5 GMP Case Studies REPORT

Including FDA Analysis

The GMP inspection case studies Barreto-Pettit provided include an in-depth analysis of the findings, lessons learned, and how
companies can avoid similar shortcomings. Areas examined in the case studies are:

– The first countrywide import alert issued by FDA

– Inadequate deviation investigation
– Inadequate product specifications and a product recall
– Process validation
– A different perspective on process validation and the culpability of the quality unit

WRITTEN BY PUBLISHED BY

JERRY CHAPMAN REDICA

SENIOR GMP EXPERT 6800 KOLL CENTER PARKWAY
SUITE 120
PLEASANTON, CA 94566
REDICA SYSTEMS
[email protected]
844-332-3320

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5 GMP CASE STUDIES INCLUDING FDA ANALYSIS

PART I: COUNTRYWIDE IMPORT Russian Drug Regulator”). She also reviewed the top ten 211
ALERT AMONG RECENT FDA citations in FDA drug GMP warning letters for FY 2015 to FY
2020, through July 2020 (FIGURE 1 ).
ENFORCEMENT ACTIVITIES
Barreto-Pettit commented, “As you can see, 21 CFR 211.100(a)
Part I covers Barreto-Pettit’s summary and analysis of recent
for process validation was cited the most in warning letters in
FDA enforcement activities and the case study on a countrywide
2020. It was fourth in the 483s frequency but is the top citation
FDA import alert.
in warning letters. And overall, over the years, inadequate
RECENT FDA ENFORCEMENT ACTION STATISTICS
investigations, which is 21 CFR 211.192, and process validation,
have been the most common deficiencies that have been cited
Barreto-Pettit began her summary of recent FDA enforcement in warning letters.”
activities with a review of the agency’s inspection priorities
during the last year and the impact of the COVID-19 pandemic FDA FY2020 FDA IMPORT ALERTS
on its activities.
She next addressed import alerts. In addition to issuing warning
Beginning in July 2020, onsite inspection activities resumed letters, FDA has the authority to place non-compliant foreign
in domestic regions with lower COVID-19 risks based on data firms under import alert. “This means that their products
from the COVID-19 advisory rating system. “We conducted would not be allowed entry to the US while the import alert is
mission critical inspections domestically and in foreign countries in place. We use this regulatory tool to protect our consumers
throughout the pandemic,” Barreto-Pettit emphasized. She from potentially unsafe or ineffective products,” Barreto-Pettit
noted that “mission critical” inspections are those with the explained. In 2020, the most common reasons for FDA issuing
highest priority based on public health benefits or where the import alerts were equally distributed among inadequate GMPs,
risks of not conducting the inspection outweigh the potential for analytical test results, and refusal to inspect.
investigators to potentially be exposed to COVID-19.
In 2020, Mexico received about 33.66% of the import alerts
In reviewing the top FDA 483 observations for FY 2020, the FDA due to issues with analytical results for hand sanitizers,
National Drug Expert commented that the same observations which contained methanol or did not meet the label content
recur year after year, sometimes in a slightly different order (for a specifications. Import alerts for Europe were mostly for
review of how and why 483 observations perennially repeat, see inadequate GMPs. In China, India, South Korea, and Taiwan,
“Top 10 Pharma Inspection Findings from FDA, MHRA, and the the main reason for import alerts was refusal to allow inspection.

FIGURE 1: Top Ten Part 211 Warning Letter Citations By Fiscal Year FY2015 To FY2020*
FISCAL YEAR
CFR CITATION 2015 2016 2017 2018 2019 2020 TOTAL

211.192 - Investigations of discrepancies, failures 6 6 16 21 32 21 109

211.100(a) - Absence of Written Procedures 2 7 13 26 28 33 99
211.84(d)(1)(2) - Reports of Analysis (Components) 0 3 7 28 17 17 72
211.165(a) - Testing and release for distribution 3 8 10 19 12 14 72
211.166(a) - Lack of written stability program 1 6 2 15 22 11 66
211.22(a) - Lack of quality control unit 2 4 6 17 19 5 53
211.194(a) - Complete test data included in records 3 4 6 11 12 5 41
211.160(b) - Scientifically sound laboratory controls 2 5 10 6 7 9 39
211.113(b) - Validation lacking for sterile drug products 2 4 12 3 9 5 35

