Mohammed Junaid

Assignment for BIO307

1710110217

Question 1:
There are five main players in GLP, they are
1. Sponsors
2. Management
3. Study Director
4. Principal Investigator
5. Quality Assurance Unit (QAU)

The principal investigator is responsible for the study that is performed on site. The role of
Principal Investigator is:
1. The principal investigator makes sure whether they follow the GLP Principles at all
phases of the study conducted on site.
2. The principal investigator should keep the study director with the progress of the
study. Any deviation or unforeseen circumstances seen during the study on the site
should be immediately reported to the study director.

The management responsibilities are

1. The management takes responsibility to adhere that all the Good Laboratory Practices
is been followed in the testing facility as per the protocols.
2. The management should ensure that there are sufficient number of qualified
personnel, appropriate facilities, equipment, and materials at any point of time during
the study.

The sponsors responsibilities are

1. The sponsor is the one who initiates the process of the support and supports the study
financially. The safety checks with regard to the non-clinical health and environment
safety needs to be performed.
2. Sponsor needs to document all the study related activities, i.e., before, during and
after the study that need to be submitted to the FDA whenever required.

The study director responsibilities are

1. The study director is the lead of the study. He/she is responsible to plan the study,
involve themselves during the execution process and look whether the GLP practices
are followed during the study. All the activities are reported to the study director.
2. The study director is responsible for documenting all the activities with the raw data
collected along with the process used during the study. This can be referred back by
the FDA during the audits.

The QAU responsibilities are

1. The QAU is appointed by the testing facility management to look after the internal
audits of the test.
2. They need to ensure that all the parties are following the GLP protocols.
 Question 2:

The key players in the GCP guidelines are as follows:

1. Investigator:
 The investigator leads the clinical study and he ensures that the GCP guidelines
are followed throughout the study.
 All the information needs to be recorded and stored according to the protocol.
 The investigator needs to ensure that all the personnel need to be instructed and
see that they are properly trained.
 It is the job of the instructor to get consent of the subjects before the study and
update the IRB accordingly.

2. Sponsor:
 The sponsor is the body that takes responsibility for the initiation, management
and the financing of the clinical trial.
 They need to be in constant contact with the IRB and the investigator.
 The sponsor needs to ensure that he is always updated with all the details of the
study.

3. Institution Review Board:

 IRB is the body that ensures that the investigator follows the protocols and
procedures of the GCP.
 It safeguards the rights and safety of all the trail subjects.
 It reviews all the information that is submitted by the sponsor and the lead
investigator.
 Any ethical related concerns is dealt by the IRB.

Controlled Study: Controlled study is the method where the subjects are given placebo to
ensure that there is randomness in the trial. This is mainly used to check the effectiveness of
the drug.
Uncontrolled Study: Uncontrolled study is the method where all the subjects are given the
drug to check the toxicology aspect of it and the safety measures of the drug.
 Question 3:

On January 16, 2020, the Center for Drug Evaluation and Research (hereafter referred to, as
CDER) sent a warning letter to a Ms. Britt N. Schendekhel, the CEO of Dental-Kosmetik
GmbH & Co. KG. The US FDA inspected their manufacturing facility and found violations
of current good manufacturing practices (hereafter referred to, as CGMP) under 21 CFR 210
and 21 CFR 211

The FDA categorised the drug products manufactured as adulterated due to non-conformance
of CGMPs as per the meaning stated in their rules. The violations are as follows:

1) The firm failed in establishing written procedures for production and process design.
This would have assured that manufactured products have identity, strength, quality
and purity information.
a. There was a failure in validating the processes used to manufacture drug
products.
b. There was no control over manufacturing processes. No process performance
qualification studies were neither conducted, nor initiated. The firm only
tested the first production batch. For others, the firm deviated from the
manufacturing instructions to achieve passing results. Therefore, the firm’s
non-conformity management is ineffective.

Suggestion by FDA: Drug product assessment should have a sound program that identifies
and controls all sources of variability, such that, production processes currently meet
appropriate specifications and standards. A detailed summary of validation program is
required to monitor intra/inter-batch variation and ensure continuing state of control. A
timeline of all performed processes should be maintained and a independent assessment of
overall systems must be made.

Suggestion as regulatory expert: The company must adapt a sound data-driven statistical
process control mechanism to ensure there are no non-conformance related productivity
losses in manufacturing processes. The company must install state-of-the art machinery to
ensure that the process control integrates with the production facility to sort and study the
variability on-spot to avoid such future issues.

There is an inadequate control system

- The component used to clean drug product and equipment is not established to be
designed, maintained and monitored to be meeting USP monograph specifications and
violations. The firm also lacked appropriate testing of this component.

Suggestion as regulatory expert: procurement of such components must be looked-at in detail

and ensured that industry best practices are followed in the purchase, storage and usage of
said component in facility. The firm must also request the facility management department to
perform FDA licensed tests on this component to ensure this is safe, and authorised to be
used on machinery and equipment that comes in contact with the produce.

2) The firm failed to establish and follow an adequate written testing program to assess
stability characteristics of drug products to determine appropriate storage conditions
and expiration dates.
 a. The firm didn’t have an adequate stability testing program to demonstrate that
the chemical and microbiological characteristics of your over-the-counter drug
products remain acceptable throughout their labeled expiry period.
b. There was no long-term stability test data found to support the 3-year
expiration date
c. The program did not include an adequate number of batches for each drug
product.

Suggestion by FDA: A comprehensive CAPA plan must be implemented to ensure the

adequacy of the stability program. The remediated program must include the stability
indicating methods and stability studies for each drug product in its container model before
distribution is authorised. Detailed definition of specific attributes to be tested at a designated
time must also be given.

Suggestion as regulatory expert: The firm must establish a testing program that is robust and
addresses the issue of stability way beyond just the adequate standards. A detailed cost-
benefit analysis of the cost of this implementation to made to determine at what point the said
testing program must be made such that it both matches the FDA regulation and minimises
the risk that such error be caused in further inspection. This program, being more robust and
detailed as suggested, naturally includes the stability attribute that the FDA suggestion
demands.

3) The firm failed to test samples of each component for identity and conformity with all
appropriate written specifications for purity, strength, and quality. The firm also failed
to validate and establish the reliability of your component supplier's test analyses at
appropriate intervals.
a. There was a lack in adequate testing of the incoming active pharmaceutical
ingredient to determine the purity, identity and other important quality
attributes.
b. The firm relied on the supplier’s certificates of analyses to verify the identity
of the API which shouldn’t have been the case.
c. The firm maintains that all raw materials are sourced from long standing and
trusted suppliers. However, the supplier fails to mention if the API supplier is
qualified. Additionally, the firm did not conduct at least a specific identity test
for each incoming lot.

Suggestion by FDA: A comprehensive and independent review of material systems must be

maintained to determine the qualification of all ingredients. A description of how the lot is
tested must be maintained. The summary of results obtained from testing components must
be maintained.

Suggestion as regulatory expert: In compliance with said demands, the firm must have a
designated team to handle the archival and maintenance of all such data, not only pertinent to
this violation, but to the above two too. This team shall be tasked with the review of if the
summary answers all the FDA guidelines, and if all data is coherent. Furthermore, the firm
must explore the possibility of backward integration where the firm produces its own API’s
therefore eliminating long term supplier-relation issues and supplier vetting costs. However,
for temporary purposes, the firm should task its procurement department with a detailed
review of not only API supplier, but all suppliers and other agencies that come in contact
with, or are essential to the functioning of the produced material.