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Warning Letter 320-24-52

July 11, 2024

Dear Mr. Chile:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Brassica Pharma Pvt. Ltd., FEI 3014129013, at Plot No. T-68, T 68 (Pt), T-63, Midc, Tarapur, Boisar, Thane from January 15 to 19, 2024.

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 February 8, 2024 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 ensure that laboratory records included complete data derived from all tests necessary to ensure compliance with established specifications and standards (21 CFR 211.194(a)).

Microbiology Laboratory Data Integrity

Your firm failed to test every batch for sterility as required by your procedures. For example, sterility samples that should have been under incubation from batches produced just prior to the FDA inspection start, were not present and a review of sterility test records compared to biometric access data for the sterility testing room did not align. Interviews with the sole analyst that is trained for sterility testing revealed that it is his routine practice to not test all batches for sterility and fabricate records for those samples not tested.

Furthermore, when sterility testing was performed for batches manufactured during the FDA inspection, four failing sterility tests, including one U.S. product, were observed during the incubation period.

In addition, your firm failed to collect samples for environmental monitoring and personnel monitoring, including active air samples, surface samples, and settle plates, as required in your procedure. A reconciliation of samples required by your procedure and those that were physically present and under incubation at the start of the FDA inspection did not match. Interviews with your microbiology staff revealed that it is their routine practice to fabricate records and results for samples that were not taken.

During the FDA inspection, investigators observed multiple sample collections in the ISO 5 and ISO 7 areas that resulted in plate readings with numerous colony forming units (CFUs). Your firm stated that prior to the start of the inspection, where you admitted routine fabrication of environmental monitoring results, no single action level excursion had been documented. However, FDA investigators observed the following during the inspection from samples collected January 10-18, 2024:

• 37 action level excursions for ISO 5 area environmental monitoring samples
• 17 action level excursions for ISO 7 area environmental monitoring samples

Laboratory technicians falsified data which is critical to maintaining an ongoing state of control in your aseptic processing facility. Data integrity is critical throughout the CGMP data life cycle, including in the creation, modification, processing, maintenance, archival, retrieval, transmission, and disposition of date after the record’s retention period ends.

Your response states that an investigation will be opened and code of conduct for data integrity implemented. The investigation failed to include a retrospective review of all data recorded and did not include a review of data recording practices outside of the microbiology laboratory. This is not adequate to ensure the integrity of all data produced at your facility.

Data Integrity Remediation

Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture. See FDA’s guidance document Data Integrity and Compliance With Drug CGMP for guidance on establishing and following CGMP compliant data integrity practices at https://www.fda.gov/media/119267/download.

We acknowledge that you are using an independent third-party consultant to audit your operation and assist in meeting FDA requirements. In response to this letter, provide:

• A comprehensive investigation into the extent of the inaccuracies in data records and reporting. Your investigation should include:

o A detailed investigation protocol and methodology; a summary of all laboratories, manufacturing operations, and systems to be covered by the assessment; and a justification for any part of your operation that you propose to exclude.
o Interviews of current and former employees to identify the nature, scope, and root cause of data inaccuracies. We recommend that these interviews be conducted by a qualified third party.
o An assessment of the extent of data integrity deficiencies at your facility. Identify omissions, alterations, deletions, record destruction, non-contemporaneous record completion, and other deficiencies. Describe all parts of your facility’s operations in which you discovered data integrity lapses.
o A comprehensive retrospective evaluation of the nature of the testing/manufacturing/other data integrity deficiencies. We recommend that a qualified third party with specific expertise in the area where potential breaches were identified should evaluate all data integrity lapses.

