8. GMP History
The basics…

9. Objectives
 Have a basic understanding of the history
of GMPs
 Have an understanding of how our idustry
responds to tragic events
 Understand the importance of GMPs

10. Don’t forget “Current”
Current
Good
Manufacturing
Practices

11. History of the
FDA

12. History of the FDA
 ”

13. History of the FDA
 Started as one chemist in U.S.
Department of Agriculture in 1862, quickly
grew

14. 1900’s
 Early in this country’s history, traveling
medicine shows sold bottles of ointment or
“miracle elixir” from the backs of wagons.
 Such medication was said to be good for
aches and pains; for rheumatism, and gout
 of course it completely cured cancer —
and it worked on horses too.
 Luckily, those days are long gone.

17. Morphine

18. 1902
 At least 12 children died from a diphtheria
antitoxin that was contaminated with live
tetanus bacilli.
 Congress responded to that tragedy by
passing the Biologics Control Act of
1902, which required inspections of
manufacturers and sellers of biological
products and testing of such products for
purity and strength.

19. Upton Sinclair’s “The Jungle”

20. History of the FDA
 Widespread public outrage
 Petition to Congress demanding action

21. 1905
 In 1905, a book called The Jungle helped
catalyze public opinion for change.
 “Muckraker”social reformer Upton Sinclair wrote
about the Chicago meat packing industry — the
unsanitary conditions in which animals were
slaughtered and processed and the practice of
selling rotten or diseased meat to the public.
 He also reported that ground meat sometimes
contained remains of poisoned rats and even
unfortunate workers who fell into the machinery.

22. 1906
 The Jungle had a major impact on the American
public.
 Congress passed the Pure Food and Drug Act in
1906, and for the first time it became illegal to
sell contaminated (adulterated) food or meat.
 Also for the first time, labeling had to be truthful
 no longer could anyone promise on a label “the
moon and the stars.”

23. 1935
 Sulfa drugs were introduced in 1935.
 Many manufacturers began making the
new anti-infectives.
 One company used diethylene glycol, a
poisonous solvent and chemical analog of
anti-freeze, in an oral “elixir of
sulfanilamide.”
 Before the problem was discovered, 107
people died, many of them children

25. 1938
 Congress passed the Federal Food, Drug and
Cosmetic (FD&C) Act of 1938.
 For the first time companies were required to
prove that their products were safe before
marketing them.
 it extended FDA oversight to cosmetics and
therapeutic devices, explicitly authorized factory
inspections, required standards for foods, and
added injunctions to previous penalties of
seizures and criminal prosecutions

26. 1941 sulfathiazole
 In 1941 nearly 300 people were killed or
injured by one company’s sulfathiazole
tablets, a sulfa drug tainted with the
sedative, phenobarbital.
 That incident caused FDA to revise
manufacturing and quality control
requirements, leading to what would later
be called GMPs

27. 1955 Polio vaccine
 In 1955, Jonas Salk discovered a way to
vaccinate against polio.
 Many manufacturers began making his polio
vaccine.
 One company failed to inactivate the virus
completely in a single lot.
 About 60 individuals inoculated developed polio,
and another 89 of their family members
(mothers, fathers, brothers, sisters, and
grandparents) contracted polio from them.

28. 1950sThalidamide
 Thalidomide was marketed in Europe as a
sleeping pill and to treat morning sickness.
 When regulatory agencies gave permission to
sell the drug for that indication, they had no
knowledge of its serious side effects.
 Children whose mothers took thalidomide in the
first trimester were born with severely deformed
arms and legs
 An estimated 10,000 cases of infant deformities
in Europe were linked to thalidomide use

29. 1962 KeFauver-Harris Amendment
 Thalidomide galvanized public opinion.
 Two legislators, Kefauver and Harris, pushed
more stringent legislation through Congress that
required companies to test not only to ensure
that products were safe, but that they were
efficacious for their intended uses.
 Regulating clinical trials, the amendments
required drugs to be tested in animals before
people.

30. 1978 GMPs finalized
 In 1978, good manufacturing practices for
drugs (21 CFR Parts 210 and 211) were
greatly expanded
 medical devices (21 CFR 820)
 GMPs were, for the first time, made final.

37. Holism in science, or Holistic science, is
an approach to research that emphasizes
the study of complex systems. This
practice is in contrast to a purely analytic
tradition which purports to understand
systems by dividing them into their
smallest possible or discernible elements
and understanding their elemental
properties alone. The holism/reductionism
dichotomy is often evident in conflicting
interpretations of experimental findings and
in setting priorities for future research.

38. cGMP Goals
 Avoid and prevent mix-ups
 Prevent contamination
 Minimize and detect errors
 Traceability and investigations
 Assure product safety, identity, strength
quality and purity

39. Avoid and Prevent Mix-ups
 Separate and Defined areas
 Limited access
 Multiple inspections and checks
 Reconciliation or accountability
 Proper identification of all materials
 Requirements for label controls

40. Prevent Contamination
 Proper design of buildings and facilities
 Physical separations
 Control utilities
 Facility and equipment maintenance
 Validated cleaning procedures

41. Minimize and detect errors
 Adequate supervision
 Effective training
 Verification, reviews and double-checks
 SOPs with detailed instructions

42. Traceability and Investigations
 Detailed documentation and record
keeping
 Documentation double-check
 Identification systems
 Lot numbers
 Equipment ID

43. How and Why the Concept of
Validation Developed
 In 1972 in the U.S. large volumes of IV fluid were
contaminated. The IV fluid was manufactured by
Abbott and McGaw Laboratories, two large multi-
national manufacturers, that the US FDA realized the
GMPs were not sufficient rigor to prevent quality
mishaps occurring in pharmaceutical product
manufacture and testing and embarked on a revision
of the GMP regulations, which are still virtually
unchanged today.
 At that time, release of materials was based only on
sterility testing- instead of a sterilization process
validation.

