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  5. Global Calcium Pvt. Limited - 692000 - 01/16/2025
  1. Warning Letters

WARNING LETTER

Global Calcium Pvt. Limited MARCS-CMS 692000 —

Delivery Method:
Via Electronic Mail - Delivery and Read Receipt Requested
Reference #:
320-25-30
Product:
Drugs
Recipient:
Recipient Name
Mr. Arif Vazirally
Recipient Title
Executive Chairman
Global Calcium Pvt. Limited

No. 882, 6th Cross, 6th Block
Koramangala
Bengaluru 560095
India

Issuing Office:
Center for Drug Evaluation and Research (CDER)

United States

Warning Letter 320-25-30

January 16, 2025

Dear Mr. Vazirally:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Global Calcium Pvt. Limited, FEI 3004094136, at Bangalore - Hosur Highway, 125/126, Sipcot Industrial Complex, Hosur, Tamil Nadu, India 635126, from July 29 to August 2, 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 August 23, 2024 response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

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

1. Failure of your quality unit to prepare, review, and approve documents related to the manufacturing of APIs in accordance with written procedures.

You provided production records for two different APIs that showed manufacturing activities occurred simultaneously on the same equipment. For example, your batch records and equipment logbooks show the same equipment including, but not limited to,(b)(4) were used at the same time to manufacture (b)(4) USP and (b)(4) USP.

Additionally, you deleted multiple electronic records during the inspection. For example, on the initial morning of the inspection, investigators observed Microsoft Excel documents on a desktop computer in the Plant (b)(4) production office including, but not limited to, “(b)(4) Cleaning validation samples,” “(b)(4) Production Details-2024,” “Plant-(b)(4) production Report Jun-2024,” and “Planning June-2024.” On the second day, investigators returned to the production office to review these files. However, all files had been deleted and could not be recovered during the inspection. Without access to the files, the investigators were unable to determine their purpose and adequately evaluate your adherence to CGMP.

In your response, you acknowledge your production head directed the creation of falsified manufacturing records to misrepresent API production activities so incentives could be claimed regarding production in plant (b)(4). Additionally, you state a lack of training and other factors resulted in deficient documentation control, then explain you have revised your SOP for document issuance and control. You also state Microsoft Excel files were deleted to “avoid unwanted conversation” with the investigators, and add the computers in question are for “personal use to record day to day activities” so there is no impact on product quality. We also acknowledge you performed a product quality impact assessment.

Your response is inadequate. Your product quality impact assessment relies, in part, on data generated by your facility’s deficient documentation practices, and therefore is inherently unreliable. Furthermore, you do not adequately evaluate how widespread the practice of record fabrication extends throughout your facility, and you do not share in sufficient detail how you will prevent, detect, and investigate non-contemporaneously prepared records. You also do not adequately explain which, if any records were legitimate and pertain to actual product produced on your equipment. Considering your response states you created records that “falsely attributed” production activities to claim incentives, FDA is concerned about the adequacy of your remediation efforts given you have not sufficiently reconciled all CGMP records.

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 you are using an independent third-party consultant to audit your operation and assist you in meeting FDA requirements.

In response to this letter, provide:

  • A full reconciliation of all APIs manufactured at your facility intended for the US market over the past 3 years, including:
    o Name and lot numbers of API manufactured and released.
    o Plant or building identification where the API was made, including date of manufacture.
    o All API or intermediates received and packaged for further distribution from any or your manufacturing plants in the current location.
    o Determination if singular or multiple batch records exist, or if records are incomplete.
    o For each instance of CGMP record anomalies identified by an independent third party, a description of the issue, as well as a detailed root cause and corrective action plan.
    o Status of each employee involved in record fabrication as described above and as part of your investigation, and whether they are currently employed or still performing CGMP functions at your company.
  • 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 manufacturing 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 2 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.

2. Failure to properly maintain buildings and facilities used in the manufacture of APIs.

You failed to maintain your facility in an acceptable state of repair. For example, investigators observed a room with (b)(4) liquid in a floor cavity surrounding the exit pipe of a (b)(4). A similar liquid was dripping from a ceiling pipe junction in the (b)(4) area below this room. The liquid was dripping onto processing equipment labeled as clean and ready for use.

It is essential your facility is in a good state of repair, and sanitary conditions are maintained to ensure ongoing suitability for drug manufacturing.

In your response, you state no production activities were taking place in the (b)(4) area, as it was partially shut down to make various upgrades, and you state the damaged flooring has since been repaired. You also state personnel did not display proper signage in the area, as required by your procedure, and a change control had been initiated. Additionally, your deviation report submitted with your response states personnel were not aware of ongoing maintenance activities in Plant (b)(4).

