BSPh 303:

PHARMACEUTICAL
MANUFACTURING
(with Regulatory Pharmacy, Quality Assurance and cGMP)

Jean Kathleen Gran, RPh

Pharmaceutical Manufacturing
Manufacture, preparation, propagation of drug products in a large scale basis;
mass production.
Making by physical, chemical, biological means that meet the definition of drugs
(according to Pharmacy Law):
◦ Official compendia ex. USP/NF, BP, JP
◦ Agent other than food that is used for treatment of diseases.
◦ Alters body functions.
◦ Excipients and additives

Extemporaneous Compounding –patient-specific; small-scale.

Pharmaceutical Manufacturing
•Quality Assurance (QA)
-quality monitoring, auditing.
-oversees all departments.
•Quality Control (QC)
-involves testing or QC procedures
Raw Materials QC –concerned with identity and purity.
In-Process QC –random sampling.
Final Product QC –involves packaging, repacking, wrapping, and labeling (most critical part).
Drug Establishments
1. Drug Manufacturer
Proprietary/Non-proprietary –branded and generic drugs.
Ethical –prescription drugs
Veterinary –animal drugs
Biological –vaccines, toxoids, immunoglobulins.
Chemical/Medicinal –excipients or additives.
Toll –manufactures products of other drug companies.
Drug Establishments
2. Drug Trader –registered owner of a drug product; subcontracts toll
manufacturers.
3. Drug Distributor –distributes raw material, APIs, and final products in a whole-
sale basis.
4. Drug Importer –imports raw materials, APIs and final products for local
distribution.
5. Drug Exporter –exports raw materials, APIs and final products to other
countries.
6. Drug Supplier –manufacturer, trader, importer.
Departments
1. Research –research and development.
-try to formulate new products and improve existing products.
2. Marketing –sister department of research.
-conducts forums, seminars, conventions, advertisements and promos.
3. Production –manufactures products, receives supply, warehousing and
storage, personnel and procedure control (e.g. Master Batch Record –validated
specification)
4. Engineering –installs and maintains equipment.
Departments
5. Quality Control (QC) –heart and soul of the drug establishment; ensures
quality and public safety.
-conducts systematic sampling, assaying and recording.
6. Quality Assurance –audits the results of the tests and assays of the QC
department.
7. Purchasing –buys raw materials; inventory control.
8. Medical –annual physical exam of employees, treatment of sick employees.
-conducts clinical studies; creates package inserts, house
organization/newsletter.
Current Good Manufacturing
Practices
FDA ensures the quality of drug products by carefully monitoring drug
manufacturers' compliance with its Current Good Manufacturing Practice
(CGMP) regulations.
The CGMP regulations for drugs contain minimum requirements for the
methods, facilities, and controls used in manufacturing, processing, and packing
of a drug product.
The regulations make sure that a product is safe for use, and that it has the
ingredients and strength it claims to have.
Current Good Manufacturing
Practices:
Brief History
1905: The Jungle by Upton Sinclair
 Pure Food and Drug Act 1906
-adulterated and misbranded drugs became illegal
Bureau of Chemistry (USDA) –Harvey Wiley, Chief Chemist

1933: America’s Chamber of Horrors –shortcomings of the 1906 law.

