Storage areas

▪ Storage areas should have sufficient capacity for orderly storage

of various categories of materials and product with proper

separation and segregation

▪ Storage areas should be designed or adapted to ensure good

storage conditions

▪ Special storage conditions (provided, controlled, monitored and

recorded appropriately)

▪ Quarantine area must be allocated to restrict access to

unauthorized personnel

▪ Secure areas for storage of controlled substances and radioactive

pharmaceuticals

▪ Storage area should be designed such that receiving and dispatch

batches are separated to protect materials and products from the

weather

▪ Receiving areas should be designed and equipped to allow

containers of incoming materials to be cleaned if necessary before

storage

▪ There are should a separate area for sampling of raw materials to

avoid contamination if sampling is done in the storage area

▪ Storage area must have a weighing area, close to the production

area to avoid or minimize transit distance

o Design for production areas

▪ Dedicated and self-contained facilities must be provided for

production of particular pharmaceutical products (e.g. penicillin

or biological preparations)

▪ Manufacture of technical poisons e.g. pesticides and herbicides

must never be allowed in premises for manufacture of pharmaceutical

products

o Design for quality control areas

▪ Quality control laboratories should be separated from production

areas

▪ Areas for biological, microbiological or radioisotope test

methods are employed should be separated from each other

▪ Quality control laboratories should be designed to suit the

operations to be carried out

▪ Sufficient space should be given to avoid mix-ups and cross-

contamination

▪ Should prevent fumes and allow ventilation

▪ There are should be separate air supply to laboratories and

production areas

▪ Separate air handling units and other provisions are needed for

biological, microbiological, and radio-isotope laboratories

▪ A separate room may be needed for instruments

o Design for services

▪ In the building design provisions must be made for drains, water,

steam, electricity and other services to allow easy of maintenance

▪ Access should be possible without disruption of activity with the

actual rooms provided with the services

o Construction features

▪ Adequate space for orderly placement of equipment and materials

▪ Adequate space to allow flow of components, drug product

containers, closures, labelling, in-process material and drug

products to prevent contamination

▪ Floors, walls and ceilings should be smooth, hard surfaced for

easy cleaning

▪ Should have temperature and humidity controls

▪ Air supply filtered through high-efficiency particulate air

(HEPA) filters under positive pressure, regardless of whether the

flow is laminar or nonlaminar

▪ There are should be a system for monitoring environmental

conditions;

▪ Cleaning and disinfecting rooms and equipment

▪ Maintenance of equipment used to control aseptic conditions

▪ Adequate lighting in all areas

▪ Ventilation, air filtration, air heating and cooling

▪ Adequate ventilation

▪ Air filtration system

▪ Pre-filters and particulate matter air filters are used to

control recirculation of dust

▪ Air handling system

▪ For manufacturing, processing and packing of penicillin must be

separate from those of other drug products for human use

▪ Plumbing

▪ Portable water is supplied under continuous positive pressure in

a plumbing system free of defects that could contribute to

contamination

▪ Drains should prevent back-siphonage

▪ Sewage, trash and other refuse in and from the building and

immediate premises must be disposed of in a safe and sanitary

manner

▪ Pharmaceutical industry considers disposal in forms of;

• Product disposal

• Printed packaging disposal

• General trash and sewage

▪ Washing and toilet facilities

▪ Adequate washing facilities must be provided

▪ with hot and cold water, soap or detergent, air driers or single-

service towels

▪ adequate and clean toilet facilities easily accessible to working

areas

STEP 5: Maintenance of Premises (20 minutes)

|Activity: Buzzing (5 minutes) |

| |

|ASK students to pair up and buzz on the following question for 2 |

|minutes |

| |

|How are premises for pharmaceutical manufacturing maintained? |

| |

|ALLOW few pairs to respond and let other pairs to add on points not |

|mentioned |

| |

|WRITE their response on the flip chart/board |

| |

|CLARIFY and SUMMARIZE by using the content below |

• Buildings used in manufacture processing, packing or holding of a drug

product must be maintained in good state of repair

• The following must be maintained;

o Cracks and holes in the wall, floor and ceilings

o Damage to insulation or pipes

o Dust accumulation on light fittings etc

• Building inspection and maintenance programs should be defined in writing

and records kept

• Essential services to monitor include water, steam, vacuum, compressed

air and other gases, electricity, dust extraction, product/material pipe

line and drainage

STEP 8: Key Points (5 minutes)