211.22(a)(d) Procedures not in writing, fully followed 0 0 1 10 11 10 32

*AS OF JULY 31, 2020

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5 GMP CASE STUDIES INCLUDING FDA ANALYSIS

If the manufacturer does not let us inspect the facility where they recall of all the affected drug batches already distributed in the
manufacture products that they bring into the United States, we United States. The warning letter was issued for an adulterated
will not allow their products to enter the U.S. market.” product, which means a product that was not manufactured
under CGMPs or does not meet specifications.
CASE STUDY: HAND SANITIZERS WITH DEADLY
TOXINS Barreto-Pettit pointed out that the agency had not conducted an
inspection of the facility. “We asked for a detailed investigation
The first case study the national drug expert discussed is from a
into how these hand sanitizer drug products manufactured at
warning letter issued to a hand sanitizer manufacturer in Mexico
the facility and labeled as containing ethanol were substituted
that imported its products into the United States. FDA collected
in part or in whole with methanol. We also requested a list of
samples and its test results showed that even though the drug
the raw materials used to manufacture all their hand sanitizer
product was labeled to contain 70% of the active ingredient as
drug products, including the supplier’s names, addresses, and
ethanol, it contained an average of 44% ethanol instead of 70%
contact information.”
and the remaining was methanol, about 30%.

Therefore, these hand sanitizer drug products were adulterated IMPORT ALERT EXPANDED TO INCLUDE ENTIRE
COUNTRY
under the Food, Drug and Cosmetic Act in that the active
ingredient of ethanol was substituted in whole or in part with She explained that the requested information was useful to
methanol. the agency because the manufacturer receiving the warning
letter was not the only one having this kind of problem. FDA
found many others that had methanol contaminated hand
FDA has the authority to place non- sanitizers and it needed to investigate whether the root cause of
compliant foreign firms under import the problem was a supplier providing contaminated ethanol to
multiple manufacturers.
alert. This means that their products
would not be allowed entry to the US FDA also requested a list of all the batches of any hand sanitizer
drug products that were shipped to the United States by the firm
while the import alert is in place. and a full reconciliation of all the materials they distributed. “And
since we had not done an inspection, we wanted to see how
“You may have seen this in the news,” Barreto-Pettit commented. it was manufactured,” Barreto-Pettit said. “So, we requested
She pointed out that methanol is not an acceptable ingredient copies of the complete batch records for all the batches that
for hand sanitizers and should not be used because it is toxic. were distributed to the US.”
When methanol is applied to the skin, it can cause dermatitis as
In January 2021, FDA issued a MedWatch announcement and
well as more serious events facilitated by transdermal absorption
placed all alcohol-based hand sanitizers coming from Mexico
resulting in systemic toxicity.
on import alert to help stop products that are in violation from
Substantial exposure to topical methanol can result in symptoms entering the United States until it could review the products’
such as nausea, vomiting, headache, blurred vision, permanent safety. “And what we at FDA have seen is a significant number of
blindness, seizures, coma, permanent damage to the nervous hand sanitizer products from Mexico that were labeled to contain
system or even death. Although all persons using these products ethanol test positive for methanol or 1-propanol contamination.”
on their hands are obviously at risk, young children who
A subsequent FDA analysis of alcohol-based hand sanitizers
accidentally ingest these products and adolescents and adults
imported from Mexico found that 84% of the samples analyzed by
who drink the product are at a potential life-threatening risk.
the agency from April to December of 2020 were not in compliance
After confirming the test results, FDA issued a warning letter with FDA regulations or their specifications. More than half of
to the firm and an import alert to prevent its products from the samples were found to contain toxic ingredients including
continuing to come into the United States. It also requested a methanol and/or 1-propanol at extremely dangerous levels.

