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NTA Level 6 • Semester 1 • PST06103 Introduction to Tablets Pharmaceutical Production • Source Session/Topic 15 Full source-text version: all educational wording from the extracted learning source is retained; only presenter/tutor metadata and web-layout noise are removed, while formatting is improved for readability. 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 |Step |Time |Activity/ |Content | | | |Method | | |1 |5 minutes |Presentation |Introduction, Learning Tasks | |2 |10 minutes |Buzzing |Definitions | | | |Presentation | | |3 |20 minutes |Presentation |Characteristics of Tablets | |4 |50 minutes |Presentation |Classification of Tablets | |5 | |Small Group |Advantages and Disadvantages of | | |15 minutes |Discussion |Tablets | | | |Presentation | | |6 |10 minutes |Presentation |Unit Processes in Tablet | | | | |Manufacturing | |7 |5 minutes |Presentation |Key Points | |8 |5 minutes |Presentation |Evaluation | 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

NTA Level 6 • Semester 1 • PST06103 Soft Gelatin Capsules Pharmaceutical Production • Source Session/Topic 14 Full source-text version: all educational wording from the extracted learning source is retained; only presenter/tutor metadata and web-layout noise are removed, while formatting is improved for readability. 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 |Step |Time |Activity/ |Content | | | |Method | | |1 |05 minutes |Presentation |Introduction, Learning Tasks | |2 |20 minutes |Presentation |Definition and Shell Composition | |3 |10 minutes |Presentation |Advantages and Disadvantages of Soft | | | | |Gelatin Capsules | |4 |30 minutes |Presentation |Formulation of Fill Materials | |5 |20 minutes |Presentation |Filling Process for Soft Gelatin | | | | |Capsules | |6 |10 minutes |Presentation |Packaging of Soft Gelatin Capsules | |7 | |Small group |Difference between Hard and Soft | | |15 minutes |discussion |Gelatin Capsules | | | |Presentation | | |8 |05 minutes |Presentation |Key Points | |9 |05 minutes |Presentation |Evaluation | 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

NTA Level 6 • Semester 1 • PST06103 Filling Hard Gelatin Capsules Pharmaceutical Production • Source Session/Topic 13 Full source-text version: all educational wording from the extracted learning source is retained; only presenter/tutor metadata and web-layout noise are removed, while formatting is improved for readability. 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 |Step |Time |Activity/ |Content | | | |Method | | |1 |05 minutes |Presentation |Introduction, Learning Tasks | |2 |10 minutes |Presentation |General Filling Process | |3 |35 minutes |Presentation |Filling Methods | |4 |25 minutes |Presentation |Capsules Filling Machines | |5 |15 minutes |Presentation |Sealing the Capsules | |6 |10 minutes |Presentation |Cleansing and Polishing Process | |7 | |Presentation |Common Problems during Manufacturing | | |10 minutes |Take home |of Capsules | | | |assignment | | |8 |05 minutes |Presentation |Key Points | |9 |05 minutes |Presentation |Evaluation | 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 it 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

NTA Level 6 • Semester 1 • PST06103 Formulation of Capsule Content Pharmaceutical Production • Source Session/Topic 12 Full source-text version: all educational wording from the extracted learning source is retained; only presenter/tutor metadata and web-layout noise are removed, while formatting is improved for readability. 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 |Step |Time |Activity/ |Content | | | |Method | | |1 |05 minutes |Presentation |Introduction, Learning Tasks | |2 |15 minutes |Brainstorming |Formulation | | | |Presentation | | |3 |45 minutes |Presentation |Preparation of Fill Materials for | | | | |Encapsulation | |4 |15 minutes |Presentation |Selection of Capsule Size | |4 |30 minutes |Presentation |Determination of Capsule Fill Weight | | | | |and Volume | |5 |05 minutes |Presentation |Key Points | |6 |05 minutes |Presentation |Evaluation | 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

NTA Level 6 • Semester 1 • PST06103 Gelatin Capsule Shells Pharmaceutical Production • Source Session/Topic 11 Full source-text version: all educational wording from the extracted learning source is retained; only presenter/tutor metadata and web-layout noise are removed, while formatting is improved for readability. 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 |Step |Time |Activity/ |Content | | | |Method | | |1 |05 minutes |Presentation |Introduction, Learning Tasks | |2 |15 minutes |Presentation |Definitions | |3 |30 minutes |Presentation |Composition of Hard Gelatin Capsule | | | | |Shells | |4 |30 minutes |Presentation |Production of Hard Gelatin Capsule | | | | |Shells | |5 |30 minutes |Presentation |Size and Specification of Hard Shell | | | | |Capsules | |6 |05 minutes |Presentation |Key Points | |7 |05 minutes |Presentation |Evaluation | 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

