Good Manufacturing Practices for BioTechnology

1. Good Manufacturing Practices for BioTechnology • Steven S. Kuwahara, Ph.D. • GXP BioTechnology, LLC • PMB 506, 1669-2 Hollenbeck Ave. • Sunnyvale, CA 94087-5042 • Tel. & FAX (408) 530-9338 • E-Mail: stevekuwahara@yahoo.com AUCBMedProd2005

2. History of U.S. Food and Drug Law. • 2,000 BCE, Sumerian clay tablets and the Ebers papyrus (oldest known medical text) refer to analgesic properties of Willow and Myrtle leaves. • English Common Law: 1202 King John proclaims the Assize of Bread. • Prohibits adulteration of bread with ground peas or beans. • 1668 Merck begins business as an apothecary shop in Darmstadt, Germany AUCBMedProd2005

3. Early Drug Laws & History • Napoleonic Code: 1804. • Producers of beverages must declare the contents of the beverages. • Results in makers of “eau de toilette” declaring them to be “scents” and eventually called “Colognes.” • 1830 -1840 Schering, Hoffmann-La Roche, Burroughs Wellcome, Etienne Poulenc, Abbott, Smith Kline, Parke-Davis, Eli Lily, Squibb & Upjohn all begin as apothecaries or drug suppliers. AUCBMedProd2005

4. Early Drug History I • 1830 – 1840 Agfa, Bayer, Hoechst, Ciba, Geigy, Sandoz, Imperial Chemicals, & Pfizer begin producing organic chemicals. • 1880’s Analgesics: acetanilide & phenacetin synthesized. N-acetyl-p- aminophenol found to be metabolite becomes active ingredient in Tylenol and Panadol. • 1897 Felix Hoffmann at Bayer synthesizes aspirin. AUCBMedProd2005

5. Early Drug History II • Late 1800’s: Vaccines for diphtheria and tetanus were developed. • 1906: Paul Ehrlich postulates that synthetic chemicals can selectively kill disease-causing microbes. He pursues first systematic search for a drug and produces the arsenical, Salvarsan, which is the first antisyphilitic. AUCBMedProd2005

6. History of U.S. Food and Drug Law 1820. • 1498: First pharmacopeia/formulary written for apothecaries in Florence, Italy. • 1820: 11 physicians meet in Washington, D.C. and establish the U.S. Pharmacopeia. • Compendium, but no legal status. • Legal status comes later with recognition by congress as a source of pharmaceutical standards. AUCBMedProd2005

7. History of U.S. Food and Drug Law 1848. • 1848: Drug Importation Act requires inspection by U.S. Customs Service. • Prevents importation of adulterated drugs. • U.S. was like a third world country. All kinds of ineffective nostrums and adulterated preparations were being imported. • 1862: Lincoln forms the U.S. Department of Agriculture and appoints a chemist as head of the Bureau of Chemistry. AUCBMedProd2005

8. History of U.S. Food and Drug Law 1880. • 1880: Chief Chemist of USDA recommends passage of national Food and Drug law based on his investigations. • The bill is defeated. In the next 25 years 100 more bills will be introduced and defeated. • 1883: Harvey Wiley (chemist and M.D.) is appointed as head of the Bureau of Chemistry. He will be known as the “Crusading Chemist” and “Father of the Pure Food and Drugs Act.” AUCBMedProd2005

9. History of U.S. Food and Drug Law 1898. • 1898: Association of Official Agricultural Chemists (Now AOAC International) Forms a committee on Food Standards headed by Dr. Wiley. • 1902: Biologics Control Act is passed to control purity and safety of sera, vaccines etc. U.S. Hygenic Laboratory will eventually become the Center for Biologics Evaluation and Research • 1902: Congress gives $5,000 to the Bureau of Chemistry to study preservatives and colors. AUCBMedProd2005

10. History of U.S. Food and Drug Law 1906. • 1906: With the strong support of Theodore Roosevelt, the Food and Drugs Act is passed on the same day as the Meat Inspection Act. • The act prohibits interstate commerce in misbranded or adulterated foods, drinks and drugs. • Meat becomes a special class of food and will be regulated by the USDA. • Result of unsanitary conditions, use of poisonous additives, cure-all claims for ineffective or dangerous patent medicines. AUCBMedProd2005