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5 GMP CASE STUDIES INCLUDING FDA ANALYSIS

Under this import alert, alcohol-based hand sanitizers from as the warning letter states, investigations did not sufficiently
Mexico that are offered for import are subject to heightened address the root causes and the company allowed manufacturing
FDA scrutiny. FDA import staff may detain the shipment. As part risks to persist for extended periods. An overview of the two
of their entry review, they will consider any specific evidence issues is provided in FIGURE 2 .
offered by the importers or the manufacturers that the hand
CASE STUDY 1: INADEQUATE DEVIATION
sanitizers were manufactured according to US CGMPs. This is
INVESTIGATIONS FOR DEPYROGENATION TUNNEL
the first time the FDA has issued a country-wide import alert for
any category of drug product. One investigation reviewed by the agency was related to the
depyrogenation tunnel for vials. The firm manufactured a
PART II: GMP INSPECTION lyophilized sterile injectable drug product in glass vials and
various batches of the lyophilized drug product were found to
CASE STUDY FOCUSES ON
contain black particles over a period of several months.
INADEQUATE DEVIATION
INVESTIGATIONS The company investigation found that the particles were metal
shavings that were falling from the upper surfaces of the tunnel
Part II covers a case study involving failures to adequately into the empty vials that were subsequently filled with the drug
investigate root cause. product. Various repairs were conducted on the tunnel but the
problem continued intermittently.
WHAT HAPPENS WHEN A DEVIATION
INVESTIGATION IS INADEQUATE? Rejection of batches of injectable drug product took place due
to vials that contained black particles upon visual inspection.
Barreto-Pettit presented a case study that involved two related
The investigation did not extend to other batches manufactured
but different scenarios found at a firm that pointed to inadequate
with the same equipment during the same time frame.
investigations under 21 CFR 211.192 involving equipment
maintenance issues as the root cause of the problem. However, “What was concerning about this was that they were rejecting

FIGURE 2 | Inadequate Investigations and Equipment Maintenance

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5 GMP CASE STUDIES INCLUDING FDA ANALYSIS

FIGURE 3 | Corrective Actions Requested in the Warning Letter Maintenance

vials that they could see these particles in,” Barreto-Pettit At the time of the FDA inspection, the requalification of the
stressed. “This is a lyophilized cake. They were only rejecting autoclave had failed in that the bioindicators had shown positive
vials where they could see contamination on the outside of the growth. Even after the requalification failure, the equipment
cake. However, particles embedded within the cake would not was still being used for commercial manufacturing. The firm
be detected upon visual inspection.” was certain that the requalification failure was due to using
improper bioindicators with the wrong D value and not due to
CASE STUDY 2: INADEQUATE DEVIATION the malfunctioning of the autoclave.
INVESTIGATIONS FOR MALFUNCTIONING
AUTOCLAVE However, this investigation was still open at the time of the
inspection, which occurred about a month into the investigation,
In the second scenario at the same facility, another injectable
and the equipment continued to be used. This issue was noted
drug product was filled in syringes and terminally sterilized in an
in the FDA 483 and also cited in the warning letter issued to the
autoclave. At the time of the inspection, the terminal sterilization
company.
cycle for the injectable drug product was exceeding the validated
autoclave parameters as the ramping time to achieve the set
FDA WARNING LETTER CORRECTIVE ACTIONS
parameters was increasing. It was taking longer to achieve the
set parameters for the autoclave. This resulted in various batches In the warning letter, information was requested from the firm
of the product being rejected because the sterilization cycle was regarding the impact of undetected particles, adequacy of
taking longer and was not meeting its validated parameters. investigations and competencies of those conducting them, and
an assessment of the malfunctioning equipment (FIGURE 3 ).
Different investigations identified different root causes for the
malfunctioning of the equipment. Various repairs were performed Importantly, the agency targeted what appeared to be issues
but nothing seemed to resolve the issue completely. The related to aging equipment (the last bullet point in FIGURE
investigations did not extend to all batches that may have been 3 in blue). “We questioned their equipment as being obviously
potentially impacted that were sterilized using the same equipment. malfunctioning and possibly aging,” Barreto-Pettit pointed out.
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5 GMP CASE STUDIES INCLUDING FDA ANALYSIS

