lseidman@matcmadison.edu quality: the big ( but relatively brief ) picture

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QUALITY: THE BIG (BUT RELATIVELY BRIEF) PICTURE

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OVERVIEW

Talk about product quality systems In broad way Apply ideas to the various

work places we talked about

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QUALITY SYSTEMS

Broad systems of regulations, standards, or policies that ensure the quality of the final product

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Discussion of product quality and quality systems leads to… Regulatory affairs Interaction of government with

the industry

Which for biotechnology…. Takes us to GMP

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WHAT IS PRODUCT QUALITY?

What is a “good” product in biotechnology?

That depends… Consider biotech:

Research labs Testing labs Production facilities

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QUALITY PRODUCT: RESEARCH LAB

Research lab, knowledge is product: Knowledge of nature

(basic research) Understanding of

technology (applied research, R&D)

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QUALITY SYSTEMS IN RESEARCH LABS

Quality system in research

Ensure meaningful data has been around a long

time It is called:

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“DOING GOOD SCIENCE”

Less formalized than other quality systems

No one book spells it out No laws to obey But it exists

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INFORMAL SYSTEM

Consequences of poor quality product not life-threatening so Government seldom

involved in monitoring research quality

Oversight not generally by outside inspectors or auditors

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BUT THERE IS OVERSIGHT

Oversight is by peersGrant reviewPublicationsReputation

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CHANGE: RESEARCH LABS

Change is good Basis for advances Flexibility is valued Willingness to change

directions is necessary

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SUMMARY: RESEARCH LABS

Quality system: “Doing Good Science”

Least formal Not found in any one book No laws to follow No enforcement by regulatory

agency Change is accepted Oversight is by peers

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Compare and contrast situation in research labs and other work places

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PRODUCT QUALITY: TESTING LAB

Testing lab: Information about samples

that can be relied on when making decisions

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CONSEQUENCES

A poor quality product can be life-threatening or have serious effects

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QUALITY SYSTEMS IN TESTING LABS

Include most of what we call “doing good science” plus

Specific formal requirements Personnel Equipment Training Facilities Documentation…

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You can find a book that spells it out for: Clinical labs Forensic labs Environmental labs…

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ENFORCEMENT: TESTING LABS

Since consequences of poor product can be life-threatening Is outside oversight

FBI EPA Etc.

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CHANGE: TESTING LABS

Change is controlled May improve test methods,

but Test new methods against

old ones Document changes Control change

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PRODUCT QUALITY: PRODUCTION FACILITY

Make tangible items Quality means fulfill

intended purpose Ex.: reagent grade salt

vs road salt vs table salt

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QUALITY SYSTEMS IN PRODUCTION FACILITIES Depends on nature of

product Poor product may or may

not have life-threatening consequences

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SO, FOR EXAMPLE

Products for research use, not generally regulated

Agricultural products are regulated in one way

Pharmaceutical products are regulated in another

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VOLUNTARY STANDARDS

Companies that are not regulated may choose to comply with a product quality system for business reasons

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ISO 9000

ISO 9000 Formal product quality

system Extensive Exists in a series of books Companies comply

voluntarily to improve the quality of products

…and to make more money

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Developed by the International Organization for Standardization (ISO)

International

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OVERSIGHT: ISO 9000

Oversight by outside auditors, paid by company

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CHANGE: ISO 9000

Change is controlled Deviations monitored Operation of systems

maintained in narrow range

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BIOTECH AND MEDICAL PRODUCTS

Many biotech companies that make money make medical/pharmaceutical products

Consequences of poor product can be life-threatening

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SO…

These products are highly regulated by the government

But, it wasn’t always this way…

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Gallery Guide Introduction

From http://www.fda.gov/cder/about/history/Gallery/Gallerypg.htm

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http://www.fda.gov/cder/about/history/Gallery/Gallerypg.htm

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http://www.fda.gov/cder/about/history/Gallery/Gallerypg.htm

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http://www.fda.gov/cder/about/history/Page6.htm

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http://www.fda.gov/oc/history/historyoffda/section4.html

Early biomedical device

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“THE JUNGLE”

Upton Sinclair described shocking conditions in food industry in U.S.

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FEDERAL FOOD, DRUG AND COSMETIC ACT 501[351]

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CANNOT SELL ADULTERATED PRODUCTS“A drug or device shall be deemed

adulterated – (a)1 if it consists in whole or part of any filthy…substance (2) (A) If it has been prepared, packed, or held under insanitary conditions whereby it may have been contaminated with filth…

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Or (B) if it is a drug and the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or are not operated in conformity with current good manufacturing practice to assure that such drug meets the requirements of the Act as to safety and has the identity and

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strength, and meets the quality and purity characteristics, which it purports or is represented to possess…”

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KEY IDEAS: 1906 FDCA

Adulteration Good manufacturing practices,

which we now call cGMP FDA (Food and Drug

Administration) eventually established to interpret and enforce this law

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SULFANILAMIDE -- 1937

Diethylene glycol used to dissolve sulfanilamide

Hundreds of people died, mainly children

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First drug recall, because the drug was labeled “elixir” and had no alcohol

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KEY IDEAS: 1938 FDCA

Required new drugs to be shown SAFE

Eliminated requirement to prove intent to defraud in drug misbranding cases.

Extended control to cosmetics and therapeutic devices.

Authorized factory inspections…      

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CROSS-CONTAMINATIONSULFATHIAZOLE Nearly 300 deaths and injuries

resulted from sulfathiazole tablets tainted with phenobarbital.