Your response is inadequate. You do not sufficiently address potential contamination of previously manufactured lots caused by leaks from the flooring. During the inspection, no information was provided to support a partial shutdown, or that a change control was initiated as indicated in your response. Additionally, you do not adequately evaluate the potential quality impact to previously manufactured lots produced during maintenance shutdowns, and thus outside your standard manufacturing controls. Furthermore, based on your documentation deficiencies, it is unclear whether you manufactured lots of API during partial shutdown activities. You also lack evidence you comprehensively evaluated the state of repair throughout your entire facility.

In response to this letter, provide:

  • 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.
  • A comprehensive evaluation and risk assessment of lots that may have been impacted by leaks from damaged flooring and other facility deficiencies.
  • A list of lots produced on equipment, or in areas, that were in a shutdown status.
  • Your training records and updated procedures to show your staff is aware of procedures related to maintenance and shutdown activities.

3. Failure to establish an impurity profile for identified and unidentified impurities.

You failed to conduct a comprehensive evaluation of your manufacturing processes to identify all potential impurities. For example, the impurity profile you provided for (b)(4) USP, only listed those impurities described in the United States Pharmacopeia (USP), without considering your unique processes and materials to describe additional impurities in a typical lot. Furthermore, you failed to sufficiently classify each identified impurity. Our inspection also noted impurities are not monitored during stability studies.

In your response, you include impurity profiles and data from forced degradation studies, which you state was provided to investigators on the final day of the inspection. We acknowledge you also include updated impurity profiles with further details completed since the inspection. You also state drug product manufacturers who you supply perform testing of the drug products for impurities, and you have not received any returned APIs due to quality issues.

Your response is inadequate. Our inspection found you have received at least two lots of returned product due to quality issues in the last two years. You also received a complaint for one lot of (b)(4) USP that failed the customer’s identity testing. Furthermore, you do not provide a retroactive risk assessment of distributing APIs with incomplete impurity profiles, and you lack evidence that you communicated your updated impurity profiles to your customers who you state test the drug products for impurities. Additionally, your APIs are distributed to (b)(4) who typically do not test components for compliance with quality specifications, including impurity testing.

In response to this letter, provide:

  • A retrospective review of all API lots released without appropriate testing for impurities and how that may impact finished drug quality.
  • A plan to address any product quality or patient safety risks for out-of-specification lots of APIs in U.S. distribution, including recalls.
  • Specifications, including test methods, used to release APIs. Your response should address your capability to detect and quantify a wide array of potential impurities or contaminants.
  • Improved procedures for performing a systemic evaluation for identifying impurities and establishing a control strategy from the process development stages.
  • Results from release testing of all lots of (b)(4) USP that remain within the established retest or expiry date.
  • Updated risk assessments for the potential presence of impurities in (b)(4) USP manufactured at your facility. Include your program for ongoing evaluation of impurity profiles for all drugs and starting materials you produce.
  • Identify corrective actions to ensure adequate quality oversight of establishing appropriate impurity and degradant limits for all drugs and starting materials, you produce, using well-studied, scientifically based impurity profiles specific to their own manufacturing processes.

CGMP Consultant Recommended

Based upon the nature of the deviations we identified at your firm, you should engage a consultant qualified to evaluate your operations and to assist your firm in meeting CGMP requirements. The qualified consultant should also perform a comprehensive audit 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.

Additional API CGMP Guidance

FDA considers the expectations outlined in ICH Q7 when determining whether API are manufactured in conformance with CGMP. See FDA’s guidance document Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients for guidance regarding CGMP for the manufacture of API at https://www.fda.gov/media/71518/download.

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.

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.

FDA placed products offered for import into the United States from your firm on Import Alert 66-40 on December 20, 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 Global Calcium Pvt. Limited, Tamil Nadu, 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).

We request you email Christina Reyes, Christina.Reyes@fda.hhs.gov, within five days of receipt of this letter to schedule a call with FDA.

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 days1. 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 3004094136 and ATTN: Matthew Jensen.

Sincerely,
/S/

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

_______________________________

1 Under program enhancements for the Generic Drug User Fee Amendments (GDUFA) reauthorization for fiscal years (FYs) 2023-2027, also known as the GDUFA III Commitment Letter, your facility may be eligible for a Post-Warning Letter Meeting to obtain preliminary feedback from FDA on the adequacy and completeness of your corrective action plans.

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