GMPs History And The 2008 Revisions

(c) 2009 Veracorp LLC

GMPs - History and the 2008 Revisions What does GMP mean to me?

Frank Settineri

Veracorp [email protected]

908-499-5540



Agenda

• History

• Current GMPs

• Revisions



What is a GMP?

Good Manufacturing Practice or GMP

current Good Manufacturing Practice

or cGMP



What is a GMP?

Recognized worldwide for the control and management of manufacturing and testing of foods, pharmaceuticals,

medical devices

http://en.wikipedia.org/wiki/Current_good_manufacturing_practice



What is a GMP?

In the US, "current good manufacturing practice"

appears in 501(B) of the 1938 Food, Drug, and Cosmetic Act

(21USC351)



What is a GMP?

US courts may decide that a drug product is adulterated even if there is no specific regulatory requirement

that was violated



What is a GMP?

Today GMPs mean a process must be

performed according to industry standards



What is a GMP?

Requirements will apply to all manufactures of dietarysupplements by June, 2010

http://www.fda.gov/bbs/topics/NEWS/2007/NEW01657.html




Agenda

• History

• Current GMPs

• Revisions



Why were GMPs initiated?

Regulations don’t happen on their own

Events precipitate them




1202

King John of England proclaimed the first

English food law, Assize of Bread




1202

Assize of Bread prohibited adulteration of bread with

ingredients such as ground peas or beans




1820

USP was established

Eleven physicians in Washington

First compendium of standard drugs for US




1848

Drug Importation Act

Requires U.S. Customs Service to stop entry of adulterated

drugs from overseas




1862President Lincoln appoints a

chemist, Charles M. Wetherill, to serve in new Department of

Agriculture

Beginning of Bureau of Chemistry, the predecessor of the Food and

Drug Administration




1883Dr. Harvey Wiley becomes chief chemist of Bureau

of Chemistry's food adulteration studies




Dr. Wiley called the "Crusading Chemist" and "Father of the Pure Food and Drugs Act."

Retired from government in 1912 and died in 1930




1897Tea Importation Act passed

Customs inspection of all tea entering U.S. ports, at the expense of the importers




1898 Association of Official Agricultural Chemists (AOAC International)

establishes Committee on Food Standards

headed by Dr. Wiley



Why were GMPs initiated?1902

The Biologics Control Act is passed to ensure purity and safety of serums, vaccines, and similar products used

to prevent or treat diseases in humans




1902

Congress appropriates $5,000 to study chemical preservatives and colors

and their effects on digestion and health




Dr. Wiley's studies draw widespread attention to the

problem of food adulteration

Public support for passage of a federal food and drug law grows









Despite these laws, there was a cavalier attitude regarding drugs and

medicines




Chemical preservatives and toxic colors were virtually uncontrolled




Sanitation was primitive

Ice was principal means of refrigeration




Milk was unpasteurized and cows were not

tested for tuberculosis




Pioneers of bacteriology were

just starting their string of victories over infectious

diseases




Thousands of so-called ‘patent’ medicines such as ‘Kick-a-poo Indian Sagwa’ and ‘Warner's Safe Cure

for Diabetes’ were available




Jamba Juice?




Medicines containing opium, morphine, heroin, and

cocaine were sold without restriction and their labels gave no hint

of their presence




Saw Palmetto?

Ephedrine?




I lost twenty pounds by

eating cookies!




Labels did not list ingredients and warnings against misuse

were nonexistent

The information the public received came frequently from bitter experience




Steve Warshak, founder of Berkeley Premium Nutraceuticals, sentenced

to 25 years in prison

Charged with deceptive ads for Enzyte, a sexual

performance product




Also found guilty for an automatic credit card charging scheme that

took money from customers without letting them return

or cancel orders




Medicine men competed with the circuses, the minstrel shows, and "wild west" performers to entertain the public – and to sell

their products




Hamlin's Wizard Oil was one of the most popular and

spectacular drugs of the big touring medicine shows

This liniment (for minor aches and pains) was sold long after

the shows had eased




Snake oil?


GMPs - History and the 2008 Revisions What does GMP mean to me? Why were GMPs initiated?

