cGMPs for Pharmaceutical Manufacturing

Objectives
1.

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

2.

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

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?

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

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 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)

Found in Code of Federal Regulations (CFR)

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Guidance documents published by FDA and International Conference on Harmonization (ICH) Draft guidance documents Preamble documents published by government FDA 483 inspectional observations documents Warning letters from FDA to various companies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

What Happens if cGMPs 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
Legal Consequences

FDA 483s

FDA warning letters

Consent decree

Recall of product

Product seizure

Plant

Injunction

Company

closure

Debarment

Consequences of Non-compliance
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

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

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 crosscontamination 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 cGMPs

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 cGMPs

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

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

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 outof-specifications (OOSs)

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

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)

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

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)

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.

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

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

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

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

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

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

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

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

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!!!