• A current risk assessment of the potential effects of the observed failures on the quality of your drugs. Your assessment should include analyses of the risks to patients caused by the release of drugs affected by a lapse of data integrity and analyses of the risks posed by ongoing operations.
• A management strategy for your firm that includes the details of your global corrective action and preventive action (CAPA) plan. Your strategy should include:

o A detailed corrective action plan that describes how you intend to ensure the reliability and completeness of all the data you generate including analytical data, manufacturing records, and all data submitted to FDA.
o A comprehensive description of the root causes of your data integrity lapses including evidence that the scope and depth of the current action plan is commensurate with the findings of the investigation and risk assessment. Indicate whether individuals responsible for data integrity lapses remain able to influence CGMP-related or drug application data at your firm.
o Interim measures describing the actions you have taken or will take to protect patients and to ensure the quality of your drugs, such as notifying your customers, recalling product, conducting additional testing, adding lots to your stability programs to assure stability, drug application actions, and enhanced complaint monitoring.
o Long-term measures describing any remediation efforts and enhancements to procedures, processes, methods, controls, systems, management oversight, and human resources (e.g., training, staffing improvements) designed to ensure the integrity of your company’s data.
o A commitment to have a qualified consultant conduct extensive annual audits, for at least two years, to assist in evaluating CAPA effectiveness after you have executed your data integrity remediation protocol.
o Inform FDA if you will be hiring a Chief Integrity Officer who is fully empowered to receive anonymous complaints from employees reporting data integrity concerns and with the authority to ensure any potential breach is promptly investigated (by independent quality assurance function, along with expertise from outside entities whenever needed).
o A status report for any of the above activities already underway or completed.

Inadequate Sterility Test Method Validation

The test method validated for sterility testing is not adequate. You failed to perform method validation for all drug product formulations intended for distribution to the United States. Additionally, during the inspection, sterility testing was observed to have multiple steps or materials used that were not included as part of the initial validation.

Your response is not adequate because it fails to address the impact that a deficient method validation has on distributed drug products. In addition, you do not make a commitment in your response to include all formulations intended for distribution in the United States in your validation.

It should be noted that a sterility test, while a critical final quality control for all aseptically processed products that purport to be sterile, cannot be solely relied upon as justification to release each drug product batch as the test is only the last in a series of design and control provisions intended to protect the consumer from distribution of an unsafe batch. Finished product testing alone does not establish sterility of all units because contamination is typically episodic and not uniformly distributed. Larger contamination problems may go undetected for substantial periods if your firm is placing too much reliance on the final quality control test for sterility to become aware of a problem in aseptic manufacturing. It should also be noted that any positive sterility test result represents a serious CGMP issue that requires a comprehensive investigation into the cause and extent of the problem, and a prompt review of the qualification status of your aseptic process.

In response to this letter, provide the following:

• A comprehensive, independent assessment of your laboratory practices, procedures, methods, equipment, documentation, and analyst competencies. Based on this review, provide a detailed plan to remediate and evaluate the effectiveness of your laboratory system.

2. Your firm failed to establish and 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)).

Poor Practices in the Aseptic Processing Areas

During the inspection of your facility, we observed poor practices and behaviors in ISO 5 and ISO 7 areas during the manufacturing of sterile drug products. These poor practices included, but are not limited to:

• Operators touching the inside of empty sterile tubes, prior to loading onto the filling line.
• Operators leaning over the filling line with their head and torso, near the filling station, and blocking unidirectional airflow.
• Operators in the ISO 5 area leaning their head and torso over the bulk drug product (b)(4) to manually check the fill level of the sterile bulk drug product.
• Operators with exposed skin working in the ISO 5 area.

Your response discusses retraining the operators on aseptic behaviors, which is inadequate. This response does not address how you plan to ensure compliance with the processes and procedures that were already in place at the time of the inspection and not followed. Your response also fails to consider line design changes that would minimize the need for frequent operator interaction with the aseptic processing line.

Inadequate Gowning for Aseptic Processing

Gowning worn by operators during aseptic processing activities was observed to be stained and torn. For example, the gowns donned for aseptic operations contained (b)(4) stains, booties that were ripped, and gowning hoods with tears. This is inadequate for performing operations in classified spaces where the risk of product contamination is high (i.e., in ISO 5 and 7 areas). Additionally, your procedure instructs that stained or not intact garments are to be discarded.

