Cipla Limited MARCS-CMS 597511 — February 25, 2020

WARNING LETTER

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• Delivery Method: VIA UPS
• Reference #: 320-20-26
• Product: Drugs

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• Recipient: Mr. Umang Vohra; Managing Director and Global CEO; Cipla Limited; Cipla House, Peninsula Business Park, Tower C; Ganpatrao Kadan1 Marg, Lower Parel; Mumbai 400013; India

• Issuing Office: Center for Drug Evaluation and Research | CDER; 10903 New Hampshire Avenue; Silver Spring, MD 20993; United States

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February 25, 2020

Warning Letter 320-20-26

Dear Mr. Vohra:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Cipla Limited, FEI 3004081307, at L138; Ll39 - 146; L147/A; L147/1 - 147/3; S103 - 105; S107 - 112; M61 - 63, Verna, Goa, from September 16 to 27, 2019.

This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. See Title 21 Code of Federal Regulations (CFR), parts 210 and 211 (21 CFR parts 210 and 211).

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug products are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).

We reviewed your October 21, 2019, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

During our inspection, our investigators observed specific violations including, but not limited to, the following.

1. Your firm failed to clean, maintain, and, as appropriate for the nature of the drug, sanitize and/or sterilize equipment and utensils at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or established requirements (21 CFR 211.67(a)).

Your cleaning procedure for non-dedicated equipment, including your (b)(4) and tablet (b)(4) equipment ((b)(4)), is inadequate. Our investigators observed multiple (b)(4) and (b)(4) containing residues of what appeared to be different products inside the exhaust ducts. Analytical testing conducted by your firm on the residues collected from this manufacturing equipment confirmed the presence of multiple active ingredients.

After our inspection, your firm also tested reserve samples of selected batches to assess the potential for cross contamination. Your testing confirmed the presence of active ingredients from a previous product in batches of the next product, including but not limited to:

• Residues of (b)(4) active ingredient in (b)(4) tablets
• Residues of (b)(4) active ingredient in (b)(4) ((b)(4)) tablets

Your response stated that 261 out of 268 batches tested did not show traces of previous product manufactured. You also indicated your belief that the layer of (b)(4) drug product residue seen in the exhaust duct did not pose a risk of contamination to your drug products.

Your response is inadequate. Retain samples from several batches were found to be contaminated with another drug. However, your response continues to be equivocal about the source of the contamination. This lack of a clear root cause casts doubt on whether you have fully resolved a serious cross-contamination problem.

In addition, reserve sample testing alone is insufficient to determine the scope of the cross-contamination issue and mitigate risks associated with it. Your response also failed to address that, in about 10 percent of the batches tested, your firm detected unknown peaks eluting at the retention time of a previous product. Your firm indicated that the carryover was not confirmed because the peak did not match the (photo-diode array) peak spectra of the standard solution from the previous product. However, your firm did not provide an adequate investigation that addressed the identity of each unknown peak and its source. Your response also acknowledged challenges with the analytical methodology due to interference of product matrix and poor peak response, but it lacked supporting documentation demonstrating that these challenges were adequately resolved.

There is no assurance that the scope of your evaluation was comprehensive. Your rationale for testing reserve samples consisted solely in selecting products with the largest amount of potential carryover, as represented by the longest campaign prior to a product changeover. Your selection also did not seem to include a toxicological hazard assessment to identify active ingredients that may represent a higher risk to patients due to low permitted exposure levels. ·

In response to this letter, provide the following:

• A comprehensive, independent retrospective assessment of your cleaning effectiveness to evaluate the scope of cross-contamination hazards. Include the identity of residues, other manufacturing equipment that may have been improperly cleaned, and an expanded assessment to determine whether cross-contaminated product batches may have been released for distribution. The assessment should identify any inadequacies of cleaning procedures and practices, and encompass each piece of manufacturing equipment used to manufacture more than one product.

• A corrective action and preventive action (CAP A) plan, based on the retrospective assessment, that includes appropriate remediations to your cleaning processes and practices, and timelines for completion. Provide a detailed summary of vulnerabilities in your process for lifecycle management of equipment cleaning. Describe improvements to your cleaning program, including enhancements to cleaning effectiveness; improved ongoing verification of proper cleaning execution for all products and equipment; and all other needed remediations.

o In addition to this holistic remediation, provide specific CAP A activities that are being undertaken to effectively remediate the conditions that caused the specific cross-contamination incidents discussed above. Provide an independent review by your consultant that determines the effectiveness of your CAPA, including but not limited to:
• a list of all enhancements to cleaning and maintenance procedures including specific frequencies and locations to be cleaned in all relevant equipment (e.g., (b)(4), (b)(4), ductwork)
• identify any other sources of cross contamination other than (b)(4) equipment, (b)(4) and ductwork
• determine the adequacy of your analytical methodology to identify residual carryover
• your investigations into the unknown (unidentified) peaks detected in your reserve samples
• supporting evidence to demonstrate that the challenges identified during your study, such as interference of product matrix and co-eluting peaks, were adequately resolved
• adequacy of scope of the investigation and its related CAPA

o We also understand that you are performing a study to determine cleanliness of ducts and assessing them (b)(4). Explain your interim plan for preventing any cross-contamination from the ducts before the given (b)(4) cleaning interval elapses.

