1. Good Manufacturing Practices

2. The History of the FDA

3. Before Regulations  Medicine shows  Miracle, Wonder Tonics Guaranteed to cure all ills  Usually products which might contain alcohol, opium, morphine Led to addiction by users  No quality standards or manufacturing controls

4. Public Outcry  1905  Intended to bring attention to the miserable working conditions and the plight of impoverished factory workers, the book instead causes public outcry about food safety

5. The First Regulations  1906 Pure Food and Drug Act:  Illegal to sell adulterated (contaminated) food or drugs  Labeling must be truthful  Dangerous ingredients must be listed  Predecessor to FDA is created Bureau of Chemistry  Authority to seize illegal food and drugs  Twenty five years of lobbying to get this act passed

6. Human Tragedy  1935 Diethylene glycol (antifreeze) accidentally used in oral “elixir of sulfanilamide” resulting in 107 deaths, many of them children

7. Additional Regulations  1938 Food, Drug and Cosmetic Act:  Companies required to prove safety of their products  FDA is formalized and given additional authority Authority to prevent companies from making products (Injunctions) Authority to inspect companies Criminal prosecutions Define manufacturing and quality control requirements

8. More Human Tragedy  1941 Sulfathiazole cross-contaminated with Phenobarbital resulting in nearly 300 deaths  1960 Thalidomide used to treat morning sickness in pregnant women. Lack of testing results in 10,000 children born with serious deformities (phocomelia)

9.  1960 Amendment to FD&C Act:  Companies required to prove efficacy of their products  Drugs to be tested in animals before humans  Clinical studies required before approval Additional Regulations

10. Industry Guidelines - GMPs  1978 FDA establishes regulations known as Good Manufacturing Practices (cGMPs) for Finished Pharmaceuticals.  Contain minimum requirements to ensure purity, safety and efficacy of products.  The “c” in cGMP means current.  Holds everyone accountable for the quality and safety of products.

11. The FDA Today The FDA is responsible for protecting the public health by assuring the safety, efficacy, and security of human and veterinary drugs, biological products, medical devices, our nation’s food supply, cosmetics, and products that emit radiation. The FDA is also responsible for advancing the public health by helping to speed innovations that make medicines and foods more effective, safer, and more affordable; and helping the public get the accurate, science-based information they need to use medicines and foods to improve their health.

12. The FDA Website

13. Good Manufacturing Practices 21 CFR Part 211

14. Why GMPs? No more human tragedy! GMPs help prevent mix-ups and contamination GMPs are general and contain only minimum requirements Pharmaceutical Industry needs to go beyond the minimum requirements – Standard Operating Procedures (SOPs) Internal documents written by the company management You must read, understand and follow SOPs

15. GMP Compliance GMP compliance is about developing a sense of responsibility. This includes taking the time to learn GMPs, to be aware of your surroundings at all times, to follow all regulations and procedures, and to hold yourself and others around you to the highest standards of quality, performance, and professionalism.

16. When In Doubt Ask Questions One of the most important basic requirements of GMPs is to never assume anything. If you are unsure or unclear about anything, stop what you are doing and ask questions.

17. A. General Provisions B. Organization and Personnel C. Buildings and Facilities D. Equipment E. Components, Containers and Closures F. Production and Process Controls G. Packaging and Label Controls H. Holding and Distribution I. Laboratory Controls J. Records and Reports K. Returned and Salvaged Drug Products Subparts of 21 CFR Part 211

18. Subpart B Organization and Personnel

19. Presence of a Quality Control Unit Role of the QC Unit Approve or reject all components and finished products Approve or reject all procedures or specifications impacting the identity, strength, quality, and purity of the drug Review production records to assure no errors have occurred

20. Personnel Qualifications

21. Personnel Responsibilities Follow SOPs Wear clean clothing appropriate for the duties being performed Wear protective apparel to protect drug products from contamination Follow good hygiene practices Observe restricted access requirements Access cards Signs

