Pharma FDA Warning Letter -October 16, 2023
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility from April 26 to May 9, 2022.
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 May 31, 2022, 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 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)).
Inadequate Media Fills
Your media fills failed to accurately simulate commercial operations. Our inspection found the aseptic operations simulated during your media fills were not sufficiently representative of commercial aseptic manufacturing operations for medroxyprogesterone acetate injectable suspension USP, 150 mg/mL, 1 ml prefilled syringes and vials. For example, data from the inspection indicated:
A. Personnel simulated the manual addition of approximately (b)(4) grams of sterile (b)(4) to the compounding tank for up to (b)(4). However, for commercial manufacturing, approximately (b)(4) grams of sterile active pharmaceutical ingredient (API) was added to the compounding tank. This hand (b)(4) operation took up to (b)(4) and included a (b)(4) change during routine commercial manufacturing.
B. Approximately (b)(4) grams of sterile (b)(4) was hand-(b)(4) from (b)(4) sealed (b)(4) container into (b)(4) or more (b)(4). This process was not consistent with commercial manufacturing, where approximately (b)(4) grams of sterile API was hand-(b)(4) from (b)(4) different (b)(4) pouches into (b)(4). Pouches used in commercial manufacturing may also have been previously opened and re-sealed.
The dispensing and compounding steps were high-risk steps, and there were no additional sterilization steps following these operations.
Your operators performed lengthy, highly manually intensive aseptic operations. As such, the duration of process simulation should closely resemble the actual manufacturing process. If a media fill program fails to incorporate contamination risk factors and closely simulate actual drug product exposure, the state of process control and sterility assurance cannot be accurately assessed.
Poor Aseptic Behavior
Media fill and smoke studies of your manually intensive aseptic operations, such as dispensing of sterile API, and addition of sterile API to the compounding tank, revealed poor aseptic techniques by your operators. Examples include, but are not limited to:
- An operator inserted his gloved hand inside the (b)(4) to (b)(4) out sterile (b)(4) with a (b)(4) utensil.
- An operator touched the product contact surface of the (b)(4) stopper prior to placing it back on the (b)(4).
- Operator movements in the critical areas were not always slow and deliberate.
- An operator blocked (b)(4) air during various activities, including but not limited to, reaching over the open sterile (b)(4) container multiple times, and tilting the (b)(4) towards his body to visualize its interior while (b)(4) out the sterile (b)(4).
Your response is inadequate. You experienced a significant media fill failure in November 2021, which revealed serious flaws and risks in your operation. You failed to perform a timely risk assessment to evaluate if the quality and sterility of your distributed drug products were affected by these deficiencies. You waited over five months to initiate a recall of the affected batches. The failure to proactively identify deficiencies and implement timely and sustainable corrective actions and preventive actions (CAPA) is unacceptable because it puts patients at risk.
We acknowledge you discontinued medroxyprogesterone acetate injectable suspension pre-filled syringe and vial manufacturing operations in Block (b)(4) as of November 30, 2021. This decision was based on the risks identified through your media fill failure investigation. You recalled all batches of the drug product following the FDA inspection. We also acknowledge that you intend to move the manufacturing operations to a new block equipped with (b)(4).
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:
- 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 (QU) 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 drug products.
- A comprehensive review of your media fill program, and CAPA to ensure an accurate simulation, including appropriately incorporating the worst-case conditions of commercial manufacturing.
- A list of the third parties performing consulting functions for your firm. Include their responsibilities and an estimated time frame for completion of their activities.
2. 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)).
Your ISO 5 cleanroom areas used for aseptic compounding and filling were poorly designed and lacked adequate protection. For example, your ISO 5 area in Room (b)(4) lacked physical barriers to prevent potential contamination of your sterile components, including the sterile API, during manually intensive dispensing and compounding operations. Operators’ bodies and hands were in immediate proximity to the sterile API during dispensing, compounding, and syringe-loading in the filling station. Additionally, operators hand-(b)(4) sterile components into a compounding tank through a large funnel with a wide opening. Your smoke studies demonstrated non-unidirectional, recirculating airflow on and around the funnel.
The ISO 5 area is critical because sterile drug products are exposed and therefore vulnerable to contamination. Your aseptic manufacturing process should be designed and operations should be executed to minimize contamination hazards to your sterile drug product. Basic design deficiencies and manually intensive interventions in your operation undermine the ability to maintain asepsis.
You failed to establish an adequate system for monitoring environmental conditions. For example, you did not perform viable (surface and air) environmental monitoring in close proximity to aseptic dispensing operations in Room (b)(4). Likewise, no environmental monitoring was performed where sterile API was manually added to the compounding tank. Data reviewed during the inspection noted this aseptic operation lasted up to (b)(4). Your protocol failed to identify these locations as “high-risk” sampling points for environmental monitoring. Furthermore, personnel monitoring data was not captured appropriately.
