1. IF IT WAS NOT DOCUMENTED, THEN IT WAS NOT DONE”
Fundamentals of US Regulatory Affairs
Chapter 8

2. Objectives Understanding GMP
Understanding basic quality system concepts and quality system regulations
Overview of key GMP regulations
Differences and similarities between pharmaceuticals and medical devices
Concept of clean design and process validation

3. Objectives (cont) Basic elements of sanitary equipment design
Effective cleaning and sanitation programs
CAPA system (Corrective And Preventative Action)
Cross-contamination risk within the manufacturing environment

4. cGMP (Current Good Manufacturing Practice)
GMP should be “Designed” to be flexible to allow each manufacturer to decide individually how to implement the necessary controls by using scientific sound design, processing methods and testing procedures
The “C” in GMP means current – up to date technologies
Overall concept
Quality should be built into the product
Testing alone cannot be relied on to ensure product quality
A product that is ‘fit for its purpose”

5. cGMP Principles
Build QUALITY in - you cannot test or inspect quality in to a product – it must first be quality
Have controls in place for each step of the process – increase the likelihood the product produced in safe and fit for its intended purpose
Product the product from contamination and cross-contamination and prevent mix-ups.

6. cGMP Principles (cont)
Know what you are doing in advance and document what really happened (document everything)
Work towards consistency and control and monitor your system
Have an independent Quality Assurance Group

7. GMP is global It is influenced by international bodies ICH
International Organization for Standardization (ISO)
cGMP Harmonization Analysis working group (FDA 2003) Modify 21CFR210 and 211 to meet ICH

8. GMP Regulations Non-biologics – FD&C Act section 501(a)(2)(b)
Finished Pharmaceuticals – 21CFR211 – Clinical supply dosage forms (including placebo) and commercially marketed dosage form
ICH Q7A GMP for Active Pharmaceutical Ingredients
Biologic Drug Products – 21CFR 210 and 211; 21CFR ; comply with BLA commitments and applicable standards
Quality Systems - ISO9000, non-US Pharmaceutical quality management requirements FDA Quality Requirement System (QRS)
Guidances and CPGM (Compliance Program Guidance Manuals) – for FDA GMP inspections – details cleaning validation, water systems, microbiological and QC labs, sterile bulk substance

9. cGMP Requirements (as many regulations as GCP)
A Quality System (change control, validation, CAPA
Qualified and trained personnel
Fit for use buildings and facilities to meet the purpose
Equipment that is suitable, clean, maintained and calibrated

10. cGMP Requirements (cont)
Controls in place to prevent degradation or contamination of materials (raw, in process and final)
Production and in-process controls for performance monitoring and deviations
Proper packaging and labeling – ID and Protection
Laboratory controls – specifications , samples, testing

11. Generic Drugs and GMP
Is identical or bioequivalent to a brand-name drug in dosage form, safety, strength, route of administration, quality, performance characteristics and intended use
Analytical testing of the chemical composition of the generic is determined to be the same as the branded product

12. Medical Devices FD&C Section 501(h) and 520(f)(1)
Amended in Medical Device Amendment
1978- Device GMP initiated
1996 – Revised ‘Quality System Regulations’
Human factors techniques and data should be integral considerations in all medical device design control components
Each manufacturer must establish and maintain procedures for verifying the design input
Design validation must ensure devices conform to defined user needs and intended users and must include testing of production units under actual or simulated use conditions
Design validation must include risk analysis and use error

13. Combination Products
Utilize the capabilities of two or more different product types to provide effective health care (21CFR3.2(c)) and cGMP (21CFR Part4 Subpart A)
The drugs and devices are still covered by individual regulations (21CFR210 and 211; 21CFR810 respectively)

14. cGMP for Phase 1 Investigational Drugs
Guidance for Industry: Current GMP Practice for Phase 1 Investigational Drugs (July 2008)
21CFR201.2 – If the Phase 1 drug is already marketed or used in Phase 2 or 3 trials, then it is exempt from 21CFR211
Trial Materials need
Well-defined and written procedures
Adequately controlled equipment and manufacturing environment
Accurately and consistently recorded data

15. cGMP for Phase 2 and Phase 3 Investigational Drugs
Guidance: Preparation of Investigational New Drug Products (1991)

16. Adulterated Drugs or Devices
A drug or device is considered adulterated unless it is manufactured in conformity with cGMP practices (newest industry standards)
A robust quality system is required to provide the necessary framework for implementing Quality by Design, continuous improvement and risk management
Whether documented on paper or electronic all data must be able to be traced back to the source and verified

17. Device Quality System Regulation (QSR)
Quality System is the organizational structure, responsibilities, procedures, processes and resources for implementing process management
Medical devices QSR are found in 21CFR820
ICH Pharmaceutical Quality System Q10
QSR states specific requiremnts for such key elements as management responsibility, quality planning, CAPA, design controls and purchasing control