22. Subpart C Buildings and Facilities

23. Design and Construction Features Aseptic Suites – Floors, walls, and ceilings of smooth hard, easily cleanable surfaces – Control of pressure, temperature, humidity, dust, and microorganisms – A system for cleaning and disinfecting the room and equipment to produce aseptic conditions

24. Breakrooms and Restrooms Breakrooms – Eating, drinking and smoking only allowed in designated areas Restrooms – Hot water and detergent must be available – Air dryers or single-service towels must be used

25. Waste Removal and Maintenance Sewage, Trash, and other Refuse – Dispose of in a timely, safe and sanitary manner Maintenance – Maintain buildings in a good state of repair

26. Sanitation – Maintain buildings in a clean and sanitary condition – Keep buildings free of infestation by rodents, birds, insects and other vermin – Written procedures detail and document the cleaning schedules, methods, and equipment used

27. Subpart D Equipment

28. Design and Construction Features Purchase and use equipment specifically designed for its intended use Materials of Construction – Non-reactive – Non-absorptive – Non-additive

29. Cleaning & Maintenance – Follow SOP – Use only approved cleaning agents and/or lubricants – Document – Independent verification

30. Calibration & Controller Access Calibration – Routinely calibrate, inspect or check equipment and document according to written procedures Access to Controls – Restricted to authorized personnel only

31. Subpart E: Control of Components

32. Receipt, Storage & Testing Handle and store in a manner to prevent contamination and mix-ups Store in a quarantine area until released Identification – Each lot is identified with a distinctive code and status Testing – Written sampling and test plans are used to ensure identity, strength, and quality

33. Subpart F Production and Process Controls

34. Production and Process Controls Written Procedures – Follow to ensure identity, strength, quality, and purity of every batch – Document production and process control functions at the time of performance – Record and justify all deviations (Variances) Charge-in of components Follow appropriate procedures for weighing, measuring, or subdividing components Ensure the correct identification and status of components Each component is to be added to a batch by one person and verified by a second person

35. Production and Process Controls Time limitations – For each phase of production when necessary to assure the quality of the product Equipment identification Proper identification is maintained at all times of the status of all compounding and storage containers, processing lines and major equipment The phase of the process is identified when necessary Each batch record shows the distinctive identification number or code of major equipment used to produce that batch

36. Subpart G: Packaging and Labeling Control

37. Physical or spatial separation of all packaging and labeling materials from other product batches Unique lot number is used to track the manufacture and control of the batch Expiration date required on label Every unit of finished product must be inspected for defects Physical Separation, Lot Number/Exp Date & Inspection

38. Subpart H: Holding and Distribution

39. Warehouse and Distribution Procedures Warehouse Quarantine products prior to release Store products under appropriate conditions so that the strength, quality and purity of the drug are not affected Distribution –Oldest stock used first (First In, First Out - FIFO) –System in place to facilitate a recall if necessary

40. Subpart I: Laboratory Controls

41. Specifications, standards and test procedures used are scientifically sound and proceduralized Release testing for each batch of product is performed Stability testing is performed to determine storage conditions and expiration dates Reserve samples of each lot are kept as necessary for investigations Laboratory Controls

42. Subpart J: Records and Reports

43. Batch Records – Consist of complete information relating to the production and control of each batch – Used to assure uniformity from batch to batch: recipe – All drug product and control records are reviewed by QC before a batch is released – Unexplained discrepancies are investigated Record Retention – Production, control and distribution records must be kept for a minimum of 1 year after the expiration date of each batch of product Annual Product Review – Used to identify trends or the need to change specifications and/or manufacturing processes Batch Records, Record Retention & APR

44. Documentation Practices Record all information immediately – never trust your memory Never fill out records in advance Never document someone else’s work Never assume that undocumented work has been completed Never destroy documentation or obliterate mistakes

45. Potential for Contamination Mix-ups cGMP Violations Resulting in Loss of dollars and profit Recall Regulatory Action Loss of life

46. YOU and GMPs Save Lives