Shocking disclosures of insanitary conditions in meat-packing plants,

use of poisonous preservatives and dyes, and cure-all

claims for worthless and dangerous patent medicines








1906

Spurred by Dr. Wiley’s efforts, the Food and Drugs Act was passed

on June 30

Signed by President Theodore Roosevelt



1906

Interstate commerce of misbranded and adulterated foods, drinks and drugs

was prohibited




Food adulteration continued to flourish because judges

could find no specific authority for the

standards of purity and

content




Such products as "fruit" jams made with water, glucose, grass seed, and artificial

color undercut the market for honest

products




Today’s Gatorade?




1906

The Meat Inspection Act is passed the same day




1907

First Certified Color Regulations, requested by manufacturers and users, list seven colors

found suitable for use in foods




1911

In U.S. vs Johnson, Supreme Court rules that 1906 Food and

Drugs Act does not prohibit false therapeutic claims but only false

and misleading statements about the ingredients or identity of a drug




1911

Science + Politics =

Disaster




1912

Congress enacts Sherley Amendment to reverse

Johnson ruling

Prohibits labeling medicines with false therapeutic claims

Difficult to prove




Cavalier attitude remained




1933FDA recommends complete revision of 1906 Food and Drugs Act. Bill introduced

into Senate, launching a five-year legislative battle




1937

Elixir of Sulfanilamide, containing diethylene

glycol, kills 107 persons, many of whom are children









Precipitates Federal Food, Drug,

and Cosmetic (FDC) Act




1938

The Federal Food, Drug, and Cosmetic (FDC) Act of

1938 passed by Congress




• Extended control to cosmetics

and therapeutic devices • Required new drugs to be safe before marketing • Eliminated Sherley Amendment requirement to prove intent to defraud




• Required safe tolerances for unavoidable poisonous substances • Authorized standards of identity, quality and fill for foods• Authorized factory inspections• Authorized court injunctions




1944

Public Health Service Act passed

Regulated biologicals and control of communicable

diseases




1945• Penicillin Amendment required FDA testing and certification of safety and effectiveness • Extended to all antibiotics• Abolished in 1983 (control no longer needed)




1949FDA publishes first guidance to

industry "Procedures for the Appraisal of the Toxicity of

Chemicals in Food"

Known as the "black book"




1953Factory Inspection Amendment

requires FDA to give manufacturers written

reports of conditions observed during inspections and analyses

of factory samples




1962Thalidomide found to cause birth

defects in thousands of babies born in western Europe

Aroused public support for stronger drug regulation









1962 Drug Amendments

Congress instructed FDA to require that all drugs be produced according to

Good Manufacturing Practices




The word “current” was later added to make it “cGMP” to

imply that the regulation allows for changing

technology in attaining GMPs




1973US Supreme Court upholds

1962 drug effectiveness law and endorses FDA to control

products by regulations rather than litigation




1978

cGMPs were rewritten to deal with personnel and facilities,

processes and products




FDA officially established as an agency of the Department of Health and Human Services

Commissioner officially appointed by the President









Judge Wolin

Barr Laboratorieshttp://www.gmp1st.com/barrsum.htm

http://www.gmp1st.com/barrsum.htm



Why were GMPs initiated?• Ruled that USP's established standards

are absolute and that firms cannot stretch them

• Out-of Specification Results – instead

of "product failure“

• OOS result identified as a laboratory error is not a product failure




• Laboratory error • Non-process related

operator error • Process related or

manufacturing process error




Laboratory investigationconsists of more than a retest

Inability to identify an error's cause affects retesting

procedures, not the investigation inquiry




When a laboratory investigation is inconclusive:

• Cannot conduct 2 retests and base release on average of three tests

• Cannot use outlier test in chemical tests

• Cannot use a resample to assume a sampling or preparation error

• Will allow a retest of different tablets from the same sample when a retest is appropriate




Barr Decisionraised the “bar”

(sic)




1997

FDA Modernization Act

Required consistent and efficient regulatory

requirements




FDA has since proposed

• Systems-based approach for cGMP compliance • Risk analysis approach• Critical Path Initiative • Opportunities List









These newer laws, partially provoked by political pressure, have been designed to provide

safer, risk-free medicines




They may unintentionally raise development costs and obliterate research

programs




Regulations have evolved from simple, low impact

rules to complicated, daunting guidelines




Provided the impetus for individuals to subvert the

production of safe and effective drugs in favor of creating all types of redundant documents,

SOPs and policies




The lesson?