Your response states that washing and sterilization of the gowning will be monitored and includes a new checklist to inspect the garments before use. This response is inadequate because it does not describe any corrective actions taken for the gowning observed to be in use during the inspection with stains and rips.

Inadequate Media Fill Program

Your media fills were not sufficiently representative of commercial aseptic manufacturing operations. It is your routine practice not to document interventions of the filling line, line speed, or line stoppages in the manufacturing batch record during production. Because of this, your program lacks reliable data to determine the type, quantity, and duration of interventions to simulate during media fills. For instance, during the inspection there were numerous interventions performed during routine manufacturing that were either not simulated as part of a media fill, or lacking in quantity and duration in the media fills compared to what was observed during production.

The evaluation of media fill vials for microbial growth after incubation relies solely on color change and does not include a review for visual evidence of microbial growth.

Your response is inadequate. For instance, you mention revising your media fill protocol, but do not include details describing how you will determine which interventions to include and their frequency during the media fill. In addition, evaluating the media fill units for color change alone is not sufficient to detect microbial growth. It is essential that media fill units also be examined for evidence of microbial contamination, including but not limited to presence of pellicles, particles, and turbidity.

Inadequate Airflow Visualization Studies

You lack airflow studies in critical areas that evaluated the effect of interventions on the unidirectionality of air. For example, your study for (b)(4) does not provide assurance that unidirectional airflow is achieved and can minimize contamination as it did not include set-up activities or interventions of the (b)(4) by operators.

Your response is inadequate. You commit to reperform airflow visualization studies to include set-up and interventions but do not provide information regarding how you will determine which interventions to include. These interventions are not recorded as part of your standard practice in the batch record during manufacturing.

Deficient Bulk Drug Product Sterilization Validation

The (b)(4) sterilization validation for sterile ophthalmic ointments prior to filling into the (b)(4) packaging configuration is deficient. The validation was not performed using biological indicators to ensure an appropriate worst-case challenge.

Your response is inadequate. While you include a commitment to revalidate the sterilization process, you do not include a retrospective review of batches produced using this process.

See FDA’s guidance document Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice to help you meet the CGMP requirements when manufacturing sterile drugs using aseptic processing at https://www.fda.gov/media/71026/download.

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 remediation plan that better assures ongoing management oversight throughout the manufacturing lifecycle of all drug products. Provide a more data-driven and scientifically sound program that identifies sources of process variability and assures that manufacturing (including both production and packaging) operations meet appropriate parameters and quality standards. This includes, but is not limited to, evaluating suitability of equipment for its intended use, ensuring quality of input materials, determining the capability and reliability of each manufacturing process step and its controls, and vigilant ongoing monitoring of process performance and product quality.
• Your plan to ensure appropriate aseptic practices and cleanroom behavior during production. Include steps to ensure routine and effective supervisory oversight for all production batches. Also describe the frequency of quality unit oversight (e.g., audit) during aseptic processing and its support operations.
• A thorough retrospective review and risk assessment that evaluates how poor aseptic technique and cleanroom behavior may have affected the quality and sterility of your drugs.
• A detailed summary of your validation program for ensuring a state of control throughout the product lifecycle, along with associated procedures. Describe your program for process performance qualification, and ongoing monitoring of both intra-batch and inter-batch variation to ensure a continuing state of control.

3. Your firm failed to perform operations within specifically defined areas of adequate size and to have separate or defined areas or such other control systems necessary to prevent contamination or mix-ups in aseptic processing areas (21 CFR 211.42(c)(10)).