• The latest update on your improvements to your cleaning validation program, with special emphasis on incorporating conditions identified as worst case in your drug manufacturing operation. This should include but not be limited to identification and evaluation of all worst-case:

o drugs with higher toxicities
o drugs with higher drug potencies
o drugs of lower solubility in their cleaning solvents
o drug~ with characteristics that make them difficult to clean
o swabbing locations for areas that are most difficult to clean
o maximum hold times before cleaning

In addition, describe the steps that must be taken in your change management system before introduction of new manufacturing equipment or a new product.

• A full description of the correction factor for recovery that your firm applied in the reserve sample study. Include examples of the calculations and their applications for all seven batches in which you confirmed carryover. Describe whether any lot that appeared to have cross-contamination was discounted from your risk assessment due to the application of your correction factor.

• For the seven products that were found contaminated with traces of other actives, provide details of at least the 30 prior batches manufactured in all non-dedicated equipment. Include the name of the product, stage of processing, all equipment identifications, and dates of manufacture. Also highlight any correlation between these preceding batches, residues present in the ductwork, and finished product batches found to be contaminated.

2. Your firm failed to thoroughly investigate any discrepancy or failure of a batch or any of its components· to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192)

In late 2018, your firm experienced excessive and atypical High Efficiency Particulate Air (HEPA) filters failures in a short period. More than 45 filters failed due to side leakages and media failures. The filters were often adjacent in the same room. You failed to adequately investigate these filter integrity test failures:

• DEV-1011-2018-00322, December 2018, Line (b)(4) (Unit (b)(4)), 11 filter failures discovered during routine integrity testing of laminar air flow (LAFs) units IE/153, IE/154, IE/155 and IE/156, in Room (b)(4) (sterile (b)(4) area).
• DEV-1011-2018-00246, September 2018, Line (b)(4) (Unit (b)(4)), filter media leakage observed in 14 filters and side leakages observed in 22 filters in sterile corridor, sterile vial filling and plugging, and (b)(4) loading & unloading room area (Room (b)(4)).
• DEV-1011-2018-00261, October 2018, filter failure discovered major visible damage during routine cleaning in sterile injectable filling line (b)(4) (Unit (b)(4)), Room (b)(4).

According to your investigations, the most probable causes were gasket deterioration and lack of timely filter replacement. Notably, some filters were installed more than (b)(4) years ago, exceeding the already permissive limit of (b)(4) years in your procedure. Approximately 80 batches intended for the U.S. market (commercial and/or registration) were compromised.

HEPA filter integrity is essential to ensure aseptic conditions. Your firm's investigation did not substantially evaluate environmental data and other manufacturing information to sufficiently determine whether the HEPA filter failures compromised the aseptic conditions of your sterile processing line and product quality.

We acknowledge your commitment to conduct an independent retrospective review of the deviations related to the HEP A filter integrity failures. However, your response is insufficient. Your response lacked sufficient data to support that there was no impact on marketed batches. For example:

• Your response' documented missing and/or unclear information in your assessments for products potentially impacted by the filter failures. Unclear elements include but are not limited to correlations of viable excursions with breached filters; inconsistencies in the exposure time of settle plates; and lack of assurance that the cleaning and (b)(4) activities were performed as per the procedures. It is not clear if these and other weaknesses in the investigation have been addressed and CAPA identified.

• Your response acknowledged a trend increase in environmental monitoring excursions from May 2018 to August 2018 in Room (b)(4), but you lacked sufficient evidence to indicate that these excursions were unrelated to the HEPA filter failures. Your response acknowledged that the environmental trend warranted a review of the existing controls.

• We acknowledge that you rejected certain batches during this period due to microbiological environmental excursions in critical (ISO 5) areas. Your response indicated that approximately 18 batches processed in Unit (b)(4) were rejected from April 2018 to September 2018. Your response failed to include information about what type of failure occurred, the root causes, the impact on other products manufactured under the same conditions, and all CAPA implemented regardless of whether the specific rejected batches were intended for the U.S. market.

There is no assurance that all batches produced under inadequate conditions have been thoroughly evaluated, and that your firm has identified all contamination hazards associated with your sterile process.