Vigilant and responsive environmental and personnel monitoring programs should be designed to provide meaningful information on the state of control of your aseptic processing environment. Operations that include highly manually intensive aseptic activities warrant a more extensive environmental and personnel monitoring program, including but not limited to emphasis on well-timed sampling that appropriately monitors batch manufacturing conditions.
In your response you acknowledge the inadequacies of your environmental and personnel monitoring program. You state the drug products impacted by the observation are being recalled, and the specific filling line ((b)(4)) involved in the observation is no longer in use. You provide a high-level overview of an action plan with assurance to map the manufacturing process from a contamination prevention perspective.
You fail to adequately explain how your quality and operations management will ensure appropriate cleanroom design, control, aseptic practices, and cleanroom behavior during production.
In response to this letter, provide the following:
- A comprehensive, independent 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)
Provide this comprehensive assessment for each of your aseptic 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.
- A comprehensive, independent review of your personnel and environmental monitoring programs, including but not limited to a plan to fully remediate these programs. For example, describe changes to equipment, procedures, and practices that will ensure meaningful ongoing data is collected to promptly detect and respond to emerging risks in your classified areas. Also include your plan to perform appropriate non-viable particulate monitoring to sufficiently support manufacturing of aseptically filled powdered drug products. Provide an updated timeline for implementation of your program, including a summary of the CAPA steps you will be undertaking to ensure effective remediation.
3. Your firm failed to use equipment in the manufacture, processing, packing, or holding of drug products that is of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance (21 CFR 211.63).
You failed to identify and use equipment suitable for the filling of your viscous parenteral drug product. Inappropriately designed vial filling equipment led to substantial extraneous matter contamination in testosterone cypionate injection 200 mg/mL, 1 ml vials. Further, your production department failed to establish adequate personnel practices and supervisory oversight to prevent the use of damaged equipment.
You determined the design of the filling equipment ((b)(4)) in combination with the viscous nature of your drug product generated friction. This friction caused an abrasive effect on the surface of (b)(4) during (b)(4) movement which introduced blackish fine metallic particles into your vial during filling. You explained that these (b)(4) could not be fixed once damaged. Although reportedly removed from service, the damaged (b)(4) were listed as approved equipment in your master manufacturing batch record approved on April 5, 2022, approximately two years after they were identified as the root cause for cross-contamination.
Notably, one of the damaged (b)(4) (H102) was used to fill numerous batches of testosterone cypionate injection.
It is your responsibility to ensure that only appropriately designed and maintained equipment are used in the manufacture of your drug products.
We acknowledge that after our inspection you voluntarily recalled five marketed testosterone cypionate injection lots associated with the (b)(4) investigations.
Your response is inadequate. Your response fails to address the flaws in your change management system that permitted continued use of damaged and inappropriately designed (b)(4). Your response states that damaged (b)(4) were isolated and not used in filling testosterone cypionate injection but were inadvertently not removed from the manufacturing batch record. You also state that an associated (b)(4) (H102) was reconditioned and was acceptable for use. However, your firm indicated during the inspection that these damaged (b)(4) could not be reconditioned and acknowledged that they were not suitably designed. Your response also did not include a risk assessment that thoroughly evaluates the design and lifecycle control of manufacturing equipment including (b)(4) and (b)(4).
In response to this letter, provide:
- Your CAPA plan to implement routine, vigilant operations management oversight (corporate and local) 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, appropriately qualified production management personnel, and improved systems for ongoing management review. Your plan should also ensure that appropriate actions are taken throughout the company network.
- A thorough evaluation and risk assessment that addresses the suitability of your equipment for its intended use. You should include a determination of whether equipment is of appropriate design and a robust program for ongoing control and maintenance. Also describe how Quality Assurance will oversee the efficacy of systems used by operations to accomplish these critical objectives.
- An independent retrospective review of your manufacturing batch records to ensure that defective (b)(4) manufactured by (b)(4) or (b)(4) were not used during filling operations.
- An independent retrospective review of all complaints, including the associated investigations, for discoloration and particulates, for sterile drug products within expiry as of the date of this letter. Include the drug product name, batch number, and date of manufacture, line number, along with a summary of the complaint, description of likely root cause(s), CAPA plan, and status of CAPA.
- An independent, comprehensive review of your complaint system that identifies deficiencies in the system and corresponding CAPA that are needed.
- 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 appropriately justified, evaluated, and reviewed to a final determination of acceptability by your QU. Your change management program should include provisions for determining change effectiveness.
