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Warning Letter 320-25-21

December 3, 2024

Dear Mr. Ranka:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Micro Orgo Chem, 3004513977, at 57, C-1/B, LIC sector, GIDC, VAPI, 396195, Gujarat, from April 11 to 18, 2024.

This warning letter summarizes significant deviations from Current Good Manufacturing Practice (CGMP) for active pharmaceutical ingredients (APIs).

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your APIs 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 May 3, 2024 response to our Form FDA 483 in detail.

During our inspection, our investigator observed specific deviations including, but not limited to, the following.

1. Failure to adequately validate written procedures for the cleaning and maintenance of equipment.

You failed to adequately validate cleaning procedures for your non-dedicated manufacturing equipment to ensure it is fit for its intended use. You also failed to properly maintain your equipment as they were observed to be in a state of disrepair.

Your quality assurance personnel stated that your firm has not carried out cleaning validation for non-dedicated manufacturing equipment routinely used for the manufacture of intermediates and APIs for the U.S. market. Additionally, you failed to follow established cleaning procedures. Your firm was unable to demonstrate rinse and swab samples were collected and tested as required by your procedure. Furthermore, (b)(4)-03 and other equipment used to manufacture (b)(4) appeared dirty and not appropriately maintained. A failure to adequately clean and maintain non-dedicated equipment may lead to cross-contamination between drug products.

In your response, you acknowledge “the facility was not maintained to uphold the sanitary conditions required for manufacturing and laboratory areas” and you commit to voluntarily recall all APIs shipped to the U.S. market. You also commit to initiate a change control to include a protocol-based cleaning validation in your procedures and to train personnel to document the cleaning and release of equipment.

Your response is inadequate. You do not provide a cleaning validation protocol and a revised equipment maintenance plan to ensure your APIs are free from cross-contamination.

In response to this letter, provide:

• 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
• 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.
• A comprehensive evaluation of your facility cleaning and maintenance program. Also provide your CAPA plan to improve routine cleaning and preventative maintenance at your facility.
• 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.

2. Failure to demonstrate your manufacturing process can reproducibly produce an API that meets its predetermined quality attributes. Also, there is no assurance that your facilities, equipment, and testing methods are suitable for their intended use.

Your firm failed to establish a protocol and implement a plan to ensure all API manufacturing processes, equipment and facilities are fit for use. For example,

• Your firm could not provide records that process performance qualification (PPQ) had been performed for any of your APIs (e.g., (b)(4)) manufacturing processes.
• Your firm had not adequately qualified equipment used to manufacture APIs and could not provide records confirming that your API manufacturing equipment would operate as intended.
• Your firm failed to ensure that test methods used were suitable for their intended use as in-house methods were not validated and USP methods were not verified.

Process validation evaluates the soundness of design and state of control of a process throughout its lifecycle. Each significant stage of a manufacturing process must be designed appropriately to assure the quality of raw material inputs, in-process materials, and finished APIs. Process qualification studies determine whether an initial state of control has been established.

Successful PPQ studies incorporating the use of appropriately qualified equipment and validated test methods are necessary prior to commercial distribution. Thereafter, ongoing vigilant oversight of process performance and product quality is necessary to ensure you maintain a stable manufacturing operation throughout the product lifecycle. Failure to implement adequate analytical method validation practices can result in insufficient understanding of process variables or failure to detect a drift in capability, which increases the risk of drug quality defects.

See FDA’s guidance document Process Validation: General Principles and Practices for general principles and approaches that FDA considers appropriate elements of process validation at https://www.fda.gov/media/71021/download.

In your response, you commit to issuing a CAPA to review the instrument qualification process, qualify all equipment for your new facility and verify that process methods and specifications are approved before starting operations at your new facility.

Your response is inadequate. You do not commit to performing an assessment of the impact of using non-validated processes, equipment, test methods and systems on APIs already distributed to the United States. Additionally, you fail to provide a detailed PPQ protocol for conducting validation activities.

In response to this letter, provide:

• 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.
• A timeline for performing PPQ for each of your marketed drugs.
• Process performance protocol(s), and written procedures for qualification of equipment and facilities.
• A detailed program for designing, validating, maintaining, controlling and monitoring each of your manufacturing processes that includes vigilant monitoring of intra-batch and inter-batch variation to ensure an ongoing state of control. Also, include your program for qualification of your equipment and facility. Improved procedures regarding validation/verification requirements and updated analytical methods.
• An independent, retrospective review of results obtained using unverified/unvalidated compendial and non-compendial methods.
• A summary of the impact assessment for released batches.
• A comprehensive, independent review of your laboratory practices, methods, equipment, and analyst competencies. Based on this review, provide a detailed CAPA plan to fully remediate your laboratory system.

3. Failure to design a documented, on-going stability testing program to monitor the stability characteristics of API and to use the results to confirm appropriate storage conditions and retest or expiry dates.

Your firm’s stability program was inadequate. Your firm failed to place at least one batch of each API manufactured in 2021, 2022, and 2023 on stability. Additionally, there were no stability chambers nor stability and reserve samples available at your facility.

In your response, you indicate that stability studies are conducted in accordance with your SOP and that your stability chambers were recently moved. You also state that new stability chambers are under qualification at your new facility for future production.

Your response is inadequate. You do not provide any records that ongoing stability studies are conducted and reserve samples could be located and tested to ensure expiry and retest dates are valid.

In response to this letter, please provide the following:

• A comprehensive, independent assessment and CAPA plan to ensure the adequacy of your stability program. Your remediated program should include, but not be limited to:
  o Stability indicating methods.
  o Stability studies for each drug in its marketed container-closure system before distribution is permitted.
  o An ongoing program in which representative batches of each product are added each year to the program to determine if the shelf-life claim remains valid.
  o Detailed definition of the specific attributes to be tested at each station (timepoint).
  o All procedures that describe these and other elements of your remediated stability program.

