1 gmp essentials

GMP History

The basics…

ObjectivesHave a basic understanding of the history

of GMPsHave an understanding of how our idustry

responds to tragic eventsUnderstand the importance of GMPs

Don’t forget “Current”

CurrentGoodManufacturingPractices

History of the FDA

History of the FDA”

History of the FDAStarted as one chemist in U.S.

Department of Agriculture in 1862, quickly grew

1900’sEarly 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.

Morphine

1902At 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.

Upton Sinclair’s “The Jungle”

History of the FDAWidespread public outragePetition to Congress demanding action

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.

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.”

1935Sulfa 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

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

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

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.

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

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.

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.

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.

cGMP GoalsAvoid and prevent mix-upsPrevent contaminationMinimize and detect errorsTraceability and investigationsAssure product safety, identity, strength

quality and purity

Avoid and Prevent Mix-upsSeparate and Defined areasLimited accessMultiple inspections and checksReconciliation or accountabilityProper identification of all materialsRequirements for label controls

Prevent ContaminationProper design of buildings and facilitiesPhysical separationsControl utilitiesFacility and equipment maintenanceValidated cleaning procedures

Minimize and detect errorsAdequate supervisionEffective trainingVerification, reviews and double-checksSOPs with detailed instructions

Traceability and InvestigationsDetailed documentation and record

keepingDocumentation double-check Identification systems

Lot numbersEquipment ID

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.

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.

1992 PDUFAPrescription 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.

1982 Tylenol Tragedy

Tragedy: Acetaminophen-capsule poisoning by cyanide causes7 deaths.

Result: Revision of GMPs to require tamper-resistant packaging.

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.

1998 Draft Guidance

“Manufacturing, Processing, or Holding Active Pharmaceutical Ingredients” and “Investigating Out-of-Specification (OOS)

Test Results for Pharmaceutical Production.”

US vs. Barr

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

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

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).

ICH Categories

StabilityQ1A(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

Analytical Validation Q2(R1)

New title: Validation of Analytical Procedures: Text and MethodologyPreviously: Text on Validation of Analytical Procedures

Q2A Validation of Analytical Procedures: Methodology (in Q2(R1)) Q2B Impurities Q3A(R2)

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

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

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.

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

Questions