Basic Good Manufacturing Practices for Pharmaceutical Manufacturing

1. cGMP’s for Pharmaceutical
Manufacturing

2. Objectives
1. To understand where the regulations
come from, who has enforcement
authority, and why you need to comply
2. To understand the “Fundamentals”,
“Benefits” and “Key Parts” of cGMPs

3. What are cGMPs?
Current Good Manufacturing Practices
Come from the Food Drug and Cosmetic
Act
Rules set up by the FDA that drug
manufacturers needs to follow in order to
ensure that a safe and effective product is
manufactured

4. Where Did the Food Drug and
Cosmetic Act Come From?
1906 book by Upton Sinclair
The Jungle exposed the
dangers involved in the meat
packing industry
Helped drive public opinion to
support a new law passed by
Congress
Food Drug and Cosmetic Act

5. Provisions of the Law
(FDC Act)
– Creation of Federal Government agency
to oversee food industry
– Scope expanded later to medical
industry

6. Who Interprets and Enforces
This Law?
The FDA (Food and Drug Administration) is
an agency within the Department of Health
and Human Services and consists of eight
centers/offices.

7. FDA
The FDA consists of eight branches
Center for Biologics Evaluation Center for Devices and
and Research (CBER) Radiological Health (CDRH)
Center for Drug Evaluation Center for Food Safety and
and Research (CDER) Applied Nutrition (CFSAN)
Center for Veterinary Medicine National Center for Toxicological
(CVM) Research (NCTR)
Office of the Commissioner (OC) Office of Regulatory Affairs
(ORA)

8. Interpretations of the Law
The Code of Federal Regulations is a
government publication where Federal Agencies
post regulations
– Contain regulations enforced by the DOT, DEA,
FCC, FDA, and all other agencies
Found in Code of Federal Regulations (CFR)
– Drug (cGMP): Title 21, Part 210 & 211
– Device (QSR): Title 21, Part 820
– Combination Product: Title 21 CFR Part 3 Subpart
A (section 3.2e)

9. Interpretations of the
Regulations
Guidance documents published by FDA and
International Conference on Harmonization (ICH)
Draft guidance documents
Preamble documents published by government
FDA 483 inspectional observations documents
Warning letters from FDA to various companies
www.fda.gov

10. What Happens if cGMP’s are
not Followed?
– Adulteration: “A drug is deemed to be
adulterated if the methods used in or the facilities
or controls used for its manufacture, processing,
packing, or holding do not conform to or are not
operated or administered in conformity with
cGMP to assure that such drug meets the
requirements of this act as to Safety and has the
Identity and Strength, and meets the Quality
and Purity characteristics which it purports or is
represented to possess.”

11. Why Comply?
• Food drug and cosmetic act is the law
• When charged with a violation:
– Proof of criminal intent is not necessary. (Guilty
until proven innocent)
– Actual harm from contamination does not need
to be proven.
– (Passing product ≠ non-adulterated product)
• Consequences are numerous

12. Consequences of
Non-compliance
Legal Consequences
– FDA 483s
– FDA warning letters
– Consent decree
– Recall of product
– Product seizure
– Plant Injunction
– Company closure
– Debarment

13. Consequences of
Non-compliance
Business Consequences
– Expensive to do recalls
– Loss of sales
– Bad publicity
– Potential harm to customers

14. Fundamentals of cGMPs?
– Based on fundamental concepts of
Quality Assurance Principles
Control
Quality, safety, and effectiveness must be
designed and built into the product
Quality cannot be inspected or tested into a
finished product
Each step of manufacturing must be
controlled to maximize the chances that the
Finished Good will be acceptable

15. What are the Benefits of cGMPs?
– They outline a Quality System that reduces or
prevents errors
– Ensures products are safe for use in humans
– Prevent/control contamination and cross-
contamination
– Minimizes variations in potency of the drug
– Ensures reproducible physiological activity
– Prevent side effects and toxicity due to
variations in drug content and potency
– Prevents mislabeling and adulteration

16. Key Parts of cGMP’s
Subpart B: Organization and Personnel
Subpart C: Buildings and Facilities
Subpart D: Equipment
Supbart E: Control of Components and Drug
Product Containers and Closures
Subpart F: Production and Process Controls

17. Key Parts of cGMP’s
Subpart G: Packaging & Labeling Control
Subpart H: Holding & Distribution
Subpart I: Laboratory Controls
Subpart J: Records & Reports
Subpart K: Returned & Salvaged Drug
Product

18. Organization and Personnel
Management Responsibility
– Responsible for facility, quality system,
organizational structure, ensuring adequate
resources
– Responsible for actions of those reporting to them
– Responsible for reviewing products annually, and
procedures routinely
– Responsible for providing adequate resources to
perform operations
Facilities, personnel, training, equipment, etc