Eleanor Roosevelt campaigned for stronger consumer protection.
Current Good Manufacturing
Practices:
Brief History
1938: Elixir of Sulfanilamide (+diethylene glycol) = 107 died (DEG in the body becomes oxalic
acid which causes renal failure)
Food, Drug and Cosmetic Act –safety > market; factory inspectioons
1941: Sulfathiazole tablets (+phenobarbital) = ~300 died
Revise Manufacturing and Control Requirements (now GMP)
1941 & 1945: Batch certification of insulin and penicillin
1955: Polio vaccine (Jonas Salk) lot with improperly inactivated virus = 60 inoculated + 80
contracted.
Current Good Manufacturing
Practices:
Brief History
1962: Thalidomide Tragedy = 10,000 cases of phocomelia (teratogenic)
Kefauver-Harris Drug Amendments – safety + efficacy > market; regulating
clinical trials by animal testing; reporting adverse effects.
1978 & 1979: cGMPs Final Rules for drugs and devices and GLPs Final Rule
1982: Acetaminophen (Tylenol®) capsules (+cyanide) = 7 died (J & J recall 31
million bottles)
Anti-Tampering Act of 1983 –tamper-resistant packaging regulations.
Current Good Manufacturing
Practices:
Brief History
1987: Guidelines on General Principles of Process Validation
1989: L-tryptophan (impurities) = 1500 eosinophilia-myalgia syndrome cases.
EU and USA “Guidance for Industry: Manufacturing, Processing, or Holding of
API”
International Conference on Harmonization (ICH)
1992: Generic drug scandal (bribery and fraud case)
Generic Drug Enforcement Act + debarment penalty
Current Good Manufacturing
Practices:
Brief History
1996: Proposed Revision to US cGMPs for drugs & biologics
added detail for validation, blend uniformity, prevention of cross-
contamination, handling out-of-specification results.
1998: Draft Guidance
 + Manufacturing, Processing or Holding APIs and Investigating out-
of-specification test results for Pharmaceutical Production.
Good Manufacturing Practices
Part of QA which ensures that products are consistently produced
and controlled to the quality standards appropriate to their intended
use.
Aimed primarily at diminishing the risks of pharmaceutical
production (2 categories: cross contamination/mix-ups and false
labelling).
Includes risk assessment
Ensures that minimum standards comply with the FDA for public
safety.
Good Manufacturing Practices
Main Principles: Personnel
Pharmaceutical Quality System Training
GMP for Pharmaceuticals Personal Hygiene
Sanitation and Hygiene Premises
Qualification and Validation Equipment
Complaints Materials
Product Recalls Documentation
Contract production, analysis and other activities Good practices in production
Self-inspection, quality audits, and suppliers’ Good practices in QC
audits and approval
Packaging
Economical means of providing presentation, preservation, protection, identification,
information, convenience, containment, compliance to the drug.
Container –device that holds the drug.
2 Types of Packaging:
Primary –direct contact with the drug
Secondary –additional protection.
Packaging
Classifications:
a. According to protective ability
Well-closed –protects against extraneous solids.
Tight –protects against solids, liquids, gases and loss of drug due to efflorescence (loss of
water/dehydration when exposed to air), deliquescence (liquefy when exposed to air) and
vaporization.
Hermetic –impervious to air or any gases.
Light-resistant –protects against photodegradation.
 Packaging
b. According to quantity held (for parenterals)
Single unit –single dose, single administration; can’t ensure sterility after opening.
-(sterile) water for injection (WFI/SWFI)
-ex. Normal saline solution (NSS), dextrose solution, ampules.
-USP limit: 1000 mL/1L
Multiple unit –multiple administration; USP limit: 30 mL
-bacteriostatic water for injection (BWFI) with antimicrobial agent.
-Ex. vials
Materials Used for Containers
Glass –advantages: transparent Powder glass test –literal; tests for
leaching (material transfer from
-disadvantages: heavy, breakable. container to drug); for types I, III & IV
Type I: highly-resistant borosilicate Water attack test –glass is exposed to
glass; parenteral SO2 in 121⁰C to test for permeation
Type II: Treated soda-lime glass; (entry of gas into container); for type II.
parenteral
Type III: soda-lime glass, parenteral
Type IV: general purpose glass
Materials Used for Containers
Plastic –advantages: light-weight, resistant to impact.
-disadvantages: leaching, sorption (material transfer from drug to container),
permeation.
Polyethylene (PE) –non-autoclavable
Polypropylene (PP) –autoclavable (121⁰C, 15 psi, 15-20 minutes)
Polyethylene terephthalate (PET) –used in beverages (transparent), gamma
sterilization
Polyvinyl chloride (PVC) –used in blister packaging
Materials Used for Containers
Paper
Bond paper –no moisture resistance, opaque (light-resistant)
Vegetable parchment –limited moisture resistance, thin, semi-
transparent.
Glassine –moisture-resistant; for volatile drugs.
Wax Paper –moisture-resistant, water-proof, for volatile, hygroscopic,
deliquescent, efflorescent drugs
Safety Packaging
Child-resistant Container –principle: <5 year olds can’t open
because they are unable to coordinate 2 successive actions
(mechanisms: push then twist)
Tamper-resistant –distinctive design in which if breached or
missing indicates that tampering occurred (Ex. Foil seals,
breakable cups, tape seals)
Aerosols –only true tamper-resistant container.
Storage Conditions
Descriptive term Temperature
Cold <8⁰C
• Freezer -20⁰C - -10⁰C
• Refrigerator 2-8⁰C
Cool 8-15⁰C
Room temperature (RT) Temperature prevailing in the work area
Controlled Room temperature 20-25⁰C
15-30⁰C (for alcohols)
USP normal temperature 25⁰C
Warm 30-40⁰C
Excessive heat >40⁰C
Product Lifecycle
Management