Do the right thing




GMPs continue to evolve, partially due to mistakes

and partially based on companies wanting

more guidance








Agenda

• History

• Current GMPs

• Revisions



Current GMPs21 CFR Part 211

OrganizationBuildings and FacilitiesEquipmentControl of ComponentsProduction and Process ControlsPackaging and LabelingHolding and DistributionLaboratory ControlsRecords and ReportsReturned and Salvaged Goods



Current GMPs

Subpart A - General Provisions211.1 - Scope.211.3 - Definitions.

Subpart B - Organization and Personnel211.22 - Responsibilities of quality control unit.211.25 - Personnel qualifications.211.28 - Personnel responsibilities.211.34 - Consultants.



Current GMPs

Subpart C - Buildings and Facilities

211.42 - Design and construction features.211.44 - Lighting.211.46 - Ventilation, air filtration, air heating and cooling.211.48 - Plumbing.211.50 - Sewage and refuse.211.52 - Washing and toilet facilities.211.56 - Sanitation.211.58 - Maintenance



Current GMPs

Subpart D – Equipment

211.63 - Equipment design, size, and location.211.65 - Equipment construction.211.67 - Equipment cleaning and maintenance.211.68 - Automatic, mechanical, and electronic

equipment.211.72 - Filters.



Current GMPs

Subpart E - Control of Components and Drug Product Containers and Closures

211.80 - General requirements.211.82 - Receipt and storage of untested components, drug product containers, and closures.211.84 - Testing and approval or rejection of components, drug product containers, and closures.211.86 - Use of approved components, drug product containers, and closures.211.87 - Retesting of approved components, drug product containers, and closures.211.89 - Rejected components, drug product containers, and closures.211.94 - Drug product containers and closures.



Current GMPsSubpart F - Production and Process Controls

211.100 - Written procedures; deviations.211.101 - Charge-in of components.211.103 - Calculation of yield.211.105 - Equipment identification.211.110 - Sampling and testing of in-process materials and drug products.211.111 - Time limitations on production.211.113 - Control of microbiological contamination.211.115 - Reprocessing.



Current GMPs

Subpart G - Packaging and Labeling Control

211.122 - Materials examination and usage criteria.211.125 - Labeling issuance.211.130 - Packaging and labeling operations.211.132 - Tamper-evident packaging requirements for over-the-counter (OTC) human drug products211.134 - Drug product inspection.211.137 - Expiration dating.



Current GMPs

Subpart H - Holding and Distribution211.142 - Warehousing procedures.211.150 - Distribution procedures.

Subpart I - Laboratory Controls211.160 - General requirements.211.165 - Testing and release for distribution.211.166 - Stability testing.211.167 - Special testing requirements.211.170 - Reserve samples.211.173 - Laboratory animals.211.176 - Penicillin contamination.



Current GMPs

Subpart J - Records and Reports

211.180 - General requirements.211.182 - Equipment cleaning and use log.211.184 - Component, drug product container, closure, and labeling records.211.186 - Master production and control records.211.188 - Batch production and control records.211.192 - Production record review.211.194 - Laboratory records.211.196 - Distribution records.211.198 - Complaint files.



Current GMPs

Subpart K

Returned and Salvaged Drug Products

211.204 - Returned drug products.211.208 - Drug product salvaging.



Current GMPs

These are the GMPs we all love

We’ve all lived with them



Current GMPs

What do they really mean?



Current GMPs

1. People

2. Facilities

3. Integrity



Current GMPs

People

• Hire the right people

• Train them extensively

• Support them fully



Current GMPs

Facilities

• Design them properly

• Keep them neat and clean



Current GMPs

Integrity

• Make people well

• Keep the products safe (chemically and microbiologically)

• Speak up if there is a mistake



Current GMPs

Use common sense

That’s all you need to do



Current GMPs

GMPs are not complicated if you do what is right








Agenda

• History

• Current GMPs

• Revisions



Revisions

Summary related to microbiology

All changes, and a summary of the

reasoning behind them are available at http://www.fda.gov/OHRMS/DOCKETS/98fr/E8-20709.pdf

(Federal Register / Vol. 73, No. 174 / Monday, September 8, 2008 /Rules and Regulations pp. 51919-51933)

http://www.microbiologyforum.org/PMFNews/PMFNews.14.12.0812.pdf

http://www.fda.gov/OHRMS/DOCKETS/98fr/E8-20709.pdf




Revisions211.67 Equipment cleaning and maintenance.