11. History of U.S. Food and Drug Law 1900. • At this time the prevailing philosophy was that the public should be told what ingredients were present and should “make up their own minds” about the utility of a drug or the danger of a food. • 1911: U.S. v Johnson ruled that the Food and Drug Act did not prohibit false therapeutic claims; only false claims about ingredients or identity. AUCBMedProd2005

12. History of U.S. Food and Drug Law 1912 & 27. • 1912: Congress passes the “Sherley Amendment. • Prohibits labeling with false therapeutic claims intended to defraud the purchaser. • Manufacturer is innocent if he can claim a lack of intent to defraud. • 1927: Food, Drug, and Insecticide Administration is formed within the Bureau of Chemistry. AUCBMedProd2005

13. History of U.S. Food and Drug Law 1930 & 33. • 1930: Name is changed to the Food and Drug Administration (still within the USDA). • 1933: FDA recommends a revision of the 1906 Food and Drugs Act. • Bill is introduced into the Senate and a five-year legislative battle begins. • Deaths and a scandal will be needed to pass it. AUCBMedProd2005

14. History of U.S. Food and Drug Law 1937. • 1937: Elixir of Sulfanilamide, made by the S.E. Massengill Co., kills 107 people (many children) because the solvent (glycerin) is heavily contaminated with diethylene glycol. Scientist made substitution on the basis of taste without checking literature. • Prosecution is successful only because the term “elixir” required the use of ethyl alcohol. Product was therefore misbranded and a recall was possible. • 60 years later an almost identical event will kill 87 children in Haiti. Acetaminophen was the active ingredient. AUCBMedProd2005

15. History of U.S. Food and Drug Law 1938a. • 1938: Food, Drug, and Cosmetic Act (FDCA) is passed. • Extends control to cosmetics and therapeutic devices. • Requires that new drugs be shown to be safe before marketing. • Eliminates requirement to prove intent to defraud in drug misbranding. • Adds court injunctions to previous seizures and prosecutions as penalties. AUCBMedProd2005

16. History of U.S. Food and Drug Law 1938b. • Wheeler-Lea Act: The Federal Trade Commission (FTC) is charged with regulating advertising of FDA products with the exception of prescription drugs. This situation still exists. • 1940: FDA is transferred from the USDA to the Federal Security Agency. First commissioner named. AUCBMedProd2005

17. History of U.S. Food and Drug Law 1943. • U.S. v Dotterweich: Supreme court rules that responsible officials and the corporation itself may be prosecuted for violations. • It need not be proven that the officials intended or even knew, of the violations. • 1944: Public Health Service Act covers regulation of biologics and control of communicable diseases. • Places biologics under the Public Health Service. AUCBMedProd2005

18. History of U.S. Food and Drug Law 1949. • First FDA “Guidance to Industry” known as the “Black Book”. • Title was “Procedures for the Appraisal of Toxicity of Chemicals in Food”. • 1950: Alberty Foods Products v U.S.: Court rules that directions for use on a drug label must include the purpose for which the drug is offered. Therefore a worthless remedy cannot escape the law by not stating the condition it is supposed to treat. AUCBMedProd2005

19. History of U.S. Food and Drug Law 1951. • Durham-Humphrey Amendment: Defined the kinds of drugs that require medical supervision and restricted their sale to prescription. • 1953: Federal Security Agency becomes the Department of Health, Education and Welfare (DHEW). • 1953: Factory Inspection Amendmentclarifies previous rules and requires inspectors to provide written reports of inspection observations. AUCBMedProd2005

20. History of U.S. Food and Drug Law 1955. • NIH biologics control function becomes the Division of Biologics Control. • This is after a scandal where 260 cases of polio result from the release of a vaccine that was supposed have been inactivated. • (Inactivation method was ineffective due to process error. Laboratory testing did not detect this, and permission to release was given.) AUCBMedProd2005

21. History of U.S. Food and Drug Law 1960 - 1961. • Color Additive Amendment: Requires manufacturers to establish safety of color additives in foods, drugs, and cosmetics. Delaney clause prevents use of any color additive shown to cause cancer in humans or animals. • About this time the thalidomide scandal hits. Chemie Gruenenthal in Germany affects over 10,000 infants. AUCBMedProd2005

22. German Response • 1961: German law requires registration of all new medicines. • 1964: German law is strengthened to require that all new drugs be prescription drugs. • 1976: Germans finally pass law that formally requires safety and efficacy testing before marketing. AUCBMedProd2005

