History & Evolution of GMP Regulations

This presentation is compiled by “ Drug Regulations”
a non profit organization which provides free online
resource to the Pharmaceutical Professional.
Visit http://www.drugregulations.org for latest
information from the world of Pharmaceuticals.
6/13/2015 1

 This presentation is compiled from freely
available resource like the website of FDA.
“Drug Regulations” is a non profit
organization which provides free online
 Visit http://www.drugregulations.org for
latest information from the world of
Pharmaceuticals.
6/13/2015 2
Drug Regulations : Online
Resource for Latest Information

◦ FDA ensures the quality of drug
products
 Monitoring drug manufacturers'
compliance with its CGMP
regulations.
6/13/2015 3

◦ The CGMP regulations contain minimum
requirements for the
 Methods
 Facilities
 Controls used in manufacturing, processing,
and packing of a drug product.
6/13/2015 4

◦ The regulations make sure that a product
is
 Safe for use
 Has the ingredients and strength it
claims to have.
6/13/2015 5

 Regulations for GMP’s for are described in
 Code of Federal Regulations
 Title 21
◦ Subchapter C
◦ Part 210 and part 211: Drugs for Humans & Animals
◦ Part 225 : Medicated Feeds
◦ Part 226 : Type A Medicated Articles
6/13/2015 6

 Regulations for GMP’s for are described in
 Code of Federal Regulations
 Title 21
◦ Subchapter L
◦ Part 600 to 680 : Biological products for Human Use
 Sub Chapter F
◦ Part 1271 : Drugs that are Human cells & Tissue based
products
6/13/2015 7

 Everyone in our industry should know
the story of how the Good
Manufacturing Practices (GMPs) have
come to be.
6/13/2015 8

 Traveling medicine shows sold
◦ Bottles of ointment
◦ “Miracle elixir”
◦ Such medication was said to be good for
 Aches and pains
 Rheumatism, and gout —
◦ of course it completely cured cancer —
◦ and it worked on horses too.
 Luckily, those days are long gone.
6/13/2015 9

 Book called “The Jungle”
 Catalyzed public opinion for change
 Social reformer “Upton Sinclair” wrote about
 Chicago meat packing industry
◦ Unsanitary conditions in which animals were slaughtered and processed
◦ Practice of selling rotten or diseased meat to the public
◦ Ground meat sometimes contained remains of poisoned rats
 Sinclair’s main interest
◦ Miserable working conditions of factory workers
6/13/2015 10

 The Pure Food and Drug Act
 Congress passed the Act in 1906
 For the first time
◦ Illegal To sell contaminated (adulterated) food or meat.
◦ labeling had to be truthful
◦ No longer promise on a label “the moon and the stars.”
6/13/2015 11

 Selected dangerous ingredients required to be labeled
 Misbranding: Inaccurate or false labeling became
illegal.
 “Misbranded” applies to
◦ Statements, designs, or pictures in labeling
◦ Failure to provide required information in labeling
 “Adulterated” has been expanded
◦ Products manufactured without following GMPs.
6/13/2015 12

 Before the publication of The Jungle
 Harvey Wiley and others sought a law for 25 years.
 The Act created one of the first government regulatory
agencies, now known as FDA,
 Allowed for the seizure of illegal foods and drugs
 Wiley : Chief chemist of the bureau given authority to enforce
that act
 The Bureau of Chemistry, U.S. Department of Agriculture
 A forerunner of FDA
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 Biologic products
◦ First regulated a few years before “The Jungle”
◦ 12 children died from a diphtheria antitoxin that was
contaminated with live tetanus bacilli.
◦ Congress responded by passing the Biologics Control Act of
1902
◦ Required
 Inspections of manufacturers and sellers of biological products
 Testing of such products for purity and strength
6/13/2015 14

