QUALITY ASSURANCE FOR THE BIOSCIENCES
COMPREHENSIVE FINAL EXAM
NAME: ______KEY_______________
GRADE: ___________
Directions: Answer each question in pencil or pen on this test and turn it back to the testing
center when you are finished. Make sure your answers are legible--I cannot grade what I
cannot read! If there is not enough room in the space provided, continue your answer on the
back of the sheet the question is on.
1. Congratulations! You have been asked to consult with Acme BioCell on how to establish
quality control for their new product B4, a new diagnostic kit for Tuberculosis. This kit
will have a world-wide distribution and will be used for clinical purposes only.
a. Acme BioCell is a start-up company that has never had a QA/QC department before.
Give three advantages for having a proper QA/QC department with at least two people.
 Diagnostics require QA/QC documentation for the FDA.
 Better tracking of production processes.
 Better documentation for regulatory surveillance.
 Quality is more reliable.
 Safety is more reliable.
 Protection from litigation.
 Establish SOPs for production, packaging, and testing of product.
 Standardized process is more reliable, fewer batch failures.
 Quality systems necessary for ISO, international trade.
NO CREDIT: Vague answers such as “more success”….
b. Define the following terms and describe 3 (three) SPECIFIC responsibilities that each
department would have in making B4 kits for Acme BioCell’s company:
Definition
responsibilities
An organizational unit in a
1. Create tests and SOPs to ensure proper
Quality
company that provides
handling of materials, proper procedures in
Assurance: confidence that product quality
production.
requirements are fulfilled, in
2. Create tests and SOPs for testing quality of
part through the effective
processes and products.
deployment and management of
3. Create a documentation system.
documentation
4. Archive documentation.
5. Interface with regulatory agencies.
6. Interface with ISO auditors.
NO CREDIT creates product, tests product
Quality
Control:
A department responsible for
monitoring processing and
performing laboratory testing to
ensure that products are of
1. Run tests and create documentation on
batches in production processes.
2. Run tests and create documentation on
input materials of production and
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suitable quality.
packaging processes.
3. Calibrate equipment and test instruments.
NO CREDIT
Creates the tests or quality systems, Develops QA
manuals, anything wrt QA
c. Juran had a four-point fitness for use classification system outlined below. Give a
SPECIFIC example of something that Acme BioCell should look at or do for each in
each of these categories in order to produce a quality B4 kit product.
Product must be shown to be an accurate and reliable diagnostic.
1) Quality of Design
Product must have a niche in the market by offering better reliability,
quicker assay, etc. (market research)
Product must be robust, not prone to inactivation of reagents or
incorrect usage.
2) Quality of conformance
3) Availability
Product must meet the specifications set for the quality standard with
a high degree of reliability.
Product must meet standards of FDA.
Components must be readily available.
Production process must be robust, able to meet market demands.
Product must have a sufficient shelf life to allow stockpiling in order
to meet variable demands by the marketplace.
A shipping process must be able to deliver product without
compromising quality.
Technical assistance for problems that arise in the customers’ use.
4) Field Service
d. If you were contracted to perform a quality audit of Acme BioCell, what are 2 general
things that you would be looking for? Justify your answer.
1. An adequate quality system has been designed. Check the SOPs, quality manuals.
2. The quality system is being followed. Check the documentation and records.
3. Employees are adequately trained.
e. Give 5 examples of important documentation that Acme BioCell will maintain for cGMP
compliance. List the department responsible for that documentation.
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The documents that must be maintained include standard operating procedures, manufacturing
and packaging records, component specifications, raw material specifications, analytical
methods for testing raw materials and products, forms, and training records. A company must
also have a change control system that requires assessment of any proposed changes and a
system to retrieve and evaluate data for annual product reviews. Additional systems include
those for corrective-preventative actions, and a system for supplier qualification. Within the
testing laboratory, systems are required for the use and maintenance of reference standards, test
solutions, volumetric solutions, and data retention. Ancillary systems may be necessary to
monitor manufacturing that includes controlled substances and non-denatured and denatured
alcohol for compliance with the Drug Enforcement Agency and the Alcohol and Tobacco Tax
and Trade Bureau.