FDA dramatically revised manufacturing and quality controls -- good manufacturing practices (GMPs).

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KEY IDEAS: GMP REGULATIONS 1941

Cover actual manufacturing Raw materials must be good Must have lab testing of raw

materials, samples as you go along, products

Facilities, personnel, equipment must be good

Documentation

Safety Testing Approval Process

Revised GMP Regulations

1941

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THALIDOMIDE -- 1960

Sedative that appeared safe but in reality caused severe birth defects

Thousands of children affected throughout Europe

Led to tightened laws

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CONTAMINATED IV BAGS --1976

Septicemia 1960s and 1970s there were

many cases caused by IV fluids contaminated with bacteria.

Many people died

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FDA INSPECTIONS

Found serious problems: Contaminated cooling

water Sterilization equipment

that did not reach sterilizing temperature

Contamination

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Pharmaceutical companies had testing programs to monitor final products but Missed contaminated

products

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LED TO:

FDA emphatically states: “Quality, safety and

effectiveness are designed into a product. The quality of a product does not result from inspecting the product; that is, quality cannot be inspected or tested into the finished product.”

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HOW IS QUALITY BUILT INTO A PRODUCT? No single answer Requires:

Skilled personnel Well-designed and maintained

facility Well-constructed processes Proper raw materials Documentation Change control

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VALIDATION

Prove that it all works Test systems under all

possible conditions See how everything works Called “validation”

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ANIMAL TESTING --1976

Major deficiencies in animal testing labs company closed directors jailed

Led to GLP, Good Laboratory Practices

Pre-clinical testing

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SKIP TO PRESENT

Process for regulating drugs and other medical products

May 6, 2003

jANUARY 2011

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LIFE CYCLE OF A DRUG TODAY

Discovery Pharmaceutical company, R&D

department Academic research lab Not usually regulated or inspected

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Early research and development Characterization of product Development of assays Mode of action Chemistry Production method Purification methods

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SAFETY TESTING

Animal testing – follow GLP regulations

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If it is promising, submit Investigational New Drug Application, IND

If approved...

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CLINICAL TESTING

Clinical testing Phase I Safety Phase II Dose Phase III Effectiveness

Follow Good Clinical Practices Regulations

If approved, then…

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MANUFACTURING

Follow extremely strict regulations, GMP

Keep watching for problems

PRODUCTION FACILITY: CLEAN ROOM

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REGULATIONS

Have, GLP, GCP, GMP (cGMP) Administrative concerns;

principles e.g.personnel, equipment, materials

handling, documentation common to many different

companies and products scientific details limited

EXAMPLE OF GOOD DESIGN: FACILITY AND HOW PEOPLE WORK

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EXAMPLE: AVOIDING CONTAMINATION IN PCR FACILITY People move in one direction

through PCR facility to avoid contaminating samples with already amplified DNA

People change labcoats before entering PCR facility

Facility is designed to move samples in one direction

Security system

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ENFORCEMENT

Compliance is enforced by government FDA

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CHANGE

Change and variability are disastrous

Product quality hinges on avoiding change, reducing variability

Systems are in place to monitor and track variability

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BIOTECHNOLOGY PRODUCTS

Recombinant DNA techniques used for production of protein therapeutics 1982, recombinant insulin approved

for sale 1986 first monoclonal antibody

product 1987 first product using mammalian

cell line as host

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REGULATORY QUANDRY

Should these products be regulated in an entirely separate way?

From Time Magazine

http://bancroft.berkeley.edu/Exhibits/Biotech/25.html

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Basic answer is that same principles apply

But the details are different – what makes product safe, how do you know, etc.

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REST OF THIS COURSE

We will learn basic lab techniques

From a quality perspective Metrology

What makes a good measurement

Solutions How do we know our solutions

are right?

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CONSIDER ANTHRAX VACCINE

Political story Vaccine has been accused of

causing Gulf War Syndrome Recent cases of illness Manufacture of vaccine,

Bioport

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ONE PAGE OF 483

From 1998, 19 pages long First line is key:

“The manufacturing process for Anthrax Vaccine is not validated.”

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1a and 1b

Critical, key parameters in the fermentation process that produces the protective antigen that constitutes part of the vaccine should have been established:

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Age of bacterial strain Conditions in the fermenter Formulation of the bacterial nutrient

broth Operating parameters such as the

temperature, pressure, time, pH, stir times, agitation rates, vessel atmosphere, etc.

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Sampling periodically during antigen isolation and analyses whose results could illustrate acceptable progress

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Assessing ability of tank to heat and cool its contents consistently and uniformly

Testing the agitator for producing a homogenous suspension

Testing the materials used to make the tank to be sure they don’t adversely affect contents

Testing tank fittings, etc.

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1f

Effect of hold times was not evaluated Violates 21CFR211.111 “Time

limitations on production” which states that “time limits for the completion of each phase of production shall be established to assure the quality of the final product”.

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1d

The efficacy of a particular sporocide needs to be proven in the firm’s facility Conduct environmental monitoring

and identify the organisms recovered

See if these strains are destroyed by the sporocide; record effectiveness

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These parameters should have been clearly tested, monitored, and documented during a prevalidation study to demonstrate what quality of product is produced under specific processing conditions.

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WHAT CAN BE READ INTO THE 483S?

“The firm’s processing, testing, and monitoring was effectively a “black box”. Ingredients in – vaccine out! Someone understood the “tricks of the trade” but, for some reason, there was no documented evidence that a consistent manufacturing process or control system was in place!”.