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In 1937, medicine named sulfanilamide
was incorrectly prepared where diethylene glycol was used to dissolve the drug
and make a liquid form which lead to the poisoning of 107 people. This is known
as the 1937 Elixir Sulfanilamide Tragedy. This led to the passing of the 1938
Federal food, drug and Cosmetic Act. President Franklin Delano Roosevelt signed
this into law. This law increased federal regulatory authority for drugs and
mandated pre-market safety review for all new drugs. It also banned false
therapeutic claims in drug labeling without the FDA having to prove fraudulent

The new law fetched cosmetics and
medical devices under control, and it required that drugs be labeled with
acceptable guidelines for safe usage. The act also rectified misuses in food
packing and value, and it authorized rightfully enforceable food standards.
Tolerances for specific toxic substances were looked into. The law officially sanctioned
factory reviews, and it added restrictions to the implementation tools at the
agency’s disposal. 1

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1962 Kefauver-Harris Amendment to the Federal Food, Drug
and Cosmetic Act

In 1959 Thalidomide Tragedy led to
the passing of this act. Pregnant women took thalidomide for nausea which caused
thousands of European babies to have deformations such as, Phocomelia and
shortening/missing limbs. After this tragedy the 1962 Kefauver-Harris
Amendment to the FD Act was passed. This represented a
“revolution” in FDA regulatory authority. The most important change due to the
Amendment was the requirement that all new drug applications demonstrate
“substantial evidence” of the drug’s efficacy for a marketed
indication, in addition to the existing requirement for pre-marketing
demonstration of safety. This marked the start of the FDA approval process in
its modern form. These reforms had the effect of increasing the time required
to bring a drug to market.

The Kefauver Harris Amendment braced
the U.S. Food and Drug Administration’s control of experimentation
on humans and altered
the approach by which new drugs are accepted and controlled. Well-versed consensus was mandatory of patients playing
a part in clinical trials, and adversative
drug responses were
necessary to be stated to the FDA. 2

The 1984 Drug Price Competition and Patent Term
Restoration Act

This is more commonly known as the
“Hatch-Waxman Act”. The act extended patent exclusivity for new drugs
and tied them to the length of the FDA approval process. For generic drugs, it created
a new approval mechanism called the Abbreviated New Drug Application (ANDA). It
stated that they only need to show that their generic formula has the same
active ingredient, route of administration, dosage form, strength and pharmacokinetic
properties as the brand-name drug.    

Passing of this law provoked a rush into the generic business and a
damage of applications, which the FDA was not ready to bear 3. A chain
of disgraces rapidly rose that hampered public assurance in generic medications;
there were numerous examples in which corporations acquired bioequivalence statistics
deceptively, by means of the branded drug in their tests as a substitute of
their personal product, and a congressional examination found exploitation at
the FDA, where workers were taking bribes to accept some generic companies’ requests
and postponing or rejecting others 4, 5, 6.

With the passage of time the law developed
into effectively indorsing the overview of generics; in 1983 only 35% of
top-selling branded drugs with terminated patents had generic opposition, and
only 13% of prescriptions were for generics but in 2012, 84% of prescriptions
in the US were filled with generic drugs 4.


1 FDA’s Origin & Functions –
Part II: 1938, Food, Drug, Cosmetic Act.

2Canadian Thalidomide Experience.
(1963). JAMA, 186(10), 198.

3Drug Price Competition and Patent
Term Restoration Act (1984). (n.d.). The SAGE Encyclopedia of
Pharmacology and Society.

4 Boehm, G., Yao, L.,
Han, L., & Zheng, Q. (2013). Development of the generic drug
industry in the US after the Hatch-Waxman Act of 1984. Acta
Pharmaceutica Sinica B, 3(5), 297-311.

5 Freudenheim, Milt (10 September 1989). “Exposing
the F.D.A”. New York Times.

6 Andrews,
Edmund L. (31 July 1989). “F.D.A.
Inquiry on Generic Drugs Focuses on Changes in Ingredients”. The
New York Times.



Part 2 – Code of Federal Regulations
Title 21 – Part 210 & 211

The Code of
Federal Regulations (CFR) Part 210 & 211 covers the minimum current
good manufacturing practice for drugs and finished pharmaceuticals. Their
purpose is to ensure that medications are safe, pure & effective.
Identify 5 things within the regulations that serve that purpose and explain
how they meet the goal of safe, pure and effective manufacturing controls. 

Sec 211.22: Responsibilities of quality control unit

·       A quality control unit shall have the
duty and right to accept or discard all components, drug product containers,
closures, in-process materials, packaging material, labeling, and drug
products, and the authority to review production records to assure that no
errors have occurred or, if errors have occurred, that they have been fully
investigated. The quality control unit shall be in authority for approving or denying
drug products manufactured, processed, packed, or held under contract by
another company.