2.
a. How does a company earn ISO 9000 certification?
1. Design and implement a quality system as outlined by ISO guidelines
2. The organization hires an outside firm to audit the quality system in place. A minimum of 3
months of evidence are required before this process can take place.
3. Once the system is audited, only minor non-conformities are allowed in order to obtain a
certification.
4. Once the company is granted with a certification, periodic surveillance audits are agreed
upon in order to maintain the “certified status”.
b. Which departments and personnel must be prepared for an ISO 9000 audit?
ALL departments, ALL personnel
c. What are three key differences between ISO and GMP?
GMP
Mandatory system
ISO
Voluntary system
Federal (US) Law
International accepted standard, not law.
Applies to pharmaceutical, biological,
medical device manufacturing
Can apply to any industry
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Aim to ensure public safety by FDA
oversight of food and medicinal
manufacturing
Aim to satisfy commercial or customer
expectations of quality
Standards are generic and broad in
scope but apply to the
pharma/medical industry only
Standards are generic; they provide a
blueprint for quality and can apply to any
industy
Standards rely heavily on testing and
inspection; functional areas are
clearly defined
Standards rely on management
commitment, systems and procedures
(road map) and documentation; quality
system needs to be only as comprehensive
as necessary to meet quality objectives
Compliance is monitored by FDA
Compliance is monitored by outside
auditors paid by the company
3. a. Describe two methods by which the FDA checks for compliance. 4pts
1. Inspection of production facilities.
2. Inspection of product in the marketplace.
1.
2.
3.
4.
5.
6.
7.
8.
b. Describe five methods by which the FDA enforces its regulations, in the order of
increasing harshness. 10pts + 2pts bonus correct order
FDA 483: public notice of company’s noncompliance with GMPs; response is not required
but recommended
Requested Recall: requesting company’s voluntary recall of products in violation
Warning Letter: gives a deadline for company to address the problem(s); public notice of
FDA expectations for compliance
Border Alert: prevents entry by US Customs
License Suspension or Revocation: (licensing is required for biologics like vaccines, blood)
Seizure: approved by US Federal Court judge; carried out by US Marshals
Consent Decree: fines, reimbursements to the government for inspection costs, due dates for
specific actions, penalties for noncompliance---usually permanent (25 in the last 13 years)
Criminal prosecution: fines & prison time
4. Describe what is unique to the total quality management approach and explain how a total
quality management approach can help to reduce an adversarial relationship between the labor
force and the management of a company. 4pts
Total Quality Management (TQM) is a customer-oriented quality improvement program
focused on producing cost-effective quality products/services through effective coordination of
all production processes by management personnel, and sincere involvement of all workers.
Adoption of TQM creates a company culture that is harmonious and ensures complete
cooperation between management and workers. The TQM approach states that every employee
in the company is responsible for quality. One way to reduce an adversarial relationship is by
motivating the employees. If any employee, from the janitor to the President, feels that his/her
basic needs are of concern to the company, and that they are held in high esteem and recognized
for their achievements, then they are willing to work hard and conscientiously for the company.
Thus, a successful company finds ways to ensure the basic needs of all the employees are met.
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5. What is the mission of MedWatch, and how do they accomplish their goals? 2pts
MedWatch is the FDA safety information and adverse event-reporting program. It provides
safety alerts for drugs, biologics, devices, and dietary supplements; safety-related drug labeling
changes; and information about recalls, drug shortages, medication errors, etc. It also provides
a mechanism for reporting adverse reactions and medical product problems to the FDA.