• The premise for pharmaceutical production must meet the GMP standards

• The land and buildings where the manufacturing operations are located

must contribute towards the quality of the products

• Proper location and design help avoid the risks of contamination,

permitting effective cleaning and maintenance, minimizing the build-up of

dirt and dust and preventing quality defects

• Premises should be laid out in such a way as to allow the production to

take place in areas connected in a logical order corresponding to the

sequence of the operations and to the requisite cleanliness levels

• Buildings used in manufacture processing, packing or holding of a drug

product must be maintained in good state of repair

STEP 7: Evaluation (5 minutes)

• What are the GMP requirements for premises?

• Mention design features of a pharmaceutical manufacturing premise

• Mention the construction features of a pharmaceutical manufacturing

premise

References

Aulton M.E & Kevin M.G, (Eds): (2013) Pharmaceutics: The design and

manufacture of medicines, (4th ed.) Churchill Livingstone

Hugo and Russell (2011), Pharmaceutical Microbiology (8th ed,) Willey-

Blackwel publications

Gennaro, R. A, et.al (Eds) (1995) Remington: The Science and Practice of

Pharmacy, Volume I & II, 19th (ed.): Mack Publishing Company, Easton,

Pennsylvania 18042

Liebsch, B et al. (1988): Tanzania Pharmaceutical Handbook, Dar es Salaam

University Press.

Lund, W. Editor (1994). The Pharmaceutical Codex, Principles and Practice

of Pharmaceutics (12th ed.): The Pharmaceutical Press, London

Polderman, J., (1990) Introduction to Pharmaceutical Production: Novib, The

Hague

Rawlins E.A, Editor: (1977) Bentley’s Textbook of Pharmaceutics, (8th ed.)

Baillie're Tindall. London Kamm, G. and Kohler, B. Editors: (1995)

Manual for Decentralized Infusion Production, Infusion Unit Project

Tanzania

Schmidt, O. (ed) (2000) Pharmaceutical Quality systems, Interpharm Press,

Colorado.

Shayne C et al. (2008), Pharmaceutical Manufacturing Handbook: Production

and processes, John Wiley & Sons

Watson, D. G., (1999) Pharmaceutical Analysis: A Textbook for Pharmacy

Students and Pharmaceutical Chemists: Churchill Livingstone,

Edinburgh.

WHO (2003), Good Manufacturing Practices for Pharmaceutical Products, Annex

4 to WHO Technical Reports Series, No. 908.

Session 24: GMP for Pharmaceutical Equipments

Total Session Time: 120 minutes

Pre-requisites

• None

Learning Tasks

By the end of this session students are expected to be able to:

• Explain the GMP requirements for equipment used in pharmaceutical

manufacturing

• Explain the construction features of GMP compliant equipment

• Outline the basic equipment used in pharmaceutical production

• Explain the calibration of equipment used in pharmaceutical production

• Explain the cleaning of equipment used in pharmaceutical production

• Explain the preventive maintenance of equipment used in pharmaceutical

production

Resources Needed:

• Flip charts, marker pens, and masking tape

• Black/white board and chalk/whiteboard markers

• LCD projector and computer

SESSION OVERVIEW

SESSION CONTENTS

STEP 1: Presentation of Session Title and Learning Tasks (5 minutes)

