QUALITY: The Big (BUT RELATIVELY BRIEF) PICTURE

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BASIC LABORATORY METHODS IN A REGULATED ENVIRONMENT

QUALITY

• Everyone is familiar with the concept of product quality from our experiences as consumers
• We want the things we buy to work well for our purpose
• But now, consider product quality from the perspective of making the product
• What goes into making a quality product?

LECTURE OVERVIEW

• What does product quality mean in different biotech workplaces?
• Introduction to quality systems
• History of pharmaceutical regulations in the U.S.; the evolution of quality systems for medical products
• Life cycle of pharmaceuticals today

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LECTURE OVERVIEW

• What does product quality mean in different biotech workplaces?
• Introduction to quality systems
• History of pharmaceutical regulations in the U.S.; the evolution of quality systems for medical products
• Life cycle of pharmaceuticals today

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WHAT IS PRODUCT QUALITY?

• What is a “good” product in biotech?
• It depends on setting
• Research labs
• Testing labs
• Production facilities

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QUALITY PRODUCT IN RESEARCH LAB

• Product of a research lab is knowledge
• Knowledge about nature (basic research)
• Understanding of technology (applied research, R&D)

QUALITY SYSTEM IN RESEARCH

• Purpose is to ensure meaningful, reproducible results
• This system has been around a long time
• It is called

• Doing Good Science!
• Not formalized in any single book or document
• Consequences of poor-quality product not usually life-threatening so
• Government not directly involved in monitoring research quality
• Oversight not generally by outside inspectors
• Research quality is the topic of our next lecture
• We will see that the scientific community is trying to improve research quality

QUALITY IN RESEARCH LABS

• For now, will summarize by saying that in general:
• Quality system is “Doing Good Science”
• Not formalized in any single book
• Not encoded in laws
• Not enforced by government agencies
• Oversight is by peers; scientific community is invested in improving research quality

OTHER WORKPLACES ARE DIFFERENT

• First will think about testing labs
• Then think about production facilities where tangible items are made

PRODUCT QUALITY: TESTING LAB

• Product is information about samples
• “Good” product is one that can be relied on when making decisions
• Depending on type of lab, consequences of a poor-quality product can be severe

QUALITY SYSTEMS DO EXIST

• For example, clinical labs, that test human patient samples follow specific rules to ensure the quality of their results
• Forensic labs follow rules for performing DNA tests of samples from crime labs
• Environmental testing labs often follow rules from the Environmental Protection Agency

QUALITY SYSTEMS FOR TESTING LABS

• These systems typically outline formal requirements for:
• Personnel qualifications
• Equipment
• Training
• Facilities
• Documentation
• Sample handling

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QUALITY SYSTEMS FOR TESTING LABS

• Usually is one or more books or documents to describe requirements
• There may be monitoring by outside inspectors from outside agencies

QUALITY AND REGULATIONS

• Discussion of quality in biotech inevitably leads to topic of regulatory affairs
• Government interacts with the biotech industry
• Regulations of particular importance to us are Current Good Manufacturing Practices, CGMP

PRODUCT QUALITY: PRODUCTION FACILITY

• Make tangible items
• Quality means fulfill intended purpose
• Example: reagent grade salt vs road salt vs table salt – how do requirements vary?

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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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QUALITY SYSTEMS IN PRODUCTION FACILITIES

• 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 by the government 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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ISO 9000

• Developed by the International Organization for Standardization (ISO)
• International applicability

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ISO 9000

• Oversight by outside auditors, paid by company

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LECTURE OVERVIEW

• What does product quality mean in different biotech workplaces?
• Introduction to quality systems
• History of pharmaceutical regulations in the U.S.; the evolution of quality systems for medical products
• Life cycle of pharmaceuticals today

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BIOTECH AND MEDICAL PRODUCTS

• As we have seen, medical products are very important in biotech
• Consequences of poor product can be life-threatening
• So, these products are regulated by the government in most countries

BUT IT WASN’T ALWAYS THIS WAY

• This is a good time to check out the Frances Kelsey and Thalidomide Case Study

THINKING BACK TO EARLY 1900S

• Dangerous drugs proliferated

From FDA website

From FDA website

From FDA website

From FDA website

From FDA website

An early biomedical device intended to bring good ether from the air. What do you think?

