Mahendra Chemicals 7/13/15

Department of Health and Human Services

Warning Letter
WL: [320-15-12]
CERTIFIED MAIL
RETURN RECEIPT REQUESTED

July 13, 2015

Mr. Rajnibhai Patel

Dear Mr. Patel:

During our May 19, 2014 through May 24, 2014 inspection of your pharmaceutical
manufacturing facility, Mahendra Chemicals, B-17, 217 & 218/2, G.I.D.C. Estate, Naroda,
Ahmedabad, Gujarat, India, investigators from the U.S. Food and Drug Administration (FDA)
identified significant deviations from current good manufacturing practice (CGMP) for the
manufacture of active pharmaceutical ingredients (APIs).

These deviations cause your APIs to be adulterated within the meaning of Section
501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. 351(a)(2)(B), in that the
methods used in, or the facilities or controls used for, their manufacture, processing, packing,
or holding do not conform to, or are not operated or administered in conformity with, CGMP.

We reviewed your firm’s response dated June 16, 2014, in detail. It lacks sufficient corrective
actions.

Our investigators observed specific deviations during the inspection, including, but not limited
to, the following.

1. Failure to record activities at the time they are performed and destruction of original
records.

Specifically, your employees completed batch production records entries days after
operations had ended, released lots before the proper approvals, and failed to maintain
original manufacturing data for critical steps in the batch production records. For example,
a) Our investigators found that some of your operators used “rough notes” (unbound,
uncontrolled loose paper) to capture critical manufacturing data and then destroyed these
original records after transcription into the batch production records. For example, the (b)(4)
chemist recorded original manufacturing data as rough notes and left these rough notes for
the (b)(4) chemist to transcribe into the batch production records. The next morning, the
(b)(4) chemist signed the batch production records and destroyed the original rough
notes. We interviewed employees during the inspection who confirmed your firm’s practice of
transcribing data to batch records and destroying original records.

b) Additionally, our investigators found backdated batch production records dated February
10 to February 25, 2014, signed by your Production Manager and Technical Director in the
“Batch Manufacturing Record Reviwed [sic] by” section. The Technical Director stated that
he was not in the facility on these dates and was “countersigning” for another person who
allegedly performed these review activities. However, these records did not contain
signatures (contemporaneous or otherwise) of the alternate reviewer who purportedly
conducted the review. Furthermore, the Technical Director backdated his own signature to
the date the quality unit (QU) reviewed and released your drug product. His backdated
signatures are on (b)(4) batch records for lots (b)(4); and (b)(4) batch records for lots
(b)(4). You released these batches before the Technical Director returned to the facility and
backdated his signatures. The batch records, therefore, do not demonstrate that you
completed your required review before releasing your products. You did not distribute these
lots to the United States. However, your failure to assure proper review of production and
control records before product release raises questions about the authenticity and reliability
of your data and the quality of the APIs you producefor the U.S. market.

Your response does not explain your use of rough notes for documenting CGMP data. This
practice, in conjunction with backdating records, raises additional concerns about the
integrity, authenticity, and reliability of all your data, and the quality of your APIs. Batch
production records must include complete and accurate information on the production and
control of each batch. Employees responsible for supervising or checking significant steps in
manufacturing operations must do so and appropriately document their review of critical
steps (for example, records must not be backdated and signatures must be authentic).

In your response to this letter, describe how systems and procedures will be changed to
assure that all CGMP operations are documented at the time they occur and that original
records are preserved in the batch records. Explain how you will determine that all
personnel involved with the preparation and review of API records adhere to your
procedures. Also, provide your plans to ensure QU review of completed batch production
and laboratory records before API release.

2. Failure to prevent unauthorized access or changes to data, and to provide adequate

Your laboratory systems lacked access controls to prevent raw data from being deleted or
altered. For example,

a) There is no assurance that you maintain complete electronic raw data for your Gas
Chromatography (GC) instrument. FDA investigators observed multiple copies of raw data
files in the recycle bin connected to the GC instrument QC-04 even in the presence of “Do
Not Delete Any Data” notes posted on two laboratory workstation computer monitors.

b) Employees were allowed uncontrolled access to operating systems and data acquisition
software tracking residual solvent, and test and moisture content. Our investigators noted
that there was no password functionality to log into the operating system or the data
acquisition software for the GC, the High Performance Liquid Chromatography (HPLC)
instrument QC-17, or the Karl Fischer (KF) Titrator QC-13.
c) HPLC SpinChrome and GC Lab Station data acquisition software lacked active audit trail
functions to record changes in data, including original results, who made changes, and when.

In your response, you state that your laboratory GC, HPLC and KF systems are now
password-protected and that you have begun drafting analytical software password
procedures for the GC, HPLC and KF laboratory instruments. However, your response does
not state whether every analyst will have their own user identification and password. You
also mention plans to install a validated computer system. However, you did not provide a
detailed corrective action and preventive action (CAPA) plan or conduct a review of the
reliability of your historical data to ensure the quality of your products distributed to the U.S.
market.

Inadequate controls of your computerized analytical systems raise questions about the
authenticity and reliability of your data and the quality of your APIs. It is essential that your
firm implements controls to prevent data omissions or alterations. It is critical that these
controls record changes to existing data, such as the individuals making changes, the dates,
and the reason for changes.

In response to this letter, provide your comprehensive CAPA plan for ensuring that electronic
data generated in your manufacturing operations, including laboratory testing, cannot be
deleted or altered. Also identify your quality control laboratory equipment and any other
manufacturing-related equipment that may be affected by inadequate controls to prevent
data manipulation.