6. What do the following acronyms stand for, and describe their significance to a biotechnology
company. 1pt + 2pt each = 3pts per = 30pts total
Acrony
Specifies
Meaning and importance to a biotechnology company
m
Food & Drug
Drugs, biologicals, medical devices, vet products, many foods sold
FDA
Administration
interstate
Office of
mission: to ensure that FDA-regulated products comply with
ORA
Regulatory Affairs appropriate public health laws & regulations
Responsibility: working with additional fed agencies on compliance &
evaluating legal actions & directing criminal investigations in
coordination with other agencies
Form issued by
Ability of FDA to enforce regulations to improve the quality of
483
FDA for lack of
pharmaceutical products and protect the safety of the consumer
compliance after
an inspection
Center for Drug
Drugs-mission: to ensure that safe and effective prescription, nonCDER
Evaluation &
prescription, and generic drugs are available to the public as quickly as
Research
possible. Responsibility: 1. New drug development and review. (IND
application for approval; clinical trials; NDA application) 2. Postmarket drug surveillance.(compliance with cGMPs, inspections of
production facilities, drug labeling, reporting systems for adverse
events)
Center for
Biologics: Biopharmaceuticals, vaccines. Mission: to regulate
CBER
Biologicals
biological products including blood, vaccines, therapeutics, and related
Evaluation &
drugs & devices Responsibility: 1. monitoring pre-clinical and clinical
Research
testing of new biological products, and evaluate safety & effectiveness
before marketing 2. Licensing biological products and manufacturing
establishments 3. Compliance monitoring, lot releasing and postmarket surveillance.
Current Good
"Good manufacturing practice" or "GMP" is part of a quality system
cGMP
Manufacturing
covering the manufacture and testing of pharmaceutical dosage forms
Practice
or drugs and active pharmaceutical ingredients, diagnostics, foods,
pharmaceutical products, and medical devices. GMPs are guidance that
outlines the aspects of production and testing that can impact the
quality of a product.
Environmental
Regulates pesticides used in agriculture and substances released to the
EPA
Protection Agency environment. *GMO*
National Institute
The NIST is a non-regulatory federal agency within the U.S. Commerce
NIST
of Standards &
Dept’s Technology Administration. To develop and promote
Technology
measurement, standards, and technology to enhance productivity,
facilitate trade, and improve the quality of life.
International
ISO standards are developed by national delegations of experts from
ISO
Organization for
business, government and other relevant organizations.
Standardization
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CFR
The Code of
Federal
Regulations
The CFR provides the information on quality systems in the
laboratory (QSR), manufacturing practices, laboratory practices, and
clinical practices. The CFR is a massive set of regulations, published
annually.
7. A.What is a consent decree? 2pts
A consent decree is a negotiated agreement between the FDA and a noncompliant manufacturer,
that outlines steps that a company has to take in order to return to full, independent production.
b. What prior action does the FDA take before a consent decree becomes necessary? 2pts
The FDA implements a consent decree after the company has received repeated FDA 483s or
warning letters concerning GMP observation and deficiencies, and these repeated offenses have
not been corrected.
c. What are 3 different types of negative effects that a consent decree can have on a
pharmaceutical manufacturer? 3pts
1. The company may have to stop marketing a product
2. The company may have to stop selling a product
3. The company may have to hire an outside consultant to help bring them back into GMPs
4. Results in bad press for the company
5. Expensive to fix
8. Define the term audit and describe how it differs from an inspection or surveillance. 5pts
An audit is an inspection of an organization’s adherence to the established quality
standards and can be internal or external. Inspection is defined as a close examination of
a process or product. Unlike inspections, audits do not necessarily identify the root cause of
a problem, but ensure that areas within the company are following previously agreed upon
process and standards. Surveillance is an inspection process using similar techniques as
found in inspections and audits though less precise. Surveillance is a way to determine if the
production process is performing as planned and if the product’s quality is acceptable
9. Describe how the 3 phases of clinical trials required by the FDA differ in goals and in size.
Phase Experimental goals
Size
Designed to primarily test the safety of the proposed drug in
20-80 healthy
I
healthy humans. To see if there are any unexpected side effects
volunteers
and to establish the dosage levels that can be tolerated. In
addition to evaluating the safety of the drug, its metabolic and
pharmacologic properties in healthy humans are determined.