 A 1933 FDA exhibit of dangerous food, medicines, medical devices,
and cosmetics
 Illustrated the shortcomings of the1906 law
 “America’s Chamber of Horrors,” included
◦ A womb supporter (also used as a contraceptive) that could puncture the
uterus if inserted incorrectly;
◦ A weight-loss drug that caused death;
◦ A hair remover that caused baldness, even if not used on the head;
◦ Lotions and creams that could cause mercury poisoning;
◦ Hair dyes that could cause lead poisoning;
◦ An eyelash dye that blinded women
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 Eleanor Roosevelt took that exhibit to the
White House
◦ Asked for stronger consumer protection
◦ A tragedy was waiting around the corner that
would make her case for her.
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 Sulfa drugs were introduced in 1935.
 Many manufacturers began making the new anti-
infectives.
 One company used Diethylene glycol, in an oral
“elixir of sulfanilamide.”
◦ A poisonous solvent and chemical analog of anti-freeze
 Before the problem was discovered, 107 people
died, many of them children.
6/13/2015 17

 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
6/13/2015 18

 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
6/13/2015 19

 In 1941 nearly 300 people were killed or injured
 Sulfathiazole tablets
 A sulfa drug tainted with the sedative, phenobarbital
 FDA to revised manufacturing and quality control
requirements
 GMPs
 The Public Health Services (PHS) Act passed in 1944
 Covered a broad spectrum of concerns, including regulation
of biological products and control of communicable diseases.
6/13/2015 20

 During the WWII era
◦ Batch certification by FDA : A requirement for certain drugs.
◦ Companies submitted samples from each lot
◦ Agency would give permission for their release.
◦ 1941: Insulin
◦ 1945 : Penicillin,
◦ Later : Expanded to include all antibiotics.
◦ 1983 : Requirement dropped
6/13/2015 21

 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
◦ About 60 individuals inoculated developed polio
◦ Another 89 of their family members contracted polio
from them
6/13/2015 22

 Thalidomide was marketed in Europe
 Sleeping pill and to treat morning sickness.
 Regulators had no knowledge of its serious side
effects.
 It turned out to be teratogenic
 Caused serious deformities in developing fetuses.
 10,000 cases of infant deformities
6/13/2015 23

 The product was not allowed in the United States.
 The drug reviewer responsible : Frances Kelsey.
 Awarded President’s Distinguished Federal Civilian
Service Award
 Highest honor a government employee may earn as
a civilian.
6/13/2015 24

 Thalidomide galvanized public opinion
 Two legislators, Kefauver and Harris, pushed more stringent
legislation
 Required companies to test not only safety, but also efficacy
 Clinical Trail Regulations were amended
 Required drugs to be tested in animals before people
 Made investigators responsible for supervising drugs under
study.
6/13/2015 25

 Manufacturers to inform if a drug was for investigational
 Obtaining consent before testing was mandatory
 Drugs had to be shown to work before going on the market
 Manufacturers were required to report unexpected harm
(adverse events).
 FDA was given authority to regulate advertising of
prescription drugs
 And in 1963, the first GMPs for finished pharmaceuticals were
made final
6/13/2015 26

 A watershed for product regulation.
 1978
◦ Good manufacturing practices for drugs (21 CFR Parts 210
and 211) were greatly expanded and made final
◦ Medical devices regulations (21 CFR 820) were also made
final
6/13/2015 27

 A watershed for product regulation.
 1979 :
◦ Good Laboratory Practices (GLPs) were made final.
◦ They define:
◦ Good laboratory practices for nonclinical laboratory studies
6/13/2015 28

 Congress passed the Infant Formula Act
 FDA could create and enforce standards and specify
nutritional requirements for commercial infant formulas.
 1979
 More than 100 infants were seriously ill by a lack of chloride
in two soy-based formulas
6/13/2015 29

 Manufacturers are now required to
◦ Analyze each batch of formula for nutrient levels
◦ Make safety checks
◦ Conduct stability tests
◦ Code each container with a lot number
◦ Keep detailed records of production and analysis
◦ The food GMPs (21 CFR Part110) were finalized
6/13/2015 30

 In 1982
 12-year-old Mary Kellerman had a cold
 Extra strength Tylenol acetaminophen capsule were
used
 She died within few hours
 Six other people died in this tragic incident
 Johnson & Johnson recalled of 31 million bottles of
Tylenol.
6/13/2015 31