NTA Level 6 • Semester 1 • PST06103 Introduction to Capsules Pharmaceutical Production • Source Session/Topic 10 Full source-text version: all educational wording from the extracted learning source is retained; only presenter/tutor metadata and web-layout noise are removed, while formatting is improved for readability. 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 |Step |Time |Activity/ |Content | | | |Method | | |1 |05 minutes |Presentation |Introduction, Learning Tasks | |2 |15 minutes |Presentation |Definitions | |3 |25 minutes |Presentation |Classification of Capsules | |4 |30 minutes |Presentation |Modified Release Capsules | |5 | |Small group |Advantages and Disadvantages of | | |35 minutes |discussion |Gelatin Capsules | | | |Presentation | | |6 |05 minutes |Presentation |Key Points | |7 |05 minutes |Presentation |Evaluation | 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

NTA Level 6 • Semester 1 • PST06103 Mixing of Pharmaceutical Powders Pharmaceutical Production • Source Session/Topic 9 Full source-text version: all educational wording from the extracted learning source is retained; only presenter/tutor metadata and web-layout noise are removed, while formatting is improved for readability. 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 |Step |Time |Activity/ |Content | | | |Method | | |1 |05 minutes|Presentation |Introduction, Learning Tasks | |2 |15 minutes|Presentation |Definitions | |3 |10 minutes|Brainstorming |Reasons for Mixing | | | |Presentation | | |4 |20 minutes|Presentation |Types of Powder Mixtures | |5 |30 minutes|Presentation |Mechanisms of Mixing and De-mixing of | | | | |Powders | |6 |30 minutes|Presentation |Mixing Techniques and Equipments | |7 |05 minutes|Presentation |Key Points | |8 |05 minutes|Presentation |Evaluation | 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

NTA Level 6 • Semester 1 • PST06103 Pharmaceutical Powders Pharmaceutical Production • Source Session/Topic 8 Full source-text version: all educational wording from the extracted learning source is retained; only presenter/tutor metadata and web-layout noise are removed, while formatting is improved for readability. 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 |Step |Time |Activity/ |Content | | | |Method | | |1 |05 minutes|Presentation|Introduction, Learning Tasks | |2 |15 minutes|Brainstormin| Introduction to Powders | | | |g | | | | |Presentation| | |3 |10 minutes|Presentation|Production of Powders | |4 |30 minutes|Presentation|Preparation and Mixing of Powders | |5 |30 minutes|Presentation|Bulk and Divided Powders | |6 | |Small group |Advantages and Disadvantages of | | |20 minutes|discussion |Powders | | | |Presentation| | |7 |05 minutes|Presentation|Key Points | |8 |05 minutes|Presentation|Evaluation | 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

NTA Level 6 • Semester 1 • PST06103 Dispensing of Pharmaceutical Materials Pharmaceutical Production • Source Session/Topic 7 Full source-text version: all educational wording from the extracted learning source is retained; only presenter/tutor metadata and web-layout noise are removed, while formatting is improved for readability. 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 |Step |Time |Activity/ |Content | | | |Method | | |1 |05 minutes |Presentation |Introduction, Learning Tasks | |2 |10 minutes |Presentation |Dispensing and Dispensing Area | |3 |20 minutes |Buzzing |Dispensing Equipments | | | |Presentation | | |4 |25 minutes |Presentation |Preparation for Dispensing Raw | | | | |Materials | |5 | |Small group |Dispensing Process for Pharmaceutical| | |40 minutes |discussion |Raw Materials | | | |Presentation | | |6 |05 minutes |Presentation |Key Points | |7 |05 minutes |Presentation |Evaluation | 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

NTA Level 6 • Semester 1 • PST06103 Validation of Pharmaceutical Raw Materials Pharmaceutical Production • Source Session/Topic 6 Full source-text version: all educational wording from the extracted learning source is retained; only presenter/tutor metadata and web-layout noise are removed, while formatting is improved for readability. 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 |Step |Time |Activity/ |Content | | | |Method | | |1 |05 minutes |Presentation |Introduction, Learning Tasks | |2 |15 minutes |Presentation |Definition of raw materials | |3 |40 minutes |Presentation |Validation of Pharmaceutical Raw | | | | |Materials | |4 |20 minutes |Presentation |Approaches and Importance of Raw | | | | |Materials Testing | |5 |30 Minutes |Presentation |Tests and Equipments for Raw | | | | |Materials Validation | |6 |05 minutes |Presentation |Key Points | |7 |05 minutes |Presentation |Evaluation | 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