QUALITY: THE BIG BUT BRIEF PICTURE

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QUALITY THE BIG(BUT 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

• In a research lab, knowledge is the product
• Knowledge of nature (basic research)
• Understanding of technology (applied research,
  RD)

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Quality SystemsIn Research Labs

• Quality system in research
• Ensures 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 peers
• When grant proposals for funding are reviewed
• When publications are reviewed
• Scientists reputation is based on the quality of
  his/her work

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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 QualityTesting Lab

• Testing lab
• Product is information about samples
• A good quality product is 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 SystemsIn 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 (of crime labs)
• EPA (of environmental labs)
• 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 QualityProduction Facility

• Make tangible items
• Quality means fulfill intended purpose
• Ex. reagent grade salt vs. road salt vs. table
  salt

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What is Good Quality for Salt?

• Examples
• Road salt maybe must be of correct coarseness
• Table salt must not be harmful when eaten and is
  finer than road salt
• Lab salt is highly purified

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Quality SystemsIn 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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VoluntaryStandards

• 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 AndMedical 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 wasnt 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/Gall
erypg.htm
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http//www.fda.gov/cder/about/history/Gallery/Gall
erypg.htm
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http//www.fda.gov/cder/about/history/Page6.htm
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Early biomedical device
http//www.fda.gov/oc/history/historyoffda/section
4.html
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• Most of these products did not live up to their
  claims and a few were lethal
• But there was pressure on Congress not to
  regulate drugs

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The Jungle

• In the early 1900s, Upton Sinclair described
  shocking conditions in food industry in U.S.

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• People were so disgusted that Congress took
  action and passed a law

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Federal Food, Drug And Cosmetic Act 501351
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Key Clause of this Law Cannot Sell
Adulterated Products

• A drug or device shall be deemed adulterated
  (a)1 if it consists in whole or part of any
  filthysubstance (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

• Forbids adulteration
• Mandates 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 Ideas1938 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

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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 IVBags --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 QualityBuilt 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

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Life Cycle Of ADrug Today

• Discovery
• Pharmaceutical company, RD 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 (testing in human volunteers)
• Phase I Safety
• Phase II Dose
• Phase III Effectiveness
• Follow Good Clinical Practices Regulations
• If approved, then

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Manufacturing and Marketing

• Follow extremely strict regulations, GMP
• Keep watching for problems

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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

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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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Example OfGood Design Facility And How People
Work
PCR Facility
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Enforcement of GMP/GCP/GLP

• 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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BiotechnologyProducts

• 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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RegulatoryQuandary

• People wondered, should these products be
  regulated in an entirely separate way?

http//bancroft.berkeley.edu/Exhibits/Biotech/25.h
tml
From Time Magazine
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RegulatoryQuandary Cont

• Moratorium was called and groups convened to
  discuss biotechnology applications
• Decided that same regulatory principles apply to
  conventional drugs and biotechnology drugs
• But some details are different what makes
  product safe, how do you know it is safe, etc.