 In 1982,
 Investigation revealed that a criminal act
 Capsules were opened up and laced with cyanide.
 Company destroyed 31 million bottles
 Tamper-resistant packaging introduced for OTC
products
6/13/2015 32

 1982,
 This became part of GMPs.
 1983
 Congress passed the Federal Anti Tampering Act
 Crime to tamper with packaged consumer
products.
6/13/2015 33

 Guidance documents. ( 1980)
◦ FDA began publishing a series of guidance documents
◦ Major effect on our interpretation of cGMP
◦ One such document
◦ “Guide to Inspection of Computerized Systems in Drug
Processing”
◦ Expectations for the functioning of computer systems
◦ Signaled the beginning of computer validation
6/13/2015 34

 Guidance documents. (1987)
◦ “Guideline on General Principles of Process
Validation”
◦ Outlined current thinking on process validation
◦ Such documents,
 Provide guidance only on principles and practices that are
not legal requirements.
 Reflect current agency thinking and expectations.
6/13/2015 35

 Some 70–80 % of the APIs come from sources outside USA
 EU and the US published draft guidance documents for the
manufacture of APIs
 The ICH published “ICH Q7A GMP’s for API
 Accepted in Europe, Japan, and the United States
 De facto standard for manufacture of API
6/13/2015 36

 Medical device regulations become more thorough
 Consistent with other world standards (ISO 9000)
 Requirements
◦ Report to FDA all incidents in which a medical device probably
caused or contributed to a death or serious injury.
◦ Conduct postmarket surveillance on permanently implanted
devices
◦ Authorized FDA to order device product recalls .
6/13/2015 37

 The medical device regulations went through a
major revision
 Design control
 The need to formally review and document product
design at predetermined stages.
 The final rule became effective in June 1997
 Regulations became effective a year later in June
1998.
6/13/2015 38

 The Electronic Records
 Final Rule (21 CFR Part 11)
 Security and accuracy of all data and computer systems used
 Sweeping ramifications on the industry for years to come
 Biggest change since CGMPs were first published.
6/13/2015 39

 Generic drug scandal.
◦ Generic Drug Enforcement Act of 1992
◦ Imposes debarment and other penalties for illegal acts
involving ANDA’s
◦ Act resulted from a bribery and fraud case
◦ Generic companies bribed FDA reviewers
◦ Rather than testing its own generic version of a drug, the
company tested the brand name version
6/13/2015 40

 Generic drug scandal.
 Presidents, vice presidents are indicted in fraud
 However even the lowest-ranking employees can be
prosecuted
◦ Falsified Certificates of Analysis
◦ Destroyed samples
◦ Directed others to change manufacturing procedures
◦ Falsified records to hide or conceal manufacturing changes.
6/13/2015 41

 The Scale-Up and Post-Approval Change (SUPAC)
 Provide guidance on what is needed before changes to approved
drug applications can be made.
 The documents itemize the types of information or studies required
based upon the magnitude or risk of proposed changes.
 For biological products, companies are now preparing “comparability
protocols” to address proposed changes.
6/13/2015 42

 Abbreviated, routine drug inspections.
 2002
 FDA went to a new, abbreviated inspection technique,
 Focuses on two or more systems,
 Mandatory coverage of the quality system, in routine drug
manufacturing inspections.
 The other systems?
6/13/2015 43

 The other systems?
 Facilities and equipment,
 materials,
 production,
 packaging and labeling, and
 laboratory controls.
 FDA has said publicly that they consider a company to be “out of
control if any system is out of control.”
6/13/2015 44

 Defined in 210.1 (b)
◦ Implications of failure to comply part 211
◦ Such drugs are declared “adulterated”
 under section 501(a)(2)(B) of the act
◦ Drug is subjected to appropriate regulatory action
◦ Responsible person for the failure to comply, is also
subjected to regulatory action.
6/13/2015 45
Indian
GMP’s
does not
have this
provision

 This presentation is compiled from freely
available resource like the website of FDA.
“Drug Regulations” is a non profit
organization which provides free online
 Visit http://www.drugregulations.org for
latest information from the world of
Pharmaceuticals.
6/13/2015 46

History & Evolution of GMP Regulations

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