·       Suitable laboratory amenities for the
testing and consent (or rejection) of components, drug product containers,
closures, packaging materials, in-process materials, and drug products shall be
accessible to the quality control unit.

·       Can accept or cast-off processes
effecting the uniqueness, strength, quality and pureness.

·       The responsibilities and procedures
of the unit should be in writing to have a universal quality control unit.

Sec 211.72: Filters

·       Liquid filtration filters for
manufacture, processing or packing of injectable drugs should not release
fibers into the drug. It is only allowed if the drug cannot be made without the
use of fiber-releasing filters. These filters need a nonfiber-releasing filter
(maximum pore size of 0.2 microns and 0.45 micron if the manufacturing
conditions so dictate) to reduce the amount of fibers in the drugs.

Use of Asbestos-containing
filters are forbidden.
Helps to maintain the purity of
the drug and prevent side effects of the fibers in the body.

Sec 211.103: Calculation of yield

•The actual and theoretical yield has
to be determined at the end of each phase of manufacturing, processing,
packaging, or holding of the drug.

•Calculations have to be verified by
another person.

•Double checking the yield assures
that the value is accurate and verifies that the procedure for the drug is

Sec 211.34: Consultants

·       Consultants used for the manufacture,
processing, packing or holding of the drug should have adequate education,
training, and experience of the subject of inquiry.

There should be records of their
name, address, qualifications and type of service they provided.
Ensures that the facility is
receiving advice from a viable source.

Sec 211.58: Maintenance

•Facility used for manufacture,
processing, packing and holding the drug has to be up to date in repairs.

•Facility in bad condition can lead
to many work related accidents as it is possible for unwanted material to get
mixed in with the drug products, for example if there is a water leak.


FDA, U.S. Food and Drug
Administration, CFR title 21



Part 3 –
Current Good Manufacturing Practices (cGMP)

The Food and
Drug Administration (FDA) currently uses a risk based approach to cGMP
inspections. Explain what is meant by a risk based approach to inspection, identify
items/areas that the FDA would look at which are considered high risk, and
explain how this demonstrates to the FDA that the company is ensuring quality
throughout all phases of manufacturing, testing, distribution, and marketing.


Risk based approach to inspection
means that the FDA will look at the issues a company is having based on their
complaints, deviations, rejects, non-conformances, CAPA (corrective and
preventive action) and quality control lab investigations to see where the
company is struggling and if they are making the correct decisions to mitigate
issues and correct problems. They look at the following items/areas: Notification
to Management/Escalations, Deviations/Notice of Event, Complaints/Investigations,
FAR – Field Alert Reports, Recalls, Holds, Rejected Material, CAPA – Corrective
Action/Preventative Action, QCIR – Quality Control Investigation Reports, APR –
Annual Product Review They also look at SOPs – Standard Operation Procedures, Change
Control, Training Records, Qualification of Equipment & the PM Schedule, Stability,
Cleaning Validation, Re-introduction of products, Recap of responses to any
previous observations and anything relating to 21 CFR.

Risk based approach can be applied to
the evaluation, agreement, and inspectional constituents of FDA regulation. The
intensity of FDA action required are related to numerous aspects, including the
grade of a producer’s item for consumption and process consideration and the
robustness of the quality system regulating their development. For instance,
variations to composite products (e.g., proteins or naturally derived items)
prepared with intricate manufacturing processes may necessitate more monitoring
oversight. Process variations with acute variables that have not been
adequately defined may involve the submission of supplementary data or
comparability conventions. Further factors in accomplishing risk-based quality
valuations comprise instances after industrial progressions are critical to the
safety of the product or when produces have a critical public health impact
(e.g., products for the deterrence of infectious illnesses). This approach will
aid the Agency forecast where its assessments are likely to attain the utmost
public health effect. FDA expects that these risk-based deviations will ease
constant development in medicinal business and increase obtainability of novel
drugs while improving product value and procedure competence. FDA’s monitoring
approaches will be grounded on the extent to which a submission replicates a
producer’s knowledge of manufacturing process, method control, and quality

Within a reputable quality system and
for a specific industrial process, an individual would assume an inverse
association between the level of procedure knowledge and the threat of
manufacturing a poor class product. For procedures that are well understood,
chances are to develop less restraining controlling methods to accomplish
change (e.g., no requisite for a supervisory submission). Thus, an emphasis on
process understanding can enable risk-based regulatory choices and invention.






Part 4 –
Analytical Instrument Qualification

the purpose of analytical instrument qualification (AIQ). Identify and define
the four (4) critical components involved in generating reliable and consistent
quality data. Identify and define the four qualification phases of AIQ and when
each phase should occur.