23. History of U.S. Food and Drug Law 1962. • 1962: Consumer Bill of Rights proclaimed by John F. Kennedy in message to congress. Includes: right to safety, to be informed, to choose, and right to be heard. • 1962: Kefauver – Harris Amendments. Require that manufacturer prove that drugs are efficacious before marketing them. • Previous requirement was only for safety. Thalidomide case did have an impact. AUCBMedProd2005

24. History of U.S. Food and Drug Law 1966. • 1966: FDA initiates an NAS/NRC contract to study efficacy of 4,000 drugs approved between 1938 and 1962. • These will be known as DESI products. AUCBMedProd2005

25. History of U.S. Food and Drug Law 1966. • Fair Packaging and Labeling Act. • All consumer products in interstate commerce must be honestly and informatively labeled. • FDA enforces provisions on foods, drugs, cosmetics and medical devices. Note:This covers labeling, not advertising. • 1968: FDA Bureau of Drug Abuse Control is combined with Treasury Dept. Bureau of Narcotics to form Bureau of Narcotics and Dangerous Drugs (BNDD) in the Justice Dept. AUCBMedProd2005

26. History of U.S. Food and Drug Law 1968. • FDA is placed in the Public Health Service along with CDC & NIH. • Animal Drug Amendments place new animal drugs and medicated feeds under FDA. • EPA established and takes over FDA pesticide tolerance program. AUCBMedProd2005

27. History of U.S. Food and Drug Law 1970. • Upjohn v. Finch: Court rules that commercial success alone does not constitute substantial evidence of safety and efficacy. • 1972: Review of over-the counter (OTC) drugs to determine safety, efficacy, and appropriate labeling. • DESI extended to OTC. • 1972: Regulation of biologics transferred from NIH to FDA. DBS becomes BoB. AUCBMedProd2005

28. History of U.S. Food and Drug Law 1976. • Medical Device Amendments passed to cover safety and efficacy of devices and includes diagnostic products. Registration with FDA now required and GMPs must be followed. • Vitamins and Minerals Amendments (Proxmire amendments): Stop FDA from establishing standards limiting the potency of vitamins and minerals in food supplements or regulating them as drugs based on their potency. AUCBMedProd2005

29. History of U.S. Food and Drug Law 1977. • Saccharin Study and Labeling Act. • Prevents FDA from banning it but requires label about carcinogenicity. • 1980: Infant Formula Act. FDA controls on nutrition and safety. • 1982: Tamper-Resistant Packaging Regulations issued by FDA as GMP. • 1983: Orphan Drug Act. Promotes research and marketing. AUCBMedProd2005

30. History of U.S. Food and Drug Law 1984. • Fines Enhancement Laws: Increase penalties for all federal offenses. • $100K for individuals, $250K for felonies or if violation causes death. Amounts are doubled for corporations. • Drug Price Competition and Patent Term Restoration Act. • Generics can be marketed without repeating full safety and efficacy studies • Brand-names can receive additional 5 yr of patent coverage to make up for delays due to approval process. AUCBMedProd2005

31. History of U.S. Food and Drug Law 1988. • Food and Drug Administration Act. • Places FDA in the Department of Health and Human Services (DHHS) with a commissioner appointed by the President with advice and consent of the Senate. • 1990: Safe Medical Devices Act (SMDA). Requires post approval monitoring of medical devices and permits FDA to order the recall of medical devices. AUCBMedProd2005

32. History of U.S. Food and Drug Law 1992. • Prescription Drug User Fee Act (PDUFA) requires fees for drug and biologics submissions and services. • 1994: Dietary Supplement Health and Education Act. • Established a regulatory framework and authorized FDA to develop GMPs. Defines nutraceuticals as foods. AUCBMedProd2005

33. History of U.S. Food and Drug Law 1997. • Food and Drug Administration Modernization Act (FDAMA) • Accelerates review of devices. • Short cuts GMPs in some cases. • Regulates advertising of unapproved uses of approved drugs and devices (off label uses). • Regulates health claims for foods. • Mainly by defining meanings and restricting wording. AUCBMedProd2005

34. It is not the critic who counts, not the man who points out how the strong man stumbled, or where the doer of deeds could have done better. The credit belongs to the man who is actually in the arena; whose face is marred by the dust and sweat and blood; who strives valiantly; who errs and comes short again and again; who, at the best, knows in the end the triumph of high achievement, and who, if he fails, at least fails while daring greatly; so that his place shall never be with those cold and timid souls who know neither victory or defeat . . . .”Theodore Roosevelt Paris, The Sorbonne, 1910 AUCBMedProd2005