19. Quality Unit
Responsible for approval or rejection of
– all components, raw materials, containers, closures,
subassemblies, packaging, labeled finished
products, process validation reports, procedures
and product specifications
– Investigative reports for non-conformances and out-
of-specifications (OOS’s)

20. Quality Unit
Responsible for reviewing production records
and ensuring that no errors have occurred
(may include verification activities)
Responsible for releasing product for use
Must be independent of manufacturing

21. Buildings and Facilities
Buildings must be designed with adequate size and space
for operations (helps to eliminate mix-ups)
Facilities must be validated
There must be a good flow pattern for personnel,
materials, products and waste materials (flow from clean to
dirty)
The facility must be easy to clean and sanitize (surfaces,
equipment, exposed cords, floors, ceilings…)
Environmental controls must be in place (clean rooms)
Utilities must be validated (water systems, electrical, etc)

22. Buildings and Facilities
Must have engineering documents describing the layout of
the clean rooms – controlled documents
Changes to the layout of the room after it has been
validated must go through change control procedures and
may require revalidation of the room
Any changes that potentially impact the ventilation in the
room must be assessed for impact on the microbial levels
in the room
Microorganisms, particulates, and hazardous materials
must be controlled

23. Equipment
Equipment should be selected based on the
intended use and cleanability if it is to be in a
clean room
Equipment must be placed in an appropriate
location (temperature, humidity, etc.)
Equipment must be properly qualified (Design,
Installation, Operation, Performance)

24. Component/Materials Control
Suppliers must be evaluated and approved and
monitored for quality
Incoming Materials must be tested before they can be
accepted for use
Materials must be placed in stores or issued according
to FIFO (stock rotation)
Materials must be stored so that they are not mixed
up, damaged, or contaminated.

25. Production/Process Control
Have & Follow Procedures: A good
procedure is a written step-by-step
procedure that provides a roadmap for
Controlled and Consistent performance.
Examples:
– (Manufacturing) Work Instructions
– Operating Procedures
– Testing Procedures
– Quality Manual
Deviations must be recorded and justified

26. Procedures should address…
…verification of critical steps by a second
person
…line clearance
…monitoring of processes to make sure they
are in control
…time limits and yield calculations as
appropriate checks for critical processes
…gowning for controlled environments
(cleanrooms)

27. Packaging and Labeling Control
Label is a display of a written, printed or graphic
matter upon the immediate container of any article
Labeling is the label and any other packaging material
or container that is printed (ex. IFU, advertising
materials)
Procedures must exist that document receiving,
identity, storage, handling, sampling, and testing of
labels and ensure that integrity is maintained
throughout production and use of product

28. Packaging and Labeling Control
Labeling must be separated physically in storage to
avoid mix-ups
Wording of labels cannot be changed unless the
FDA is notified
Labeling must be inspected prior to issuing to
production
All labels must be reconciled (accounted for) if not
100% inspected.
Label control begins with the design

29. Holding and Distribution
Warehousing procedures should address…
…Quarantine of drug products
…storage of products under appropriate conditions
Distribution procedures should address…
…FEFO (First Expiring First Out)
…traceability of product lots/batches

30. Laboratory Controls
Written procedures must be established & followed
All actions must be documented at the time of
performance
Calculations need to be recorded
Second person must review records
Data must be directly recorded into appropriate records
Equipment, software, and methods must be validated
An Out-of-Specification (OOS) result must be investigated
and a root cause identified
Laboratory data is considered to be a quality record

31. Records and Reports
Quality Records are the proof that the
procedures were followed and they show
traceability of product.
Examples:
– Lot History Records
– Laboratory Notebooks
– Protocols
– Reports
– Logbooks
– Distribution Records
– Complaint Files

32. Quality Records
Records are legal documents and can be subpoenaed
in a court of law as evidence
Signatures on documentation have the same meaning
as on any kind of contract
Information must be recorded and signed for at the
time of performance on the original record

33. Website References
http://www.fda.gov (Food and Drug Administration)
http://www.fda.gov/foi/warning.htm (FDA Warning Letters)
http://www.access.gpo.gov/uscode/title21/chapter9_.html
(Food Drug and Cosmetic Act)
http://www.gpoaccess.gov/fr/index.html (Federal Register)
http://www.fda.gov/opacom/morechoices/industry/guidedc.
htm (Guidance Documents)
http://www.ich.org (International Conference on Harmonization)
http://www.pda.org (Parenteral Drug Association)

34. Q&A
Make GMP a lifestyle!!!