READ or ASK students to read the learning tasks and clarify

ASK students if they have any questions before continuing

STEP 2: General Features of Manufacturing Equipment (10 minutes)

|Activity: Buzzing (5 minutes) |

| |

|ASK students to pair up and buzz on the following question for 2 |

|minutes |

| |

|What are the features of pharmaceutical manufacturing equipment? |

| |

|ALLOW few pairs to respond and let other pairs to add on points not |

|mentioned |

| |

|WRITE their response on the flip chart/board |

| |

|CLARIFY and SUMMARIZE by using the content below |

• Equipment used in the manufacture, processing, packing or holding of a

drug product must be of appropriate design, adequate size, and suitably

located to facilitate operations for its intended use and for its

cleaning and maintenance

• Effectiveness of equipment starts at the design stage

• Pharmaceutical manufacturing companies contribute indirectly in the

design of equipment by providing information on requirements and feedback

on existing equipment

• Equipment must be located, designed, constructed, adapted and maintained

to suit the operations to be carried out

• Equipment should be constructed of materials that suit the operation and

use of the equipment for the range of products manufactured and tested on

site.

• The construction materials should not corrode or deteriorate and thus

influence the manufacturing or testing procedure.

STEP 3: GMP Requirements for Equipments (35 minutes)

|Activity: Small Group Discussion (10 minutes) |

| |

|DIVIDE students into small manageable groups |

| |

|ASK students to discuss on the following question |

| |

|What are the GMP requirements for equipment used in pharmaceutical |

|production? |

| |

|ALLOW students to discuss for 10 minutes |

|ALLOW few groups to present and the rest to add points not mentioned |

| |

|CLARIFY and SUMMARIZE by using the contents below |

• Pharmaceutical manufacturing equipment should meet the following

requirements;

o Operating criteria

▪ Should be adequate to meet process, size, speed and effectiveness

requirements

o Spare parts

▪ Availability of spares and servicing

▪ This can result in using different makes of an equipment in

different parts of the world

o Maintenance

▪ Frequency and ease of maintenance significantly impact on

productivity and even quality

▪ Equipment break down during process could adversely affect

quality

▪ Cleanability of the equipment

▪ Accessibility to the parts of equipment needed to be cleaned

▪ Easy of disassembling and re-assembling the equipment

o Environmental issues

▪ Dust dissemination

▪ Potential for contamination of other products and requiring

operators to wear additional protective clothing and frequent

cleaning of facility

▪ Noise and energy use

o Equipment design, size and space required for its location

o Construction materials of the equipment

o Process controls on the equipment

▪ Automatic weight adjustment on tablet presses

▪ Temperature recorders on ovens

o Cost of the equipment

▪ Base price of the equipment

▪ Additional costs related to installation, etc.

o Design and maintenance manuals

▪ Manuals are important for validation/qualification of the

equipment and maintenance programs

STEP 4: Construction of Equipment (20 minutes)

• Equipment layout and design must aim to minimize risks of error and

permit effective cleaning and maintenance

o This will avoid cross-contamination, dust and dirt-build up and any

adverse effect on the quality of the product

• Equipment must be installed to minimize risks of error and contamination

• The construction of the equipment must meet the following features;

o Surfaces

▪ Surfaces that contact components, in-process materials or drug

product should be smooth, nonreactive or absorptive

▪ These surfaces should not alter the safety, identity, strength,

quality or purity of the drug product beyond the official or other

established requirements

o Fixed pipework (for transfer of materials through pipelines)

▪ All pipes used must be of right standard and specification for

the material and pipeline to prevent any wrong connections and mix-

ups

▪ All pipes must be clearly labelled

▪ Labels in all pipes should indicate contents and direction of

flow

▪ Servicing pipings and devices must be adequately marked

▪ The use of adaptors is not recommended

▪ Piping system should allow monitoring and testing of materials

delivered in them at regular intervals

o Substances required for operation of equipment

▪ Coolants, lubricants and other substances required for operation

of the equipment should not come into contact with components, drug

product, containers, closures, in-process materials or drug product

▪ Lubrication needs to be of good grade, controlled and monitored

o Potential sources of contamination

▪ Construction of equipment should be in a such a way that motors,

drive belts, gears and other potential sources of lubricant

contamination are located away from vessels or package openings

that could result in product contamination

STEP 5: Basic Equipment in Pharmaceutical Manufacturing (25 minutes)