“In this warning letter, we specifically requested that the CAPA justification for the continued use that is based on documented
plan ensure the prompt detection of equipment and facility risk controls? And are you reviewing these risks periodically
performance issues, effective execution of repairs, appropriate to make sure they are not impacting the quality of the drug
preventive maintenance schedules, and a timely upgrade of product?”
technology for the equipment and the facility infrastructure. We
also asked to see how they are going to review their systems— PART III: INCORRECT
the ongoing management review. We wanted a plan for that.” SPECIFICATIONS, PROCESS
VALIDATION ISSUES AT CMO
HOW TO DETECT AND PREVENT EQUIPMENT RISKS
LEAD TO ADVERSE EVENTS,
The Drug National Expert Investigator provided the following RECALL
questions for firms that may have equipment risks like the ones
Part III covers two case studies involving GMP issues at a
discussed above to explore as a self-evaluation tool:
contract manufacturing organization (CMO).
– “Does your quality unit get involved in identifying poor
performing equipment or unreliable equipment based on CASE STUDY 3: INADEQUATE SPECIFICATIONS AND
A CONTRACT MANUFACTURER
their review of planned maintenance activities, deviations,
the history of the qualification, any findings of calibration, or The third case study Barreto-Pettit presented at the UGA
how the batch performs? Are you getting involved in this or is conference involved a scenario that resulted in a mission critical
this a responsibility of other departments such as production, inspection conducted during the COVID-9 pandemic due to
maintenance, engineering, etc.? How does the quality unit adverse events that were reported to the agency after patients
make sure that this poorly performing equipment is identified took a drug product that was intended for the treatment of
in a timely manner?” thyroid disease.

In this case, the firm, which was both the product owner and
the distributor of the product, had established the wrong assay
Both the product owner and the contract
specifications for thyroid tablets in that the upper limit was too
manufacturer share the responsibilities high. 21 CFR 211.160(b) requires the establishment of product
for adequate specifications. specifications but the company failed to do so.

The product in this case study is an unapproved prescription

drug product for which there is no approved application.
– “How does the quality unit assess and understand the risks
Therefore, the manufacturer must follow the USP monograph
and the potential impact of this poor performing or aged
for the specifications. The product is contract manufactured.
equipment to the manufacturing process capability and
“Both the product owner and the contract manufacturer share
the product quality attributes? How are you controlling or
the responsibilities for adequate specifications,” Barreto-Pettit
mitigating those risks? And are you documenting the review
stressed.
of these risks in your control strategy?”
– “Does your quality unit remove, in a timely manner, equipment The USP specification for assay for this thyroid product is
that is performing poorly or is obsolete, is unreliable, that 90.0% to 110.0%. However, the firm erroneously established its
cannot adhere to the process parameters, like the autoclave specifications with a higher and wider range. “This was probably
discussed above, or equipment that requires frequent one of the reasons patients were experiencing adverse events
interventions or adjustments by the operators? Or equipment when they were taking this medication,” she postulated.
that breaks down frequently or when you do the maintenance In the Warning Letter, which was issued to the product owner, FDA
and it really does not resolve its performance or improve it? acknowledged that the product owner changed its specifications
Do you keep using this equipment or do you remove it?” to the correct ones and recalled some lots that had exceded
– “If you keep using equipment that is aged, do you have the newly established USP specification upon release. However,
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5 GMP CASE STUDIES INCLUDING FDA ANALYSIS

since this was a product owner and not the manufacturer, the or any other batches that were distributed and were still within
agency conducted a subsequent inspection of the contract expiration dating.
manufacturer and found 13 additional lots manufactured with
FDA found that the most recent validation batches after using
an API from a previous supplier that also exceeded the USP
a new API supplier were not placed on long-term stability until
specifications but were not initially recalled (Author’s Note: See
a year later, which was about a month before the inspection
the next case study below for more detail).
discussed here. Therefore, there was no stability data.

