Granules India Limited

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Granules India Limited, FEI 3004097901, located at Survey No 160/A, 161/E, 162 and 174/A, Gagillapur Village, Dundigal-Gandimaisamma Mandal, Medchal-Malkhajgiri District, Telangana, from August 26 to September 6, 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 September 27, 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.

Our investigators observed significant contamination in multiple (b)(4) ducts of non-dedicated (b)(4) used in the preparation of (b)(4) for finished drug products manufactured at your facility. While filters were installed to prevent contamination, inadequate cleaning and maintenance processes rendered them ineffective. Swab samples collected from the (b)(4) ducts by your firm during the inspection, specifically from areas after the (b)(4)μ high efficiency particulate air (HEPA) filters, detected residues from multiple previously manufactured drug products and too numerous to count (TNTC) microbial contamination. Furthermore, you lacked documented cleaning procedures for the sections of the (b)(4) ducts located between the (b)(4)μ HEPA air filter and the cleaning (b)(4). Air flow over dirty surfaces can facilitate contamination of the drug being processed in (b)(4). Robust design, cleaning, and maintenance of this and other equipment are critical to prevent cross-contamination.

In your response, you provide an impact assessment, limited reserve sample testing results, and assurance of low microbiological contamination risk. You identify multiple potential root causes of the air handling unit (AHU) contamination and propose corrective actions and preventive actions (CAPAs). Reserve sample results confirmed cross-contamination; however, you deem the risk to drug product safety low based on your retrospective maximum allowable carry-over (MACO) calculations and additional testing results.

Your response is inadequate. Cross-contamination is not uniform, and testing of limited reserve samples alone cannot ensure products are contaminant-free. While MACO is helpful in validated cleaning scenarios, it cannot apply where cleaning has not been performed, or exposure is inconsistent. Additionally, the denominators utilized for batch size in your MACO calculations are inconsistent with the size of your (b)(4) bowls. The MACO limits outlined in your response were not adequately justified and fully encompass the contamination risk to drug product. Immediate remediation, effective cleaning protocols, and comprehensive testing are essential to resolve this serious CGMP violation.

In response to this letter, provide:

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 assessment whether cross-contaminated products 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 CAPA plan based on the retrospective assessment of your cleaning program, 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.

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 toxicitieso Drugs with higher drug potencieso Drugs of lower solubility in their cleaning solventso Drugs with characteristics that make them difficult to cleano Swabbing locations for areas that are most difficult to cleano Maximum hold times before cleaning

In addition, ensure use of appropriate limits that take into account recovery study results and 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.

A holistic review of cleaning procedures and the associated cleaning validation strategy for all manufacturing equipment to determine whether similar deficiencies exist.

Bird droppings and feathers were observed during the inspection in the AHU area, specifically on the air purification units, (b)(4) ducts, a (b)(4) tank, a cleaning (b)(4), and on the floors surrounding multiple (b)(4) inside your drug manufacturing facility. The conditions in your AHU area raise concerns about potential contamination affecting the air supplied to critical manufacturing equipment utilized in your drug manufacturing process.

In your response, you explain that birds were entering the manufacturing facility through numerous gaps in the exterior walls of the facility where the AHUs are located. You outline immediate actions to identify and block entry points for birds using nets.

Your response is inadequate. While you address the entry of birds and cleaned the area, you fail to perform a thorough root cause analysis or assess similar vulnerabilities elsewhere. Furthermore, pictures of the netting you installed appear to still allow smaller animals, such as insects, access to your AHU area.

In response to this letter provide a CAPA plan and timeline to implement routine, vigilant operations management oversight of facilities. This plan should ensure, among other things, prompt detection of facilities contamination issues, effective execution of repairs, adherence to appropriate preventive maintenance schedules, timely technological upgrades to the facility infrastructure, and improved systems for ongoing management review.

3. Your firm failed to routinely calibrate, inspect, or check according to a written program designed to assure proper performance of automatic, mechanical, electronic equipment, or other types of equipment, including computers, used in the manufacture, processing, packing, and holding of a drug product (21 CFR 211.68(a)).

You failed to adequately inspect and maintain your AHUs to ensure air filters would be effective at preventing contamination. The procedure for HEPA filter integrity and particle count testing did not clearly define the quality unit’s role in verifying the condition of critical AHU components, such as (b)(4) ducts, (b)(4)μ HEPA filters, and (b)(4)μ filters, during preventive maintenance, including assessing accumulated residues, filter integrity, and overall cleanliness. The lack of oversight led to insufficient monitoring of the filter replacement process during routine maintenance, preventing the detection of potential filter failures, air leakage, and contamination risks from compromised HEPA filters and ducting, which remained unaddressed and uninvestigated. These deficiencies demonstrate your failure to maintain a robust program to assure the proper performance of equipment essential to the manufacturing, processing, and holding of your drug products.

In your response, you note damage to the (b)(4) filters was confirmed by the original equipment manufacturer and potentially increased pressure differentials. You propose monitoring pressure differentials to determine when cleaning or replacement of filters is needed.

Your response is inadequate. While you acknowledge damage to the (b)(4) and propose periodic pressure differential monitoring, you fail to address the root cause or assess risks to airflow and cross-contamination identified during this inspection.

In response to this letter, provide your CAPA plan to implement routine, vigilant operations management oversight of equipment. This plan should ensure, among other things, prompt detection of equipment performance issues, effective execution of repairs, adherence to appropriate preventive maintenance schedules, timely technological upgrades to the equipment infrastructure, and improved systems for ongoing management review. Your plan should also ensure that appropriate actions are taken throughout the company network.

A large amount of torn CGMP records were discovered in at least 15 plastic waste bags during the inspection, including analytical balance printouts and worksheets containing manufacturing and testing data.

During the inspection and in subsequent correspondence, you provided supporting documentation asserting that the CGMP records observed in plastic waste bags did not affect product quality. You identified several root causes for these issues, including insufficient clarity in good documentation practices and data integrity protocols, inadequate SOP provisions requiring the attachment of defective or illegible printouts with appropriate annotations, employee misinterpretation of existing procedures, and inadequate controls over raw data sheets for primary packaging materials.

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.

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.

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.

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 refusing continuing to admission of articles manufactured at Granules India Limited, Telangana, 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 days1. 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 3004097901 and ATTN: Joseph Lambert, Pharm.D.