cGMP’s for Pharmaceutical

Manufacturing
 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
 What are cGMPs?

z Current Good Manufacturing Practices

z Come from the Food Drug and Cosmetic

Act

z Rules set up by the FDA that drug

manufacturers needs to follow in order to
ensure that a safe and effective product is
manufactured
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

 Provisions of the Law
(FDC Act)

– Creation of Federal Government agency

to oversee food industry

– Scope expanded later to medical

industry
Who Interprets and Enforces
This Law?

z The FDA (Food and Drug Administration) is

an agency within the Department of Health
and Human Services and consists of eight
centers/offices.
 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)
 Interpretations of the Law

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z Draft guidance documents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

www.fda.gov
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.”
 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
 Consequences of
Non-compliance

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

z Business Consequences

– Expensive to do recalls
– Loss of sales
– Bad publicity
– Potential harm to customers
 Fundamentals of cGMPs?

– Based on fundamental concepts of

Quality Assurance Principles
z Control
z Quality, safety, and effectiveness must be
designed and built into the product
z Quality cannot be inspected or tested into a
finished product
z Each step of manufacturing must be
controlled to maximize the chances that the
Finished Good will be acceptable
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
 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
 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
 Organization and Personnel

z 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
z Facilities, personnel, training, equipment, etc
 Quality Unit

z 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)
 Quality Unit

z Responsiblefor reviewing production records

and ensuring that no errors have occurred
(may include verification activities)

z Responsible for releasing product for use

z Must be independent of manufacturing

 Buildings and Facilities

z Buildings must be designed with adequate size and space

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

z Must have engineering documents describing the layout of

the clean rooms – controlled documents
z 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
z Any changes that potentially impact the ventilation in the
room must be assessed for impact on the microbial levels
in the room
z Microorganisms, particulates, and hazardous materials
must be controlled
 Equipment

z Equipment should be selected based on the

intended use and cleanability if it is to be in a
clean room
z Equipment must be placed in an appropriate
location (temperature, humidity, etc.)
z Equipment must be properly qualified (Design,
Installation, Operation, Performance)
 Component/Materials Control

z Suppliers must be evaluated and approved and

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

z Have & Follow Procedures: A good

procedure is a written step-by-step
procedure that provides a roadmap for
Controlled and Consistent performance.
z Examples:
– (Manufacturing) Work Instructions
– Operating Procedures
– Testing Procedures
– Quality Manual
z Deviations must be recorded and justified
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)
Packaging and Labeling Control

z Label is a display of a written, printed or graphic

matter upon the immediate container of any article
z Labeling is the label and any other packaging material
or container that is printed (ex. IFU, advertising
materials)
z 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
 Packaging and Labeling Control

z Labeling must be separated physically in storage to

avoid mix-ups
z Wording of labels cannot be changed unless the
FDA is notified
z Labeling must be inspected prior to issuing to
production
z All labels must be reconciled (accounted for) if not
100% inspected.
z Label control begins with the design
 Holding and Distribution

z Warehousing procedures should address…

…Quarantine of drug products
…storage of products under appropriate conditions

z Distribution procedures should address…

…FEFO (First Expiring First Out)
…traceability of product lots/batches
 Laboratory Controls

z Written procedures must be established & followed

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

z Quality Records are the proof that the

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

z Records are legal documents and can be subpoenaed

in a court of law as evidence

z Signatures on documentation have the same meaning

as on any kind of contract

z Information must be recorded and signed for at the

time of performance on the original record
 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)
 Q&A

Make GMP a lifestyle!!!