Determine the drug’s efficacy. Patients who have the illness are
100-300 patients
II
treated with various dosages and are closely monitored for the
with the illness
effects of the drug.
Double-blinded studies usually conducted at several hospital sites. 1000-3000
III
These tests usually last for over three and a half years for most new patients
drugs to establish its benefits and its long-term safety. At this
point, the recommended dosages are determined, a risk versus
benefit analysis is performed, drug interactions are explored, and
other data are collected.
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10. What are the three basic premises of ISO 9000 quality standards?
Say what you do
Do what you say
Be able to prove it
11. Describe the differences in goals of the 3 parts of equipment validation:
documents proof that the building, wiring, installation and
Installation
calibration of equipment, utilities, SOPs, spare parts, specifications,
Qualification
meets the design intention
documents proof that the system (i.e. maintenance log review, raw and
Operational
process water systems, pure and process steam systems, process gases,
Qualification
HEPA challenge, autoclaves, vessels and blenders) performs as specified
verify that facility, equipment or systems operate as intended under
Performance
challenge conditions
Qualification
12. Describe three circumstances when a piece of equipment should be validated.
When the equipment is installed.
When the equipment is moved (within the same facilities or new facilities-any movement).
In a typical biotechnology company bound by GMP or ISO9000 regulations, Equipment
validation is part of the regular Quality Control procedures, usually performed on a committed
time period (weekly, daily, or monthly).
13. What are the three federal regulatory agencies that are responsible for the evaluation of new
crops developed using genetic engineering (GMOs)? Discuss their main concern (regulatory
focus).
FEDERAL
REGULATORY FOCUS
AGENCY
Evaluates food and feed safety: The FDA’s Center for Food Safety and Nutrition (CFSAN)
and the Center for Veterinary Medicine (CVM) evaluate new GM crops focusing on the
FDA
presence of increased or additional allergens, toxins, or a change in nutrition or
composition. The main concern of the FDA is threats to human health through food and
health of animals through feed. It’s important to note that FDA does not approve a product
as safe, but rather completes a comparative evaluation of its unmodified counterpart.
Ensures agricultural and environmental safety: The USDA through the Biotechnology
Regulatory Service (BRS) office of the Animal and Plant Health Inspection Service
(APHIS) regulates all GM crops prior to commercial release. The legislative authority for
USDA
USDA oversight comes from the Plant Protection Act of 2000. The main concern of the
USDA is determining if the new plant will harm agriculture and the environment.
Evaluates food safety and environmental issues associated with new pesticides: The EPA
regulates GM crops that have altered pesticide characteristics. The main concern of the
EPA
EPA is the environmental and human health impacts of pesticides.
14. A testing method must have both precision and accuracy. Describe the following parameters
of a testing method.
The lowest concentration of the material of interest that the method can quantitate
Limit of
with acceptable accuracy and precision. This is particularly important when testing
quantitation
for impurities. The sensitivity of the assay used will determine the Limit of
Quantitation.
A measure of the extent to which a method can determine the presence of a
Selectivity
particular compound in a sample without interference from other materials present.
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Linearity
Range
Robustness
Percent error
of the Mean
Standard
Deviation
A very selective test will only give a positive result to the compound of interest
The ability of a method to give test results that are directly proportional to the
concentration of the material of interest within a given concentration range.
Defined by the limits of concentrations, from the lowest to the highest, that a method
can measure with acceptable results.
A measure of the capacity of a method to remain unaffected when there are small,
deliberate variations in method parameters. It provides an indication of the
method’s reliability during normal use.
Measures accuracy of data. Accuracy can be tested by using a reference standard
which the true or expected value for the test is known. If it is a method being tested,
the results are compared to a standardized assay. Accuracy relates to the quality of
a result.
Percent error of the mean (PEM)= (calculated mean – true value) x 100
true value
Measures precision of data. Precision relates to the quality of the operation to
obtain that result.
BONUS QUESTION:
This question must NOT be something already covered on exam. For full points it must be
answered correctly.
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