45. 1980 Infant Formula Act
 Tragedy: 100 children reported seriously ill
linked to lack of chloride in soy-based
formulas.
 Result: Congress gives FDA authority to
set and enforce nutritional and quality
standards.

46. 1992 PDUFA
 Prescription Drug User Fee Act requires
drug and biologics manufacturers to pay
fees for product applications and
supplements, and other services. The act
also requires FDA to use these funds to
hire more reviewers to assess
applications.

47. 1982 Tylenol Tragedy
 Tragedy: Acetaminophen-capsule
poisoning by cyanide causes7 deaths.
 Result: Revision of GMPs to require
tamper-resistant packaging.

48. 1989
 FDA issues a nationwide recall of all over-the-
counter dietary supplements containing 100
milligrams or more of L-Tryptophan, due to a
clear link between the consumption of L-
tryptophan tablets and its association with a U.S.
outbreak of Eosinophilia Myalgia Syndrome
(EMS), characterized by fatigue, shortness of
breath, and other symptoms. By 1990 the
Centers for Disease Control and Prevention
confirm over 1,500 cases of EMS, including 38
deaths, and FDA prohibits the importation of l-
tryptophan.

49. 1998 Draft Guidance
 “Manufacturing, Processing, or Holding
Active Pharmaceutical Ingredients” and
“Investigating Out-of-Specification (OOS)
 Test Results for Pharmaceutical
Production.”
 US vs. Barr

50. 1990 Safe Medical Devices Act
 Tragedy: Shiley heart valves and other
incidents.
 Result: FDA given authority to add
preproduction design controls and tracking
of critical or implantable devices to GMPs;
requires notification of serious device
problems by user facilities to FDA.
 The agency gains ability to order device
recalls

51. 2001 ICH Q7A API Guidance
 ICH’s “Good Manufacturing Practice
Guidance for Active Pharmaceutical
Ingredients (APIs)” is adopted by the
United States, Europe, and Japan
 This Guidance becomes the de facto
manufacturing standard for APIs

52. ICH Categories
 Quality (24 guidelines) - related to chemical
and pharmaceutical quality assurance.
 Safety (15 guidelines) - related to pre-
clinical studies.
 Efficacy (18 guidelines) - related to clinical
research in human subjects.
 Multidisciplinary (5 guidelines) – i.e.,
Medical Terminology (MedDRA).

53. Stability
Q1A(R2)

Q1B
 Stability Testing : Photostability Testing of New Drug Substances and
Products
 Q1C
 Stability Testing for New Dosage Forms
 Q1D
 Bracketing and Matrixing Designs for Stability Testing of New Drug
Substances and Products
 Q1E
 Evaluation of Stability Data
 Q1F
 Stability Data Package for Registration Applications in Climatic Zones III
and IV


54. Analytical Validation Q2(R1)
 New title: Validation of Analytical
Procedures: Text and Methodology
Previously: Text on Validation of Analytical
Procedures
 Q2A Validation of Analytical Procedures:
Methodology (in Q2(R1)) Q2B
Impurities Q3A(R2)

55. Quality of Biotechnological
Products Q5A(R1)
 Q5A
 Stability Testing of Biotechnological/Biological Products
 Q5B
 Quality of Biotechnological Products : Analysis of the Expression Construct
in Cells Used for Production of r-DNA Derived Protein Products
 Q5C
 Quality of Biotechnological Products : Characterization of Cell Substrates
Used for Production of Biotechnological/Biological Products
 Q5E
 Comparability of Biotechnological/Biological Products Subject to Changes in
their Manufacturing Process

56. More ICH
http://www.fda.gov/cber/ich/ichguid.htm#q
 Good Manufacturing Practice Q7
 Good Manufacturing Practice Guide for Active
Pharmaceutical Ingredients Q7A
Pharmaceutical Development Q8(R1)
 Pharmaceutical Development
Quality Risk Management Q9
 Quality Risk Management
Pharmaceutical Quality System Q10
 Pharmaceutical Quality System

57. GXP
 Our industry exists to relieve suffering or pain,
and to find cures for diseases.
 It also is highly regulated.
 Because of the tragedies that have occurred,
most people see the regulations and world
regulatory agencies as checks and balances on
the industry
 We all have a similar goal in common -- to bring
innovative, safe, and effective products to
market.

58. Summary
 GMP’s are required by law
 Following GMP’s assures the safety, identity,
quality , strength and purity of the manufactured
product.
 GMP’s are Common Sense
 Need to show control over operation.
 Goal is to reduce non conformance, OOS and
process deviations resulting in a lower risk to
impact product quality and to the customer
 The regulation are minimum requirements

61. Questions