Transcript quality_parts_i_and_ii - Bio-Link

QUALITY: THE
BIG (
)
PICTURE
BUT RELATIVELY BRIEF
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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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QUALITYSYSTEMS
 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 S
I 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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QUALITYSYSTEMSIN
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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INFORMALSYSTEM

Consequences of poor
quality product not lifethreatening 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
 Grant review
 Publications
 Reputation
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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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S
UMMARY: 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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QUALITYSYSTEMSIN
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 lifethreatening
 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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QUALITYSYSTEMSIN
PRODUCTION
FACILITIES
Depends on nature of
product
 Poor product may or may
not have life-threatening
consequences

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S
O, 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
S
TANDARDS

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: S
I O 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 lifethreatening
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SO…


These products are highly
regulated by the government
But, it wasn’t always this way…
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From http://www.fda.gov/cder/about/history/Galle
Gallery Guide
Introduction
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http://www.fda.gov/cder/about/history/Gallery/Ga
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http://www.fda.gov/cder/about/history/Gallery/Gal
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http://www.fda.gov/cder/about/history/Page6
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http://www.fda.gov/oc/history/historyoffda/secti
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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CANNOTSELL
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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S
ULFANILAMIDE -- 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-CONTAMINATION
S
ULFATHIAZOLE


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
REGULATIONS1941

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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
Regulatio
ns
1941
THALIDOMIDE -- 1960

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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 ISQUALITY 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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S
KIP TO PRESENT

Process for regulating drugs and
other medical products
jANUARY
2011
May 6, 2003
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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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S
AFETY 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



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Phase I
Phase II
Phase III
Safety
Dose
Effectiveness
Follow Good Clinical Practices
Regulations
If approved, then…
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MANUFACTURING


Follow extremely strict
regulations, GMP
Keep watching for problems
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PRODUCTION FACILITY: CLEAN ROOM
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 OF GOOD DESIGN:
FACILITY AND HOW PEOPLE WORK
EXAMPLE: AVOIDING
CONTAMINATION IN PCR
FACILITY

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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?
http://bancroft.berkeley.edu/Exhibits/
Biotech/25.html
From Time Magazine
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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 THISCOURSE
We will learn basic lab
techniques
From a quality perspective
Metrology

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What makes a good
measurement
Solutions


How do we know our solutions
are right?
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CONSIDER ANTHRAX
VACCINE
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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!”.
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