Agency investigators found upon further The agency also cited the quality unit under 21 CFR 211.22(b) for
not ensuring that the product was manufactured in accordance
review of the validation documents that with CGMPs, that investigations were complete, and that their
some of the validation batches also product met specifications.
exceeded the correct assay specifications
WARNING LETTER FOCUSES ON PROCESS
VALIDATION, BLEND UNIFORMITY, AND CONTROL
In addition, FDA investigators collected samples of the product STRATEGY

for testing and found several batches that had low out-of- A Warning Letter was issued to the contract manufacturer in
specification results that also had to be recalled. “This was January of this year, 2021. The first citation was 21 CFR 211.108,
interesting because their specification had a higher upper limit, which is inadequate process validation. The Warning Letter
but when we tested the products, they would come in low. We states that the company lacked data to show the homogeneity of
knew that there was an issue going on with content uniformity,” the powder blend, as the samples that were collected at different
she commented. locations within the blender were tested as a composite sample
and therefore the company only had one result and was not
CASE STUDY 4: PROCESS VALIDATION ISSUES
able to detect variability within the blend that could have led to
INVESTIGATED AT CMO
content uniformity issues of the tablets.
The fourth case study is the follow-up inspection of the contract
During the inspection, FDA collected samples of three different
manufacturer of the thyroid tablets that was the subject of the
batches, two of which were from the process validation batches.
third case study, where the agency identified an additional
All three samples had results that were low and the samples
13 lots that exceeded the USP assay specification of 90.0%
were subpotent for the active ingredient. One of them also failed
to 110.0%. Since the agency had seen variable assay values
content uniformity.
ranging from the upper 80s to values over 110%, investigators
reviewed the process validation documents for that product and “It is important to understand that blending is a very critical step
found other deficiencies. in the manufacturer of oral solid dosage forms, particularly for
narrow therapeutic drug products like these thyroid tablets,”
For example, it found that the firm lacked evidence to
Barreto-Pettit pointed out. “And when the blends are not handled
demonstrate the homogeneity of the powder blend it was
adequately, it can promote segregation, increase the moisture
formulating into tablets after it was blended in the V blender.
levels, cause particles to aggregate, and can lead to inconsistent
And even though the company collected samples from multiple
flow characteristics when they are being compressed.”
locations within the blender, personnel combined the samples
in the laboratory and tested them as a composite sample, only Additionally, because of the narrow therapeutic range of this
getting one assay result. product, content uniformity is critical. It is especially important to
prevent patients with hypothyroidism from receiving insufficient
Agency investigators found upon further review of the validation
or excessive doses. As a result of these content uniformity
documents that some of the validation batches also exceeded
issues, the company had to recall all the lots on the market.
the correct assay specifications of 90.0% to 110.0%. But
these were not identified during the company’s investigation, The Warning Letter also stated that the firm’s response to the
which did not extend to the process validation or stability lots FDA 483 was not adequate in that it did not provide sufficient
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5 GMP CASE STUDIES INCLUDING FDA ANALYSIS

