1. cGMP Training Program Current Good Manufacturing Practices Quality | Compliance | Patient Safety

2. Training Agenda • Introduction to cGMP • Quality Systems & Documentation • Contamination Control & Facilities • CAPA, Validation & QA/QC • Case Examples & Key Takeaways

3. Learning Objectives • Understand cGMP principles and regulations • Identify roles of QA and QC • Recognize contamination and microbiological risks • Apply CAPA and validation concepts in daily work

4. Objectives • Understanding GMP • Understanding basic quality system concepts and quality system regulations • Overview of key GMP regulations • Concept of clean design and process validation

5. 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

6. 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”

7. 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 • Protect the product from contamination and cross-contamination and prevent mix-ups.

8. 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

9. GMP is global • It is influenced by international bodies • ICH • International Organization for Standardization (ISO) • cGMP Harmonization Analysis working group (FDA 2003) Modify 21CFR210

10. 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

11. 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

12. 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

13. QC vs. QAQuality 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.

14. 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

15. 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)

16. Microbiology • Effects on product • Causing human illness • Product • Discoloration • Malodors • Production of gasses that can lead to package swelling or busting

17. Microbiology – areas of risk • Heat exchangers • Air compressors • Pumps • Water systems (Grades of water – WFI) • Valves • Ancillary Equipment (O-rings, pipes, clamps, gaskets

18. 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

19. 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

20. 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

21. 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.

22. 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

23. Verification, Qualification and Validation • 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)

24. 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 (21CFR211.180(e)) • Requires an interdisciplinary team approach (process engineering, industrial pharmacy, analytical chemistry, microbiology, statistics • “Begin with the end in mind”

25. 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

26. Key Takeaways • Quality must be built into the process • Documentation is critical for compliance • Prevent contamination at every stage • Consistency and control ensure patient safety