NTA Level 6 • Semester 1 • PST06103

Validation of Pharmaceutical Raw Materials

Pharmaceutical Production • Source Session/Topic 6

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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.

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