data to show where the variability was occurring in its process – How do you monitor the sources of variability and control
and what its control strategy was before the company revalidated them?
the process. – What systems do you have in place? Do you have systems
that are adequate as far as procedures to detect a shift in the
CONCURRENT PROCESS VALIDATION NOT THE
process and identify new risks?
BEST CHOICE
– And if those risks are identified or shifts are detected, how is
The firm stated it would perform a concurrent process validation
that being communicated to the appropriate parties? And how
instead of a prospective process validation. In concurrent
do they correct it? How are they documented and monitored?
validation, the firm manufactures validation batches but each
– How often do you evaluate your process to determine
batch is evaluated concurrently after meeting specifications
whether process improvements, new equipment, and/or new
but before completing the process validation. “This approach
technologies are needed? Do you have a system in place
should be rarely used, especially where process knowledge is
in writing for systematically doing this type of evaluation?
limited and a control strategy has not been identified fully,” the
And how do they correct it? How are they documented and
FDA drug expert stressed.
monitored?
The Warning Letter also cited the firm for not having continued
process verification, which is stage three of process validation,
to ensure its manufacturing process remains in control and PART IV: FLAWED PROCESS
produces a drug product that consistently meets specifications. VALIDATION, INEFFECTIVE
QUALITY UNIT CITED IN
The Warning Letter required the contract manufacturer to
provide the following: WARNING LETTER
Part IV covers a separate case study involving process validation.
– A data-driven and scientifically sound analysis identifying
all sources of variability, including but not limited to the raw
CASE STUDY 5: PROCESS VALIDATION, QUALITY
materials and any type of manual steps such as the hand
UNIT ISSUES FOR DRUG IN SHORTAGE
scooping personnel used to transfer the blend to the hopper,
etc. The fifth and final case study in Barreto-Pettit’s presentation
– A determination of the capability of this manufacturing was based on the findings from a mission-critical preapproval
process step and a CAPA to reduce the process variation inspection for an injectable drug product that was in shortage.
This was the first commercial drug product for this firm at this
– A detailed summary of the validation program to ensure the
location. The product in the application was a sterile liquid
process remains in control throughout the product life cycle
drug product filled in large volume parenteral bags that are
along with any associated procedures
terminally sterilized.conducted during the COVID-9 pandemic
– More specifics about the process performance qualification due to adverse events that were reported to the agency after
and how the company is going to monitor both intra- and patients took a drug product that was intended for the treatment
inter-batch variation to ensure they continue in a state of of thyroid disease.
control
At the time of the preapproval inspection, process validation
EVALUATING STATE OF CONTROL IN had been completed. On inspection, FDA found “a very highly
MANUFACTURING
automated and integrated manufacturing and filling process,”
The following is a set of questions Barreto-Pettit prepared for the national drug expert reported. “And according to the
firms to use in evaluating manufacturing practices: quality unit, the process validation effort had been considered
successful. Therefore, we reviewed the process validation
– Do your quality unit and the responsible departments have
documents.”
sufficient knowledge of the manufacturing process and the
sources of variability? The manufacturing process flow for the product begins with a

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5 GMP CASE STUDIES INCLUDING FDA ANALYSIS

compounding step, which in this case is a simple step in which

a few ingredients are added to water.That liquid is then pipe
transferred into form-fill-seal machines. The bags are formed
and printed, filled, and sealed in these machines.

From there, they are sent to a conveyor through an auto tray

loading and unloading into the sterilization chambers. Then the
bags go through a step to remove the moisture from the outer
surface of the bags before going into automated leak detection
equipment.
FIGURE 4 | PPQ BATCHES
From there, the bags continue on a conveyor belt to a semi-
automated bag inspection by visual inspectors.Next, they
go automatically to the next station, which is an over-wrap “they had not conducted investigations into these low theoretical
plastic bag that goes over the primary container to protect the versus actual yields or into the low reconciliation yields. And the
outer surfaces and the ports. And then from there to the final reason they had not conducted these investigations is that they
secondary packaging and labeling station. In reviewing the had not set yield parameters in each manufacturing step or a
completed process validation data, FDA was provided with total overall yield.”
a table, which contained Process Performance Qualification
A primary observation on the FDA 483 had to do with inadequate
(PPQ) information.“As you can see, the firm manufactured four
process validation. The low total batch yields and the lack of
PPQ batches, one of which required rework due to issues with
documentation for having such high rejection rates indicate that
the over-wrap step crushing the ports of the bags during sealing.
the process is not in control.
When we first got this list, it did not have the last column—the
yield column” (FIGURE 4 ). In addition, the regulations require that yield parameters be
established for each manufacturing stage. The company had
PROBLEMATIC PROCESS YIELD AND
not done that for the final or intermediate steps, including the
RECONCILIATION ISSUES
compounding and form, fill and seal, and sterilization steps.
What FDA investigators found concerning about the table was
“Each step needs to have specific yield parameters, and if they
the number of units produced for batches that had a theoretical
do not meet those parameters then an investigation needs to be
size of 30,000 liters. For a yield of 100%, the company should
conducted,” she pointed out. “They did not do that. They did
have produced around 30,000 units of the 1,000 ml bag size
not have yields even for reconciliation to make sure to account
and around 60,000 units of the 500 ml bags.
for all the materials used for each batch.”
The table shows that the number of units produced was well
In addition, other information that should be in the batch
below the expected outcome. Instead of 30,000 units produced,
record, such as extensive stoppages, interventions, or response
for batch number three, there were only about 8,000 bags. The
to critical alarms, was not in the batch records. As a result, it
same with the fourth batch, about 8,000 bags. And for the 500
was “very difficult” to determine how well each batch ran in the
ml size, there were anywhere between about 20,000 and 26,000
processing line “because there were not many comments within
bags as opposed to 60,000 bags.
the batch records.”
The investigators asked for the calculated yields and were
provided with those figures after they calculated them. And as INADEQUATE AUTOMATED SYSTEMS AND
you can see, the total yield ranged from about 28% to 45%. In QUALITY UNIT