In response to this letter, provide the following:

• A comprehensive, independent assessment of your overall system for investigating deviations, discrepancies, complaints, out-of-specification (OOS) results, and failures. Provide a detailed action plan to remediate this system. Your action plan should include, but not be limited to, significant improvements in investigation competencies, scope determination, root cause evaluation, CAPA effectiveness, quality assurance unit oversight, and written procedures. Address how your firm will ensure that all phases of investigations are conducted appropriately.

• An independent assessment and remediation plan for your CAPA program. Provide a report that evaluates whether staff possesses proper investigation competencies, effectively conducts root cause analysis, and assures CAPA effectiveness. Also determine whether your quality system ensures you regularly review investigation trends, implement improvements to the CAPA program when needed, ensure appropriate quality unit decision rights, and receive full executive management that promotes timely lifecycle manufacturing improvements.

• For all batches produced from February to December 2018 intended for the U.S. market, submit full environmental data for all ISO 5 air and contact surfaces (including operator gloves) in rooms (b)(4) and (b)(4). Submit individual results, action/alert limits for each of these locations, batch manufactured that day, microbial identification, and whether the batch was supplied to the U.S. Include potential correlations between the HEPA filter failures and these micro excursions.

• Your action plan to address any potential product quality or safety risks for any drug products in U.S. distribution.

• A detailed root cause analysis that explains why numerous and clustered HEPA filter failures occurred in such a very short period.

3. Your firm failed to follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes (21 CFR 211.113(b)).

You failed to perform adequate smoke studies to evaluate whether unidirectional flow exists in your aseptic operations. For example:

• You did not adequately document airflow patterns during aseptic interventions in units (b)(4) and (b)(4). In many instances, airflow patterns were not visible and could not be evaluated due to insufficient smoke, obstructions, and poor camera angles.

• You failed to perform an air flow pattern evaluation of the mobile trolley during dynamic conditions in unit (b)(4). The mobile trolley is used to transfer equipment parts and utensils during the setup of the aseptic fill line and for the routine transfer of primary packaging components (e.g., sterilized stoppers) into the cleanroom.

Thorough smoke studies are essential to evaluate the effects of interventions on unidirectional airflow and to ensure design modifications are made whenever necessary.

We acknowledge your commitment to conduct new smoke studies. We also acknowledge your commitment to complete facility upgrades of your sterile units including changes to your Heating, Ventilating and Air Conditioning system, and installation of additional non-viable particle counters.

In response to this letter, provide the following:

• Comprehensive risk assessment of all contamination hazards with respect to your aseptic processes, equipment, and facilities, including an independent assessment that includes, but is not limited to:
o All human interactions within the ISO 5 area
o Equipment placement and ergonomics
o Air quality in the ISO 5 area and surrounding room
o Facility layout
o Personnel Flows and Material Flows (throughout all rooms used to conduct and support sterile operations)

• A detailed remediation plan with timelines to address the findings of the contamination hazards risk assessment. Describe specific tangible improvements to be made to aseptic processing operation design and control.

Drug Production Suspended

We acknowledge your decision to suspend production in sterile units (b)(4) and (b)(4) (line (b)(4)). Note that remediating these CGMP violations will be necessary before resuming drug manufacturing operations intended for the U.S. market. Notify this office in writing when all corrections have been implemented and before resuming manufacturing and distribution of your drug products for the U.S. market.

Conclusion

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

If you are considering an action that is likely to lead to a disruption in the supply of drugs produced at your facility, FDA requests that you contact CDER's Drug Shortages Staff immediately, at drugshortages@fda.hhs.gov, so that FDA 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 or interruptions in your drug manufacture under 21 U.S.C. 356C(b). This also allows FDA to consider, as soon as possible, what actions, if any, may be needed to avoid shortages and protect the health of patients who depend on your products.

Until you correct all violations completely and we confirm your compliance with CGMP, FDA may withhold approval of any new drug applications or supplements listing your firm as a drug manufacturer.

Failure to correct these violations may also result in the FDA refusing admission of articles manufactured at Cipla Limited into the United States under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381 (a)(3). Articles under this authority may be subject to refusal of admission, 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 FD&C Act, 21 U.S.C. 351(a)(2)(B).

After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done since our inspection to correct your violations and to prevent their recurrence. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.

Send your electronic reply to CDER-OC-OMQ-Cornmunications@fda.hhs.gov or mail your reply to:

Rebecca Parrilla
Compliance Officer
U.S. Food and Drug Administration
White Oak Building 51, Room 4235
10903 New Hampshire Avenue
Silver Spring, MD 20993
USA

Please identify your response with FEI 3004081307.

Sincerely,
/S/

Francis Godwin
Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research