Design of Aseptic Processing Lines

Your aseptic processing equipment design and cleanroom layout are inadequate. Basic design deficiencies and manually intensive interventions in your operations compromise your ability to maintain aseptic conditions. For example, (b)(4) was observed to be in use without the (b)(4) for the (b)(4) and (b)(4) equipment installed.

Aseptic connections for the transfer of sterilized bulk drug product to the aseptic processing line were performed for (b)(4) under ISO 8 conditions. (b)(4) was also observed to have connections near the floor that required operators to be close to or touching the ground.

During the FDA inspection of your facility, investigators observed differential pressure reversals between the (b)(4) and the ISO 5 (b)(4) where filled and (b)(4) exit the line. This area is an (b)(4) pass through for the line with a (b)(4) separating the (b)(4) classified spaces. (b)(4) in other parts of the aseptic processing areas were observed to cause the (b)(4) into the ISO 5 area and the (b)(4) fall below your established range of (b)(4) to (b)(4) mm/wc, at times even going (b)(4).

Your response states you will initiate a risk assessment and particle count studies for the removal of the (b)(4) and (b)(4) for (b)(4) and (b)(4) equipment. This response is inadequate, as it does not commit to operate the aseptic filling line with both the (b)(4) and all equipment (b)(4) installed, nor does it consider design changes to remedy the deficiencies in differential pressure.

Aseptic processes should be designed to minimize exposure of sterile articles to potential contamination hazards, including but not limited to variation in environmental conditions. It is vital for rooms of higher air cleanliness to have a substantial positive pressure differential relative to adjacent rooms of lower air cleanliness. A suitable facility monitoring system is critical to maintain appropriate environmental conditions throughout all of your cleanrooms. All deviations from established limits should be appropriately investigated to rapidly detect atypical changes that can compromise the facility’s environment. Prompt detection of an emerging problem is essential to preventing contamination of your aseptic production operations.

Environmental Monitoring Program

Your environmental monitoring (EM) program lacks sufficient data to ensure the sterility of your ophthalmic drug products. For example, non-viable particulate monitoring is not performed during filling operations, only before and after. These data, while collected, are not recorded. In addition, your EM program lacks an assessment to determine which locations should be sampled in the aseptic processing areas. For instance, (b)(4) location, “(b)(4)” noted as “Filling Machine (b)(4) Room” is the (b)(4) ISO 5 surface sample taken during manufacturing on (b)(4). Your firm stated that the specific sample location in the ISO 5 area is chosen at random and not recorded.

Your response is inadequate. While you commit to perform a risk assessment to determine sample locations in ISO 5 areas, you did not include a review or assessment of other classified spaces (e.g., ISO 7 and ISO 8) to ensure appropriate environmental samples are taken.

A vigilant ongoing EM program, and supporting laboratory, are essential to detect and respond to potential product contamination hazards in your manufacturing environment in a timely manner. Loss of environmental control in an aseptic manufacturing facility can ultimately pose a serious hazard to patients.

In response to this letter, provide the following:

• A comprehensive, independent assessment of the design and control of your firm’s manufacturing operations, with a detailed and thorough review of all microbiological hazards.
• 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.
• An independent assessment of your EM program including, but not limited to, establishing appropriate limits, sampling frequencies, investigating deviations, and trend analysis. Also ensure the implementation of a comprehensive CAPA plan.
• Your CAPA plan to implement routine, vigilant operations management oversight of facilities and equipment. This plan should ensure, among other things, prompt detection of equipment/facilities performance issues, effective execution of repairs, adherence to appropriate preventive maintenance schedules, timely technological upgrades to the equipment/facility infrastructure, and improved systems for ongoing management review.

4. 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 other established requirements. Your firm failed to establish and follow adequate written procedures for cleaning and maintenance of equipment (21 CFR 211.67(a) and 211.67(b)).