4. Failure to prepare, review, and approve documents related to the manufacturing of API in accordance with written procedures.

You failed to document all CGMP related manufacturing activities at the time they were performed. Our investigator observed numerous unlabeled (b)(4) drums in your manufacturing areas. Your personnel indicated these drums contained (b)(4) from various processes but were unable to identify what products and processes they were associated with. In addition, you failed to maintain original batch records for APIs produced at your facility. For example, the batch record for (b)(4) batch (b)(4) with an expiry date of March 2024 was requested and not available. This batch was released and shipped to the U.S. market, prior to the start of our inspection.

In your response, you acknowledge that quality related activities were not recorded at the time of performance. You commit to issue a deviation to amend your procedure for preparing master formulas and batch manufacturing records to include language requiring all production-related activities be recorded at the time they are performed. In addition, you commit to conduct training on the amended procedures and to perform a retrospective review of batch records to ensure all activities are documented.

Your response is inadequate. You do not provide sufficient detail regarding your corrective actions and preventive actions (CAPAs). In addition, you do not specify any verification activities to ensure the effectiveness of the procedural revisions and training. You also do not describe how you will perform the retrospective review of batch records.

In response to this letter, provide the following:

• A complete assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are insufficient. Include a detailed CAPA plan that comprehensively remediates your firm’s documentation practices to ensure you retain attributable, legible, contemporaneous, original, and accurate records throughout your operation.
  o In addition to interim data retention measures, also provide more comprehensive and sustainable CAPA for retention of all CGMP data. This includes provisions that address not only the need to retain batch-related data for appropriate periods, but also the long-term retention of all source data from development studies that support design, qualification, validation, and application.
  o A detailed summary of your procedural updates and associated training, including but not limited to, document retention.
  o A detailed summary of how you intend to assess CAPA effectiveness.
• An independent retrospective review of your drug production records for all batches distributed to the United States and that remain within expiry. Your assessment should include a determination of whether appropriate documentation (e.g., manufacturing records, testing records, distribution records) is available to ensure ongoing CGMP compliance. Specify actions you will take in response to the retrospective review, such as customer notifications and recalls.
  o Provide a summary report of all API batches released that may still remain on the market where a supporting batch record could not be located. Include a summary of any measures you will take to ensure these batches meet the required expiry or any testing protocols performed to support the expiry date of these drugs.

5. Failure of your quality unit to exercise its responsibility to ensure the API manufactured at your facility are in compliance with CGMP.

Your firm’s quality unit (QU) failed to perform routine QU functions to ensure drug manufacturing operations were adequate. For example, your QU failed to:

• Follow your change control procedure for drugs shipped to the United States. You failed to evaluate the use of different (b)(4) in your (b)(4) manufacturing process through your established procedure.
• Perform annual product reviews for APIs manufactured from 2020 to 2024.
• Ensure proper documentation was maintained for raw material release and critical deviations, including out-of-specifications and laboratory investigations.

In your response, you acknowledge annual product reviews and specific change controls and deviations were not initiated due to an oversight by the QU and commit to initiate a deviation. Additionally, you commit to retrain your current quality personnel.

Your response is inadequate. You fail to commit to performing a risk assessment of your QU. Furthermore, you fail to explain how initiating deviations will adequately remediate your QU deficiencies.

In response to this letter, provide:
• A comprehensive assessment and remediation plan to ensure your QU is given the authority and resources to effectively function. The assessment should also include, but not be limited to:
  o A determination of whether procedures used by your firm are robust and appropriate.
  o Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices.
  o A complete and final review of each batch and its related information before the QU disposition decision.
  o Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all drugs.
  o Also describe how top management supports quality assurance and reliable operations, including but not limited to, timely provision of resources to proactively address emerging manufacturing/quality issues and to assure a continuing state of control.
• A comprehensive, independent assessment of your change management system. This assessment should include, but not be limited to, your procedure(s) to ensure changes are justified, reviewed, and approved by your QU. Your change management program should also include provisions for determining change effectiveness.
• A plan to ensure that you will complete, and document adequately, product quality reviews at least annually for all APIs.
• Procedures for investigating, responding to, and correcting any deviations from quality and safety standards identified as a part of your product quality review findings and risk assessments.

CGMP Consultant Recommended

Based upon the nature of the deviations identified at your firm, we strongly recommend engaging a consultant qualified to evaluate your operations to assist your firm in meeting CGMP requirements. Your use of a consultant does not relieve your firm’s obligations to comply with CGMP. Your firm’s executive management remains responsible for resolving all deficiencies and systemic flaws to ensure ongoing CGMP compliance.

Drug Recall and Production Suspended

On April 15, 2024, during the inspection, you communicated your commitment to cease manufacturing and distribution of all drugs for the U.S. market. You also informed the Agency of your decision to deregister until your new facility is qualified, and to voluntarily recall all drugs within expiry in current distribution in the United States.

On September 18, 2024, the FDA held a teleconference to inquire about the steps taken to initiate your voluntary recall. The agency recommended a recall of all drugs currently in distribution from the U.S. market.

Despite numerous attempts by the Agency to obtain recall information, you have not provided complete documentation regarding your efforts to voluntarily recall all drugs distributed to the United States.

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 CAPAs.

Conclusion

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

FDA placed products offered for import into the United States from your firm on Import Alert 66-40 on October 22, 2024.

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

Failure to address any deviations may also result in the FDA continuing to refuse admission of articles manufactured at Micro Orgo Chem 57, C-1B, LIC sector, GIDC, Vapi, 396195, Gujarat, India, 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 deviations 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 3004513977 and ATTN: Marva Taylor.

Sincerely,
/S/

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