• Balances and measuring equipment

o Must be of appropriate range and precision

▪ All balances and measuring equipment must be capable of weighing

or measuring the materials over the desired range required for

production and testing

▪ Appropriate weighing and measuring equipment must available in

the relevant areas i.e. production area and quality control

laboratories

o Must be calibrated on scheduled basis

▪ Calibration must be done on regular intervals

▪ Check weighing must be done on daily basis

▪ Proper records of calibration must be maintained

o There are should be SOPs for use, calibration, cleaning and

maintenance of weighing and measuring equipment

• Production equipment

o Production equipment must be suitably designed for the intended uses

o Must not be hazardous to the product

o Some production equipment include mixers, granulators, tablet presses,

capsule filling machine, liquid filling machine, packing machine etc

o Defective equipment must be removed or labelled to prevent use

o Must be designed to allow easy cleaning even if it is dedicated to one

product

o Relevant SOPs (use, cleaning, maintenance) must be available and in

use

• Control laboratory equipment

o Equipment and instruments in quality control laboratories must be

suitable for the tests to be performed

o Defective equipment must be removed or labelled to prevent their use

• Washing, cleaning and drying equipment

o Equipment used for washing and drying should be designed to promote

easy cleaning

▪ Cleaning on scheduled basis

▪ Procedures (SOPS) should be followed and records kept

STEP 6: Calibration, Cleaning and Maintenance of Equipment (25 minutes)

• Equipment and utensils must be cleaned, maintained and sanitized at

appropriate intervals to prevent malfunctions or contamination

o Contamination alters safety, identity, strength, quality or purity of

the drug product beyond the official or other established requirements

• Calibration of equipment

o Control, weighing, measuring, monitoring and test equipment must

calibrated according to written SOP and an established schedule

o Performed using standards traceable to certified standards

o Calibration records maintained

o Current calibration status known and verifiable

o Out of calibration instruments should not be used, and deviations

investigated to determine if these could have had an impact on the

quality of the intermediate(s) or API(s) manufactured using this

equipment since the last successful calibration

• Cleaning and Preventive Maintenance

o There should be SOPs and schedules to be followed for cleaning and

preventive maintenance of equipment

o SOPs for cleaning of equipment and its subsequent release for use

o Detailed cleaning SOPs to enable operators to clean each type of

equipment in a reproducible and effective manner.

▪ The SOPs should include;

• Assignment of responsibility for cleaning and maintaining

equipment

• Maintenance and cleaning schedules

• Descriptions of methods, equipment and materials used in

cleaning and maintenance operations. Methods for disassembling

and reassembling equipment to ensure proper cleaning and

maintenance

• Removal or obliteration of previous batch identification

• Instruction for the protection of clean equipment from

contamination prior to use

• Inspection of equipment for cleanliness immediately before use,

if practical

• Establishing the maximum time that may elapse between the

completion of processing and equipment cleaning, when

appropriate

• Documentation

o Records of calibration, cleaning and preventive maintenance of all

equipment must be kept properly

STEP 6: Key Points (5 minutes)

• Equipment used in the manufacture, processing, packing or holding of a

drug product must be of appropriate design, adequate size, and suitably

located to facilitate operations for its intended use and for its

cleaning and maintenance

• Equipment in pharmaceutical manufacturing must meet GMP requirements

• Equipment layout, design and construction must aim to minimize risks of

error and permit effective cleaning and maintenance

• Equipment must be installed to minimize risks of error and contamination

• Basic equipment in pharmaceutical production include weighing and

measuring equipment, production equipment, quality laboratory equipment

and equipment for washing, cleaning and drying

• Equipment must be calibrated, cleaned and maintained properly to ensure

safety, quality and effectiveness of drug products

STEP 7: Evaluation (5 minutes)

• Why is the design of equipment important in pharmaceutical production?

• What are the GMP requirements for pharmaceutical equipment?