3. Failure to train employees on their particular operations and related CGMP practices.

a) In interviews, multiple employees stated that they had not received on-the-job training
for their production operations.

b) There was no record of training for the GC analyst testing for residual solvent release in
final API.

c) According to your “(b)(4) Training Program” procedure, a report is generated for each
training with the names of trainer and trainees, subjects covered, evaluation sheets,
etc. However, you were not able to provide any training reports to our investigators.

In your response, you state that, per your standard operating procedure (SOP) from 2013,
your firm has trained all employees by contracting a consultant. However, as noted in item
3c, our inspection revealed that your firm is not following this procedure.

In response to this letter, provide a corrective action plan for investigating the extent of this
deficiency. Address why manufacturing and quality management failed to detect these
training deficiencies. Include updated procedures and proper quality oversight to ensure that
employees are adequately trained to perform all of their responsibilities for consistent
manufacturing and laboratory operations. Explain how you will determine the effectiveness
of your new consultant trainer, as your previous consultant was permitted to ignore your
training procedures.

The examples in this letter are serious CGMP deviations. Your quality system does not
adequately ensure the accuracy and integrity of data generated at your facility to support the
safety, effectiveness, and quality of the drug products you manufacture. Our current
significant findings also indicate that your quality unit is not able to fully exercise its
responsibilities. It is essential to give your quality unit appropriate authority and staff to carry
out its responsibilities.
We strongly recommend hiring a qualified third-party auditor/consultant with experience in
detecting data integrity problems to help you comply with CGMP requirements. Note that it
remains your responsibility to ensure that any third-party audit evaluates your sophisticated
electronic systems and their vulnerability to data integrity manipulation.

In response to this letter, provide the Agency:

1. A comprehensive evaluation of the extent of inaccuracies in your reported data. Include

2. A risk assessment of potential effects on drug product quality. Determine the effects of
your deficient documentation practices on drug products released for distribution.

3. A management strategy for your firm, including the details of your corrective action and
preventive action plans.

a) As part of your corrective action and preventive action plan, describe the actions you
have taken or will take to assure product quality. Contacting your customers, recalling
product, conducting additional tests, adding extra lots to your stability programs, and
monitoring complaints may be among the steps.

b) In another part of your corrective action and preventive action plan, describe the actions
you have taken or will take to prevent the recurrence of CGMP violations, including breaches
of data integrity. Revising procedures, implementing new controls, and training or re-training
personnel may be among the initial steps toward a comprehensive remediation.

For guidance on current good manufacturing practice for APIs, consult “Q7 Good
Manufacturing Practice Guidance for Active Pharmaceutical Ingredients” from the
International Conference on Harmonization (ICH) of Technical Requirements for Registration
of Pharmaceuticals for Human Use. This ICH Q7 CGMP guidance helps ensure that all APIs
meet international standards for quality and purity. You may download this guidance from
FDA’s website at:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
CM073497.pdf

FDA considers ICH Q7 and equivalent alternatives in determining if APIs have been
manufactured, processed, packed, and held according to current good manufacturing
practice under section 501(a)(2)(B) [21 U.S.C 351(a)(2)(B)] of the Act.

The deviations cited in this letter are not intended to be an all-inclusive list of deviations at
your facility. You are responsible for investigating and determining the causes of the
deviations identified above and for preventing their recurrence and the occurrence of other
deviations.

If, as a result of receiving this warning letter or for other reasons, are you are considering a
decision that could reduce the number of active pharmaceutical ingredients produced by your
manufacturing facility, FDA requests that you contact CDER's Drug Shortages Staff
immediately at [email protected] so that we can work with you on the most effective
way to bring your operations into compliance with the law. Contacting the Drug Shortages
Staff also allows you to meet any obligations you may have to report discontinuances in your
drug manufacture under 21 U.S.C. 356C(a)(1). FDA must consider, as soon as possible,
what actions, if any, may be needed to avoid shortages and protect patients who depend on
your products. In appropriate cases, you may be able to take corrective action without
interrupting supply, or to shorten any interruption, thereby avoiding or limiting drug shortages.
Until you complete all corrections and FDA confirms that your firm complies with CGMP, FDA
may withhold approval of any new applications or supplements listing your firm as an API
manufacturer. Failure to correct these violations may also result in FDA refusing admission
of articles manufactured at Mahendra Chemicals, Gujarat, India, into the United States under
Section 801(a)(3) of the Act, 21 U.S.C. 381(a)(3). Articles may be subject to refusal of
admission pursuant to Section 801(a)(3) of the Act, 21 U.S.C. 381(a)(3), in that the methods
and controls used in their manufacture do not appear to conform to CGMP within the
meaning of Section 501(a)(2)(B) of the Act, 21 U.S.C. 351(a)(2)(B).

Within 15 working days of receipt of this letter, please notify this office, in writing, of the
specific steps that you have taken to correct and prevent the recurrence of
deviations. Provide copies of supporting documentation. If you cannot complete corrective
actions within 15 working days, state the reason for the delay and the date by which you will
have completed the corrections. If you no longer manufacture or distribute the APIs at issue,
provide the date(s) and reason(s) you ceased production.

Send your reply to:

Mary D. Davis-López, Compliance Officer

Please identify your response with FEI # 3003802404.

Sincerely,
/S/
Thomas J. Cosgrove, J.D.
Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research