(a) Equipment and utensils shall be cleaned, maintained, and as appropriate for the nature of the drug, sanitized and/or sterilized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements



Revisions211.68 Automatic, mechanical, and electronic equipment

(c) Such automated equipment used for performance of operations addressed by §§ 211.101(c) or (d), 211.103, 211.182, or 211.188(b)(11) can satisfy the requirements included in those sections relating to the performance of an operation by one person and checking by another person if such equipment is used in conformity with this section, and one person checks that the equipment properly performed the operation.



Revisions211.72 Filters

Filters for liquid filtration used in the manufacture, processing, or packing of injectable drug products intended for human use shall not release fibers into such products. [Fiber-releasing filters may not be used in the manufacture, processing, or packing of these injectable drug products unless it] Fiber-releasing filters may be used when it is not possible to manufacture such drug products without the use of such filters. If use of a fiber releasing filter is necessary, an additional nonfiber-releasing filter having a maximum nominal pore size rating of 0.22 micron (0.45 micron if the manufacturing conditions so dictate) shall subsequently be used to reduce the content of particles in the injectable drug product. The use of an asbestos containing filter is prohibited.



Revisions211.82 Receipt and storage of untested components,

drug product containers, and closure

(b) Components, drug product containers, and closures shall be stored under quarantine until they have been tested or examined, whichever is as appropriate, and released. Storage within the area shall conform to the requirements of weighing, measuring, or subdividing operations are performed by automated equipment under §211.68, only one person is needed to assure paragraphs (c)(1), (c)(2), and (c)(3) of this section.(d) Each component shall either be added to the batch by one person and verified by a second person or, if the components are added by automated equipment under § 211.68, only verifiedby one person.



Revisions211.84 Testing and approval or rejection of

components, drug product containers, and closures

(c) Samples shall be collected in accordance with the following procedures:

(1) The containers of components selected shall be cleaned [where necessary, by appropriatemeans] when necessary in a manner to preventintroduction of contaminants into the component



Revisions211.84 Testing and approval or rejection of components,

drug product containers, and closures

(d) Samples shall be examined and tested as follows:(3) Containers and closures shall be tested for conformancewith all appropriate written [procedures] specifications. In lieu of such testing by the manufacturer, a certificate of testing may be accepted from the supplier, provided that at least a visual identification is conducted on such containers/closures by the manufacturer and provided that the manufacturer establishes the reliability of the supplier's test results through appropriate validation of the supplier'stest results at appropriate intervals.



Revisions211.84 Testing and approval or rejection of

components, drug product containers, and closures

(6) Each lot of a component, drug product container, or closure [that is liable to] with potential for microbiological contamination that is objectionable in view of its intended use shall be subjected to microbiological tests before use.



Revisions211.94 Drug product containers and closures

(c) Drug product containers and closures shall be clean and, where indicated by the nature of the drug, sterilized and processed to remove pyrogenic properties to assure that they are suitable for their intended use. Such depyrogenation processes shall be validated.



Revisions

211.101 Charge-in of components

(c) (3) The containers are properly identified. If the weighing, measuring, or subdividing operations are performed by automated equipment under §211.68, only one person is needed to assureparagraphs (c)(1), (c)(2), and (c)(3) of this section.(d) Each component shall either be added to thebatch by one person and verified by a secondperson or, if the components are added by automatedequipment under § 211.68, only verified by one person.



Revisions211.103 Calculation of yield

Actual yields and percentages of theoretical yieldshall be determined at the conclusion of each appropriate phase of manufacturing, processing,packaging, or holding of the drug product. Suchcalculations shall either be performed by one personand independently verified by a second person,or, if the yield is calculated by automatedequipment under § 211.68, be independently verifiedby one person.



Revisions211.110 Sampling and testing of in-process

materials and drug products

(a) To assure batch uniformity and integrity of drug products, written procedures shall be established and followed that describe the in-process controls, and tests, or examinations to be conducted on appropriate samples of in-process materials of each batch. Such control procedures shall be established to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product.