References

Aulton M.E & Kevin M.G, (Eds.): (2013) Pharmaceutics: The design and

manufacture of medicines, (4th ed.) Churchill Livingstone

Hugo and Russell (2011), Pharmaceutical Microbiology (8th ed.), Willey-

Blackwel publications

Gennaro, R. A, et al. (Eds) (1995) Remington: The Science and Practice of

Pharmacy, Volume I & II, (19th ed): Mack Publishing Company, Easton,

Pennsylvania 18042

Liebsch, B et al. (1988): Tanzania Pharmaceutical Handbook, Dar es Salaam

University Press.

Lund, W. Editor (1994). The Pharmaceutical Codex, Principles and Practice

of Pharmaceutics (12th ed.) The Pharmaceutical Press, London

Polderman, J., (1990) Introduction to Pharmaceutical Production: Novib, The

Hague

Rawlins E.A, Editor: (1977) Bentley’s Textbook of Pharmaceutics, (8th ed).

Baillie're Tindall. London Kamm, G. and Kohler, B. Editors: (1995)

Manual for Decentralized Infusion Production, Infusion Unit Project

Tanzania

Schmidt, O. (ed) (2000) Pharmaceutical Quality systems, Interpharm Press,

Colorado.

Shayne C et al. (2008), Pharmaceutical Manufacturing Handbook: Production

and processes, John Wiley & Sons

Watson, D. G (1999) Pharmaceutical Analysis: A Textbook for Pharmacy

Students and Pharmaceutical Chemists: Churchill Livingstone, Edinburgh

Session 25: Management of Pharmaceutical Wastes

Total Session Time: 120 minutes

Pre-requisites

• None

Learning Tasks

By the end of this session students are expected to be able to:

• Define pharmaceutical wastes

• List sources of pharmaceutical wastes

• List types of wastes in pharmaceutical production

• Explain the problems caused by pharmaceutical wastes

• Explain methods used in the disposal of pharmaceutical wastes

Resources Needed:

• Flip charts, marker pens, and masking tape

• Black/white board and chalk/whiteboard markers

• LCD projector and computer

SESSION OVERVIEW

SESSION CONTENTS

STEP 1: Presentation of Session Title and Learning Tasks (5 minutes)

READ or ASK students to read the learning tasks and clarify

ASK students if they have any questions before continuing

STEP 2: Definitions (10 minutes)

|Activity: Buzzing (5 minutes) |

| |

|ASK students to pair up and buzz on the following question for 2 |

|minutes |

| |

|What is a pharmaceutical waste? |

| |

|ALLOW few pairs to respond and let other pairs to add on points not |

|mentioned |

| |

|WRITE their response on the flip chart/board |

| |

|CLARIFY and SUMMARIZE by using the content below |

• Wastes are unwanted materials which are no longer used in the

manufacturing process that can eventually turn into hazardous or non

hazardous material to human or the environment or both

• Pharmaceutical wastes are wastes are unwanted materials resulting from

pharmaceutical production processes

• Pharmaceutical wastes are in different forms mainly as expired materials,

manufacturing wastes and others

STEP 3: Sources of Pharmaceutical Wastes (35 minutes)

|Activity: Small Group Discussion (15 minutes) |

| |

|DIVIDE students into small manageable groups |

| |

|ASK students to discuss on the following question |

|What are the sources of waste in pharmaceutical manufacturing? |

| |

|ALLOW students to discuss for 15 minutes |

| |

|ALLOW few groups to present and the rest to add points not mentioned |

| |

|CLARIFY and SUMMARIZE by using the contents below |

• Manufacturing processes

o Wastes generated during pharmaceutical production

▪ by-products from different stages of manufacturing

▪ Spillages

▪ Waste water

• Raw materials

o Unusable/expired/rejected/obsolete raw materials

o Expired/unusable/rejected active pharmaceutical ingredients

• Products

o Rejected finished products

• Packaging materials

o Unusable or damaged packaging materials

• Quality control laboratories

o Used chemical by products

o Spills

o Unused/unusable solvents, chemicals and reagents

o Waste water

• Cleaning and maintenance processes

o Cleaning substances e.g. detergents, soaps

o Waste waster

STEP 4: Types of Wastes Produced in Pharmaceutical Production and their

Problems (30 minutes)

