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lseidman@matcmadison.
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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!”.