Inadequate Cleaning of Aseptic Processing Line Equipment

The cleaning of all parts on your aseptic processing lines that contact sterile tubes is inadequate. For example, (b)(4) contains (b)(4) equipment pieces, the (b)(4), that make direct contact with the inside of unfilled sterile tubes and cannot be removed for sterilization. According to your procedure, these pieces of equipment are to be wiped down with (b)(4) without defining a frequency. During our inspection, your firm stated the frequency was (b)(4), however these equipment parts were not observed to be wiped with (b)(4) during the set-up or production. Additionally, no documentation was provided to show that this cleaning method is adequate to remove potential contamination from the equipment.

Inadequate Cleaning Validation

The cleaning validation performed by your firm is inadequate. The cleaning practices described in your procedures allow cleaning after (b)(4) batches during routine manufacturing, however, in your cleaning validation, cleaning was performed after (b)(4) batch. This discrepancy does not provide assurance that your routine cleaning procedures can prevent cross contamination between batches of different drug products produced using shared equipment.

Your response is inadequate. While you commit to reperform cleaning validation studies, your response does not include a retrospective review of batches for cross contamination from the use of a non-validated cleaning process.

In response to this letter, provide the following:

• Appropriate 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 Drugs 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 summary of updated standard operating procedures (SOPs) that ensure an appropriate program is in place for verification and validation of cleaning procedures for products, processes, and equipment.

Drug Recall & Drug Production Suspended

On February 22, 2024, you communicated your commitment to suspend manufacturing and distribution of all drugs for the U.S. market and agreed to voluntary recall all drugs in current distribution in the United States (https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/brassica-pharma-pvt-ltd-issues-voluntary-nationwide-recall-equate-lubricant-eye-ointment-equate-stye).

We acknowledge your commitment to suspend production of all drugs for the U.S. market. In response to this letter, clarify whether you intend to resume manufacturing drugs for the U.S. market at this facility in the future.

If you plan to resume any manufacturing operations regulated under the FD&C Act, notify this office before resuming your drug manufacturing operations. You are responsible for resolving all deficiencies and systemic flaws to ensure your firm is capable of ongoing CGMP compliance. In your notification to the Agency, provide a summary of your remediations to demonstrate that you have appropriately completed all CAPA.

CGMP Consultant Recommended

Based upon the nature of the violations we identified at your firm, you should engage a consultant qualified as set forth in 21 CFR 211.34 to evaluate your operations and to assist your firm in meeting CGMP requirements if your firm intends to resume manufacturing drugs for the U.S. market. The qualified consultant should also perform a comprehensive six-system audit¹ of your entire operation for CGMP compliance and evaluate the completion and efficacy of your CAPAs before you pursue resolution of your firm’s compliance status with FDA.

Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for resolving all deficiencies and systemic flaws to ensure ongoing CGMP compliance.

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 any violations and for preventing their recurrence or the occurrence of other violations.

FDA placed your firm on Import Alert 66-40 on January 30, 2024.

Correct any violations promptly. FDA may withhold approval of new applications or supplements listing your firm as a drug manufacturer until any violations are completely addressed and we confirm your compliance with CGMP. We may re-inspect to verify that you have completed corrective actions to any violations.

Failure to address any violations may also result in the FDA continuing to refuse admission of articles manufactured at Brassica Pharma Pvt Ltd, Plot No. T-68, T 68 (Pt), T-63, Midc, Tarapur, Boisar, Thane 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 that appear to be adulterated may be detained or refused 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).

This letter notifies you of our findings and provides you an opportunity to address the above deficiencies. After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done to address any violations and to prevent their recurrence. In response to this letter, you may provide additional information for our consideration as we continue to assess your activities and practices. 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-Communications@fda.hhs.gov. Identify your response with FEI 3014129013 and ATTN: Sarah Rhoades.

Sincerely,
/S/

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

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1 i.e. Quality System, Facilities & Equipment System, Materials System, Production System, Packaging & Labeling System, and Laboratory Control System per FDA’s guidance document Quality Systems Approach to Pharmaceutical CGMP Regulations.