• Pharmaceutical wastes are classified into

o Hazardous wastes

o Non-hazardous wastes

o Hazardous wastes

▪ Hazardous wastes are wastes that are dangerous or potentially

harmful to human health or environment

▪ Hazardous wastes can be liquids, solids, gases or sludges

▪ Hazardous wastes exhibit hazardous properties such as:

Ignitability

▪ Ignitibility is a property of a pharmaceutical waste to present

fire hazard under routine storage, disposal and transportation or

are capable of exacerbating a fire once it has started

▪ Ignitable wastes are easily combustible or flammable

▪ Ignitable wastes include flammable liquids and compressed gases

Corrositity

▪ Corrosive pharmaceutical wastes are wastes capable or corroding

metals or other materials or burn the skin

▪ These have a pH of 2 or lower or 12.5 or higher

Reactivity

▪ Reactive wastes are unstable under normal conditions

▪ They undergo violent changes

▪ They can cause explosions, toxic fumes, gases or vapours when

heated, compressed, or mixed with water

▪ They include glacial acetic acid, sodium hydroxide etc

Toxicity

▪ Wastes that are toxic contain toxic organic chemicals or toxic

heavy metals such as chromium, lead, mercury or cadmium

Infectivity

▪ Ability of waste to cause infection

▪ These are from microbiological laboratories or from production of

vaccines or immunological preparations

o Non-hazardous wastes

▪ Non-hazardous pharmaceutical wastes are those wastes that present

no significant hazardous properties

▪ These wastes are below the threshold of causing harm to human

health

• Problems associated with pharmaceutical wastes

|Activity: Small Group Discussion (15 minutes) |

| |

|DIVIDE students into small manageable groups |

| |

|ASK students to discuss on the following question |

|What are the problems associated with industrial pharmaceutical |

|wastes? |

| |

|ALLOW students to discuss for 15 minutes |

| |

|ALLOW few groups to present and the rest to add points not mentioned|

| |

|CLARIFY and SUMMARIZE by using the contents below |

o Environmental contamination with drug substances

▪ Fumes, dust etc.

▪ Antimicrobial resistance when antimicrobial wastes contaminate

the environment

STEP 5: Disposal of Pharmaceutical Wastes (30 minutes)

• Methods for disposal of pharmaceutical wastes;

o Incineration

▪ Incineration is an effective method for disposal of wastes

(solid, liquid and gaseous waste), in which solid organic wastes

are subjected to combustion so as to convert them into residue and

gaseous products (heat, gas, steam and ash) by use of an

incinerator

▪ Is useful for disposal of residue of both solid waste management

and solid residue from waste water management

▪ Reduces the volumes of solid waste to 20 to 30 percent of the

original volume

▪ Incinerators convert waste materials into heat, gas, steam and

ash. Incineration is carried out both on a small scale by

individuals and on a large scale by industry

▪ It is recognized as a practical method of disposing of certain

hazardous waste materials (such as biological waste)