18. Corrective And Preventive Action (CAPA)
Each Device manufacturer must maintain history files, a device ,aster record and a device history record for each type of device
Every company must have quality plans and quality system records that define its quality practices
Device Manufactures are required to establish purchasing controls and institute post-distribution device failure investigations and CAPA for defects or recurring technical problems

19. Pharmaceutical Quality System
Guidance for Industry: Quality Systems Approach to Pharmaceutical cGMP Regulations (June 2006); 21CFR210 and 211
The six-system inspection model
Quality system
Facilities and equipment system
Materials system
Production system
Packaging and labeling system
Laboratory controls
Robust Quality System will have
SPOs
Training
Records and good documentation practive

20. QC vs. QA Quality Control vs. Quality Assurance
The QC unit monitors overall compliance with cGMPs
The QA units supplies oversight by auditing the functions
They identify and investigate OOS (Out-of-Specification) results, deviations and failures in both production and the analytical laboratory.

21. Facilities and Equipment System
Areas are designated as clean and dirty,
Physical separation, equipment and staff for each operation
Specify personnel protection equipment and to prevent contamination by humans
Areas must operate to a single standard - GMP or non-GMP
Need to have designed into areas
Building materials, air handling, temperature, microbiology

22. Records Distribution records must be maintained to aid in recalls
Environmental Controls, Support systems, Alerts, Action Limits must be established
The environment must be controlled and monitored to prevent product cross-contamination and contamination by harmful microorganisms or extraneous matter (filth)

23. Microbiology Effects on product
Causing human illness
Product
Discoloration
Malodors
Production of gasses that can lead to package swelling or busting
Breakdown in viscosity or elasticity
Otherwise unable to perform as intended
Types: contact or airborne/ bacterial, yeast or mold
Resistance to product preservative system or sanitizers (think antibiotic resistance)
Classic Microbiology – takes h for aerobic bacteria; h for yeast or mold

24. Microbiology – areas of risk
Heat exchangers
Air compressors
Pumps
Water systems (Grades of water – WFI)
Valves
Ancillary Equipment (O-rings, pipes, clamps, gaskets
Effective Cleaning and Sanitation (C&S)
Autoclaves, sanitizer, alcohol, steam generators
CIP – Conducted on assembled equipment
COP – Conducted on dissembled equipment

25. Material System
The measurement and activities to control finished products, components containers and closures
Inventory Control Process
Drug Storage
Distribution Controls and Records
Written procedures for the receipt, storage, testing and approval or disapproval of raw materials components, products, containers and closures

26. Production System
Quality and manufacturing process and procedures (and changes to them) must be defined, approved and controlled.
Batch numbering and maintaining proper traceability is required
Track batch, equipment use records and labeling used, personnel, raw material controls are traceable
Verification of all steps including sign-off are required for critical process steps.
All batch records must be reviewed na d have QA approval before the product is released

27. Package and Labeling System
FDA ‘recommends’ as part of the design process and before commercial products that the controls for all processes within the packaging and labeling systems be planned and documented with written procedures.
Discriminating features of different products/strengths
Distribution of all labels to manufacturing unit
Reconciliation is performed between label issued, applied and returned (damaged) to insure 100% accountability

28. Laboratory Control system
Laboratory Controls and written documentation
Analytical Methods validation and laboratory equipment qualification
Scientifically sound stability program to support labeled expiration dating
Sampling program Statistical models to determine sample scheme
Proper training of QC staff to collect samples
Batch, water, microbiology, etc.
Retesting conditions

29. Critical Elements of Subsystems
SOPs
Describes how the company complies with the drug or device regulations and are critical to GMP compliance
See GLP review on overall view of SOPs
Change Control System – to prevent unintended consequences to product quality
Training
Records

30. Verification, Qualification and Validation apply to both Drugs and Devices
All operational methodologies and procedures utilized in manufacturing and testing be validated to demonstrate they can function as intended
Validation activities must be conducted I accordance with approved protocols and appropriate guidances
Process validation ensures that product quality, safety and effectiveness are designed and built into the final product (batch to batch output uniformity)

31. Process Validation
Guidance for Industry: Process Validation: General Principles and Practices (January 2011)
Stage 1 – Process Design: The commercial process is based on knowledge gained through development and scale-up activities
Stage 2 – Process Qualification: The process qualification is confirmed as being capable of reproducible commercial manufacturing
Stage 3 – Continued Process Verification: Ongoing assurance that the process remains in a state of control during routine production. Requires an ongoing program to collect and analyze product and process data that relate to product quality (21CFR (e))
Requires an interdisciplinary team approach (process engineering, industrial pharmacy, analytical chemistry, microbiology, statistics
“Begin with the end in mind”

32. Method Validation
Draft Guidance for Industry: Analytical Procedures and Methods Validation – Chemistry Manufacturing and Controls Documentation (August 2000)
Generics - USP
Each method used to analyze the drug or biologic must have associated validation to support the documentation of drug substance, product identity, strength, purity, and potency

33. Key GMP Concepts

34. Key GMP Concepts (cont)

35. Key GMP Concepts (cont)
IF IT WAS NOT WRITTEN DOWN, THEN IT WAS NOT DONE