Revisions211.110 Sampling and testing of in-process

materials and drug products

Such control procedures shall include, but are not limited to, the following, where appropriate:(1) Tablet or capsule weight variation; (2) Disintegration time;(3) Adequacy of mixing to assure uniformity and homogeneity;(4) Dissolution time and rate; (5) Clarity, completeness, or pH of solutions.(6) Bioburden Testing



Revisions211.113 Control of microbiological contamination

(a) Appropriate written procedures, designed to prevent objectionable microorganisms in drug products not required to be sterile, shall be established and followed.

(b) Appropriate written procedures, designed to prevent microbiological contamination of drug products pur- porting to be sterile, shall be established and followed. Such procedures shall include validation of all aseptic and any sterilization processes.



Revisions211.160 General requirements

(b) Laboratory controls shall include the establishment of scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity. Laboratory controls shall include: (Continued…)



Revisions211.160 General requirements

(1) Determination of conformanity[ce] to appropriatewritten specifications for the acceptance of each lot within each shipment of components, drug product containers, closures, and labeling used in the manufacture, processing, packing, or holding of drug products. The specifications shall include a description of the sampling and testing procedures used. Samples shall be representative and adequately identified. Such procedures shall also require appropriate retesting of any component, drug product container, or closure that is subject to deterioration.



Revisions211.182 Equipment cleaning and use log

A written record of major equipment cleaning,maintenance (except routine maintenance such aslubrication and adjustments), and use shall be included in individual equipment logs that show thedate, time, product, and lot number of each batchprocessed. If equipment is dedicated to manufactureof one product, then individual equipment logsare not required, provided that lots or batches ofsuch product follow in numerical order and aremanufactured in numerical sequence.



Revisions211.182 Equipment cleaning and use log

In cases where dedicated equipment is employed, the records of cleaning, maintenance, and use shall be part of the batch record. The persons performing and double-checking the cleaning and maintenance (or, if the cleaning and maintenance is performed using automated equipment under § 211.68, just the person verifying the cleaning and maintenance done by the automated equipment) shall date and sign or initial the log indicating that the work was performed. Entries in the log shall be in chronological order.



Revisions211.188 Batch production and control records

(b) (11) Identification of the persons performing and directly supervising or checking each significant step in the operation, or if a significant step in the operation is performed by automated equipment under § 211.68, the identification of the person checking the significant step performed by the automated equipment.



Summary - GMPs

• Reaction to egregious activities• Not unique to our period of time• Supported by government• Supported by industry• Dynamic, changing with the times• You need to follow them• Do the right thing and you’ll be OK








Thank you

Frank SettineriVeracorp LLC

[email protected]

mailto:[email protected]



References

1. www.fda.gov/opacom/backgrounders/miles.html

2. www.cfsan.fda.gov/~lrd/history1.html

3. Weschsler, J pp. 40-42 Pharmaceutical Executive January, 2007 http://pharmexec.findpharma.com/pharmexec/Legislation/Washington-Report- A-Full-Plate/ArticleStandard/Article/detail/395591

4. http://www.fda.gov/oc/history/makinghistory/firstgmps.html

5. http://www.foodsafety.gov/~lrd/histor1b.html

6. (Federal Register / Vol. 73, No. 174 / Monday, September 8, 2008 /Rules and Regulations pp. 51919-51933) http://www.fda.gov/OHRMS/DOCKETS/98fr/E8-20709.pdf

7. http://www.microbiologyforum.org/PMFNews/PMFNews.14.12.0812.pdf

8. http://www.fda.gov/bbs/topics/NEWS/2007/NEW01657.html

http://www.fda.gov/opacom/backgrounders/miles.html

http://www.cfsan.fda.gov/~lrd/history1.html

http://pharmexec.findpharma.com/pharmexec/Legislation/Washington-Report-A-Full-Plate/ArticleStandard/Article/detail/395591



http://www.fda.gov/oc/history/makinghistory/firstgmps.html

http://www.foodsafety.gov/~lrd/histor1b.html

http://www.fda.gov/OHRMS/DOCKETS/98fr/E8-20709.pdf



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GMPs History And The 2008 Revisions