o Deep burial

▪ Involves digging a pit or trench of about 2 meters deep in an

area that is not prone to flooding or erosion, and where the soil

is relatively impermeable, there are no inhabitants or shallow

wells in the vicinity, and the risk to surface water contamination

is remote

o Secure landfill

▪ Disposing of waste in a landfill involves burying the waste, and

this remains a common practice in most countries

▪ Landfills were often established in abandoned or unused quarries,

mining voids or borrow pits

▪ A properly designed and well-managed landfill can be a hygienic

and relatively inexpensive method of disposing of waste materials

▪ Older, poorly designed or poorly managed landfills can create a

number of adverse environmental impacts such as wind-blown litter,

attraction of vermin, and generation of liquid leachate

o Waste immobilization by encapsulation

▪ Encapsulation involves immobilizing the pharmaceuticals in a

solid block within a plastic or steel drum

▪ Drums should be cleaned prior to use and should not have

contained explosive or hazardous materials previously

▪ They are filled to 75% capacity with solid and semi-solid

pharmaceuticals, and the remaining space is filled by pouring in a

medium such as cement or cement/lime mixture, plastic foam or

bituminous sand

o Waste immobilization by inertization

▪ Inertization is a variant of encapsulation and involves removing

the packaging materials, paper, cardboard and plastic, from the

pharmaceuticals. Pills need to be removed from their blister packs

▪ The pharmaceuticals are then ground and a mix of water, cement

and lime added to form a homogenous paste

▪ The paste is then transported in the liquid state by concrete

mixer truck to a landfill and decanted into the normal urban waste

▪ The paste then sets as a solid mass dispersed within the

municipal solid waste.

▪ The process is relatively inexpensive and can be carried out with

unsophisticated equipment

▪ The main requirements are a grinder or road roller to crush the

pharmaceuticals, a concrete mixer, and supplies of cement, lime and

water

o Sewer

▪ Some liquid pharmaceuticals, e.g. syrups and intravenous (IV)

fluids remains or unusable, can be diluted with water and flushed

into the sewers in small quantities over a period of time without

serious public health or environmental affect

▪ Fast flowing watercourses may likewise be used to flush small

quantities of well-diluted liquid pharmaceuticals or antiseptics

▪ The assistance of a hydro geologist or sanitary engineer may be

required in situations where sewers are in disrepair or have been

war damaged

o Waste minimization

▪ This is a method of waste management that focuses on prevention

of waste material being created

▪ Involves reuse and recycle whenever possible

STEP 6: Key Points (5 minutes)

• Wastes are unwanted materials which are no longer used in the

manufacturing process that can eventually turn into hazardous or non

hazardous material to human or the environment or both

• Pharmaceutical wastes are in different forms mainly as expired materials,

manufacturing wastes, quality control laboratories, packaging materials,

raw materials and others

• Major classes of pharmaceutical wastes are hazardous wastes and non-

hazardous wastes

• Methods used for disposal of pharmaceutical wastes include incineration,

secure land fill and waste immobilization

STEP 7: Evaluation (5 minutes)

• What is a waste?

• Define pharmaceutical waste?

• Name sources of waste in pharmaceutical production

• What is waste immobilization?

References

Aulton M.E & Kevin M.G, (Eds): (2013) Pharmaceutics: The design and

manufacture of medicines, (4th ed.) Churchill Livingstone

Hugo and Russell (2011), Pharmaceutical Microbiology (8th ed.), Willey-

Blackwel publications

Gennaro, R. A, et al. (Eds) (1995) Remington: The Science and Practice of

Pharmacy, Volume I & II, (19th ed.): Mack Publishing Company, Easton,

Pennsylvania 18042

Liebsch, B., et al. (1988): Tanzania Pharmaceutical Handbook, Dar es Salaam

University Press.

Lund, W. Editor (1994). The Pharmaceutical Codex, Principles and Practice

of Pharmaceutics (12th ed.): The Pharmaceutical Press, London

Polderman, J., (1990) Introduction to Pharmaceutical Production: Novib, The

Hague

Rawlins E.A, Editor: (1977) Bentley’s Textbook of Pharmaceutics, (8th ed.)

Baillie're Tindall. London Kamm, G. and Kohler, B. Editors: (1995)

Manual for Decentralized Infusion Production, Infusion Unit Project

Tanzania

Schmidt, O. (ed) (2000) Pharmaceutical Quality systems, Interpharm Press,

Colorado.

Shayne C et al. (2008), Pharmaceutical Manufacturing Handbook: Production

and processes, John Wiley & Sons

Watson, D. G,. (1999) Pharmaceutical Analysis: A Textbook for Pharmacy

Students and Pharmaceutical Chemists: Churchill Livingstone,

Edinburgh.

———————–

PST 06103 Pharmaceutical Production

NTA Level 6 Semester 1

March 2019

Source: Aulton 2013

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