addition, the reconciliation yield for each batch was also out of During the inspection, investigators examined the electronic
the normal range with values around 69% or so. The company programming of the form-fill-seal equipment. “We found
could not account for 30% of the batch. that it had a lot of settings for critical alarms,” Barreto-Pettit
“To make things even more difficult,” Barreto-Pettit commented, commented. “Since this was such an automated system that
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5 GMP CASE STUDIES INCLUDING FDA ANALYSIS

required little intervention by the operators, they had set alarms It is expected that the process is challenged. Sometimes
to go off so the operators would take action. What we found design of experiments (DoE) is used with different component
was that some of these did not match the established process lots, different operators, different environmental conditions as
parameters.” applicable, and the measurement systems in the production
setting to identify the optimum parameters and conditions for
Some of the alarm settings were wider than the process
the specific product.
parameters, therefore, they would not go off unless they were
far out of range. The company did not have an explanation for “In this case as evidenced by the low yields and the lack of
the wider settings. information in the batch record, the company had a lot of
rejected bags that were either filled or unfilled and multiple
For these and many other reasons in the 483, investigators listed
rejections from form-fill-seal to packaging,” she pointed out.
observations for an inadequate quality control unit under 21
CFR 211.22(d). The quality unit approved the flawed process “Telling us that your company is overly conservative and it is
validation, did not conduct investigations, and did not identify rejecting more bags than needed does not mean, at least to
the deficiencies that were occurring in the process. me, that you understand the process or have confidence in the
equipment measurement systems and the control strategy that
PROCESS VALIDATION EXPECTATIONS you have implemented.”
In her presentation, Barreto-Pettit emphasized some of the “We did not feel during the inspection that there was sufficient
expectations for stage one process validation, which is also knowledge about this equipment and the rejection rate at each
known as process design (FIGURE 5 ). station and the root causes for the rejections. As I said before,
During this phase, FDA expects the company to build knowledge there were no investigations as the quality unit did not question
and understanding of the quality and interaction of raw materials the low yields for the validation batches.”
as well as the process and equipment to determine the greatest
QUALITY UNIT RESPONSIBILITIES
sources of variation to establish a control strategy. Manufacturers
need to understand the functionality and limitations of the In closing, the National Drug Expert emphasized the responsibilities
manufacturing equipment and how to detect the variation and of the quality unit in the pharmaceutical quality system.
its degree to implement procedures and strategies to maintain
“As you know, the quality unit has overall responsibility for the
the process under control.
quality and safety of the drug products that you manufacture
and distribute to the US market. If we find during inspections
that companies are not identifying issues, are not following their
responsibilities, or are not implementing systems to ensure that
the products are consistently manufactured, those observations
will appear in a 483 and could potentially be cited in a warning
letter.”

“When it comes to contract manufacturers, I often find that

the quality units do not have a robust oversight of these types
of activities. A company needs to find ways to make sure that
whatever product is contract manufactured or tested at a third-
party facility is following appropriate procedures and CGMPs and
that the product is manufactured in accordance with CGMPs.
Make sure that you always have oversight of all operations
throughout the life cycle of the product as well as the facilities
FIGURE 5 | PROCESS VALIDATION STAGE 1 and equipment.”

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