The purpose of the use of analytical
instruments is to produce consistent data and that the instrument is suitable
for its proposed use. Instrument qualification aids in accomplishing this
purpose. No imposing guide subsists that reflects the risk of instrument
failure and associates that risk with users’ technical understanding and capability
to use the instrument to provide reliable and stable data. In the nonexistence
of such a guide, the qualification of analytical instruments has become a biased
and often unproductive article-producing application. 1

4 critical components involved in the
generation of reliable and consistent quality data are as follows:

·       Analytical instrument qualification: collection of documented evidence
that an instrument performs suitably for its intended purpose. Use of a
qualified instrument in analyses contributes to confidence in the validity of
generated data.

·       Analytical Method Validation: the collection of documented
evidence that a procedure is suitable for its intended use. Use of a validated procedure with
qualified analytical instruments provides confidence that the procedure will
generate test data of acceptable quality.

·       System Suitability Test: verify that the system will perform
in accordance with the criteria set forth in the procedure. These tests are performed along with
the sample analyses to ensure that the system’s performance is acceptable at
the time of the test.

·       Quality Control Check Samples: Many analysts carry out their tests
on instruments standardized using reference materials and/or calibration
standards. Some analyses also require the inclusion of quality control check
samples to provide an in-process or ongoing assurance of the test’s suitable
performance. In this manner, AIQ and analytical method validation contribute to
the quality of analysis before analysts conduct the tests. System suitability
tests and quality control checks help ensure the quality of analytical results
immediately before or during sample analysis.

4 qualification phases are as below:

·       Design Qualification: Prior to
purchase of a new model of instrument

·       Installation Qualification: At
installation of each instrument (new, old, or existing unqualified)

·       Operational Qualification: After
installation or major repair of each instrument

·       Performance Qualification:
Periodically at specified intervals for each instrument.


1 Bansal, S. K.,
Layloff, T., Bush, E. D., Hamilton, M., Hankinson, E. A.,
Landy, J. S., Shah, V. P. (2004). Qualification of
analytical instruments for use in the pharmaceutical industry: A scientific
approach. AAPS PharmSciTech, 5(1), 151-158.





Part 5 – Method Validation

Define Transfer of Analytical Procedure
(TAP), also referred to as method transfer. Then provide three (3) examples of
approaches to performing a TAP and explain the difference between the 3
approaches. Finally, explain a Transfer Waiver and give two (2) examples of
when a Transfer Waiver would be justified.


Analysis to the requirement of an auxiliary material, intermediary, and ingredient
and product is critical in creating the quality of a completed dosage form. The
transfer of analytical procedures (TAP), also referred to as method transfer,
is the documented process that qualifies a laboratory (the receiving unit) to
use an analytical test procedure that originated in another laboratory (the
transferring unit), thus ensuring that the receiving unit has the procedural
knowledge and ability to perform the transferred analytical procedure as

TAP can be performed and demonstrated by several approaches. The most
common is comparative testing performed on homogeneous lots of the target
material from standard production batches or samples intentionally prepared for
the test (e.g., by spiking relevant accurate amounts of known impurities into
samples).Other approaches include covalidation between laboratories, the
complete or partial validation of the analytical procedures by the receiving
unit, and the transfer waiver, which is an appropriately justified omission of
the transfer process and also revalidation. The tests that will be transferred, the extent of the
transfer activities, and the implementation strategy should be based on a risk
analysis that considers the previous experience and knowledge of the receiving
unit, the complexity and specifications of the product, and the procedure.

Comparative Testing

Comparative testing requires the
analysis of a predetermined number of samples of the same lot by both the
sending and the receiving units. Other approaches may be valid, e.g., if the
receiving unit meets a predetermined acceptance criterion for the recovery of
an impurity in a spiked product. Such analysis is based on a preapproved transfer
protocol that stipulates the details of the procedure, the samples that will be
used, and the predetermined acceptance criteria, including acceptable variability.
Meeting the predetermined acceptance criteria is necessary to assure that the
receiving unit is qualified to run the procedure.

Covalidation between Two or More

The laboratory that performs the
validation of an analytical procedure is qualified to run the procedure. The
transferring unit can involve the receiving unit in an interlaboratory
covalidation, including them as a part of the validation team at the transferring
unit and thereby obtaining data for the assessment of reproducibility. This
assessment is made using a preapproved transfer or validation protocol that
provides the details of the procedure, the samples to be used, and the
predetermined acceptance criteria.


Revalidation or partial revalidation
is another acceptable approach for transfer of a validated procedure. Those
characteristics described in the USP/NF general chapter on Validation of
Compendial Procedures , which are anticipated to be affected by the
transfer, should be addressed.

In Transfer Waiver; the conventional
TAP may be omitted under certain circumstances. In such instances, the
receiving unit is considered to be qualified to use the analytical test
procedures without comparison and generation of interlaboratory comparative

The following examples give some
scenarios that may justify the waiver of TAP:

·       The new product’s composition is
comparable to that of an existing product and/or the concentration of active
ingredient is similar to that of an existing product and is analyzed by
procedures with which the receiving unit already has experience.

·       The analytical procedure being
transferred is described in the USP–NF, and is unchanged. Verification
should apply in this case.



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