PUBLICATION OF THE JUNGLE CHANGED THINGS

• Upton Sinclair described shocking conditions in food industry in U.S.
• Filth in food
• Even worker appendages in food
• Sinclair was appalled by worker conditions, but public was appalled by adulterated foods

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LED TO NEW LAW

• FEDERAL FOOD, DRUG AND COSMETIC ACT 501[351]

“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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MORE OF THIS ACT:

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

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KEY POINTS ABOUT THE 1906 FDCA

• Used term “Adulteration”
• Contamination
• Or more broadly, problems in manufacture
• Term is still sometimes used by FDA
• Introduced idea of “Good manufacturing practices,” which we now call CGMP
• Led to establishment of agency to interpret and enforce the law, eventually called the FDA (Food and Drug Administration)

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SULFANILAMIDE -- 1937

• Diethylene glycol used to dissolve sulfanilamide
• Hundreds of people died, mainly children

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SULFANILIMIDE

• First drug recall, because the drug was labeled “elixir” and had no alcohol
• Difficult in those days to find and recall the drug
• Led to modifications of the FDCA

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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 WITH�SULFATHIAZOLE 1940-1941

• Nearly 300 deaths and injuries resulted from sulfathiazole tablets tainted with phenobarbital.
• FDA dramatically revised manufacturing and quality controls – led to “modern” 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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THALIDOMIDE -- 1960

• As you saw in the Kelsey Case Study, thalidomide is a 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
• FDA inspected company and found:
• Contaminated cooling water
• Sterilization equipment that did not reach sterilizing temperature
• Contamination

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CONTAMINATED IV BAGS --1976

• Pharmaceutical company had testing program to monitor final products but
• Missed contaminated products
• Testing final products cannot reveal all problems

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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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CONCEPT OF “VALIDATION”

• Prove that it all works
• Test systems under all possible conditions
• See how everything works
• Called “validation”
• Validation of manufacturing processes is an important step in developing new medical products

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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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CONSIDER THIS HISTORY

• Increasingly stringent laws and processes introduced to ensure quality of medical products
• Usually motivated by a tragedy
• Result: a stringent process of regulations for pharmaceuticals and other medical products

WHAT HAPPENED WHEN NEW BIOTECHNOLOGY PRODUCTS WERE INTRODUCED?

• Consider insulin, one of the first biotechnology products made by recombinant DNA methods
• This was a regulatory quandary
• Should recombinant DNA products, like insulin, be regulated differently?
• They are manufactured differently, using transformed cells
• But the products are often quite like older products
• For example, insulin made by recombinant DNA methods is very similar to that made by extraction from animal sources
• There was vigorous debate over regulation of these new products

Source of image unknown

Many people – including scientists – were concerned about the implications of recombinant DNA technology

EVENTUALLY

• As information about recombinant products became available, it was decided that same regulatory/quality principles apply to recombinant DNA products
• But the details are different – what makes product safe, how do you know it is safe, etc.

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LECTURE OVERVIEW

• What does product quality mean in different biotech workplaces?
• Introduction to quality systems
• History of pharmaceutical regulations in the U.S.; the evolution of quality systems for medical products
• Life cycle of pharmaceuticals today

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LIFE CYCLE OF A PHARMACEUTICAL TODAY, DISCOVERY

• Discovery
• Pharmaceutical company, R&D department
• Academic research lab
• Not usually regulated or inspected

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RESEARCH AND DEVELOPMENT

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

PRECLINICAL SAFETY TESTING

• Before testing in humans, must be testing in cells and animals
• Must follow GLP regulations

IND

• If preclinical testing is promising, submit Investigational New Drug Application, IND
• If approved...

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CAN MOVE TO CLINICAL TESTING

• In humans
• Clinical testing
• Phase I Safety
• Phase II Dose
• Phase III Effectiveness
• Follow Good Clinical Practices Regulations
• If successful submit application to FDA
• If approved, then move to manufacturing, sales, distribution

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OVERVIEW OF PROCESS

SMALL PRODUCTION FACILITY: CLEAN ROOM

NOW

• 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
• Enforcement is by FDA
• Have inspection system and can impose consequences for failure to comply

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EXAMPLE OF GOOD DESIGN:

FACILITY AND HOW PEOPLE WORK

IN PREVIOUS PICTURE

• Example: avoiding contamination in PCR
• People move in one direction through PCR facility to avoid contaminating samples with already amplified DNA
• People change lab coats before entering PCR facility
• Facility is designed to move samples in one direction
• Security system

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CONSEQUENCES

• Begin with letter to company outlining deficiencies that must be corrected
• In worst case, can move to criminal proceedings but fines are more common

WHAT THIS MEANS FOR YOU

• Many biotech jobs are in companies that are regulated and/or that comply with standards like ISO 9000.
• Remember that the rules in these companies are there to make sure products are safe, effective, and reliable.

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THIS BASIC LAB SKILLS COURSE

• You will learn basic lab techniques from a quality perspective
• For example, metrology (measurements)
• What makes a good measurement
• Solutions
• How do we know our solutions are right?
• How do we control/understand/reduce variability in our work?
• How do we make sure our work is “good”?

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TO DELVE DEEPER INTO THE TOPICS IN THIS LECTURE

• Chapters 35-38 in Basic Laboratory Methods for Biotechnology: Textbook and Laboratory Reference, 3^rd Edition have more information about regulatory affairs, including case studies, problem sets, and details about the regulated biotechnology industry.

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