4. Your firm failed to thoroughly investigate any unexplained 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).
Your investigations into water leaks in your cleanroom were inadequate because they lacked appropriate CAPA and failed to extend to other potentially affected batches.
For example, water leaked from the service floor through the heating, ventilation, and air conditioning (HVAC) duct floor and into the ceiling directly above the ISO 5 filling area. Your investigation report noted water accumulated on the service floor due to a leak from an old, punctured (b)(4). Water then collected over the (b)(4) partition ceiling prior to entering the aseptic filling room where medroxyprogesterone acetate injectable suspension USP, was manufactured. Your personnel confirmed there was substantial water accumulation on the service floor.
Although you sealed gaps in the ceiling, you did not sufficiently inspect the service floor, (b)(4) LAF ceiling, and HVAC duct floor for mold growth and water damage after the repairs were made. You also failed to extend the scope of your investigation to potentially impacted batches of medroxyprogesterone acetate injectable suspension USP manufactured in this room since the last preventive maintenance of the (b)(4), approximately two months before the leak was observed.
In your response, you state the leak was isolated to the day it was observed. You acknowledge that your investigation did not evaluate the impact of the leak to other batches. You initiated a recall on May 17, 2022, for all marketed batches of medroxyprogesterone acetate injectable suspension USP, 150 mg/mL, 1 mL vials manufactured on this line, for events unrelated to this investigation.
Your response is inadequate. While we acknowledge you initiated actions to address this specific leak, your investigation failed to sufficiently address facility damage and the potential for microbial (i.e., particularly fungal) contamination that could persist in the facility due to water leaks and moisture.
In response to this letter, provide a comprehensive, independent assessment of your overall system for investigating deviations, discrepancies, complaints, 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 all phases of investigations are appropriately conducted.
5. 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 (21 CFR 211.67(a)).
You failed to adequately clean and maintain your equipment used for drug product manufacturing. For example:
A. Our investigators observed visible residue on (b)(4) 1 after it was identified as clean. Also, colored particles and pellets were observed inside a crevice where the (b)(4) was attached to (b)(4) 1. During the inspection your analytical testing identified that the pellets contained (b)(4) API.
The equipment cleaning record indicated a Type-B cleaning was performed on (b)(4) 1, which is defined as complete removal of previous drug product and involves dismantling of (b)(4).
B. Our investigators observed numerous scratches and dents on product contact surfaces of the (b)(4) 1 bowl-II. Additionally, shiny metal fragments were observed on the top of the (b)(4) gaskets that connected the (b)(4) in (b)(4) 4.
Inadequately cleaned and maintained equipment can lead to cross contamination and poor quality drug products.
Your response states that the (b)(4) was not disassembled during the cleaning process because engineering staff was not available. The residue and powder were from the previously manufactured drug product (which was the same drug). You also confirm the shiny fragments on the (b)(4) gaskets are (b)(4) and stated that the shedding of metal fragments most likely occurred during the assembly and disassembly process. You state that your protocol-based visual inspection of (b)(4) performed in response to this observation did not result in any similar findings.
Your response is inadequate. You state that your impact assessment is ongoing, and the batches manufactured since the last campaign are on hold. However, you do not provide information on how long the damaged and inadequately cleaned equipment has been used. You also do not provide a risk assessment for drug products manufactured and distributed using such equipment.
Your response fails to sufficiently address the confirmed complaints you received since January 2020 pertaining to stains, specks, and spots in your (b)(4) tablets, (b)(4) mg, and (b)(4) tablets (b)(4)mg drug products.
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 drug 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 drug 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.
- An independent review of your investigations and complaints of foreign matter contamination in your products. The review should comprehensively assess your program, including but not limited to sources of foreign matter, risks associated with the product, and appropriate investigations and CAPA.
- Your protocol to test any drug product, within expiry and manufactured on non-dedicated (b)(4) equipment, for contamination.
- 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, evaluating:
o whether procedures used by your firm are robust and appropriate
o sufficiency of provisions used for QU oversight throughout your operations to evaluate adherence to appropriate practices
o whether an effective and complete final review of each batch and its related information is conducted before the QU disposition decision
o implementation of oversight and approval of investigations, as well as discharging of all other QU duties to ensure identity, strength, quality, and purity of all products
Ineffective Quality Systems
Significant findings in this letter demonstrate that your firm does not operate an effective quality system in accordance with CGMP. In addition to the lack of effective oversight of production operations to ensure reliable facilities and equipment, we found your QU is insufficiently resourced or enabled with authority to carry out its responsibilities. Furthermore, internal communications and systems were not implemented by management to ensure all levels of the company can effectively identify major quality risks so they are promptly escalated to senior management, whenever needed. You should immediately and comprehensively assess your company’s global manufacturing operations to ensure that systems, processes, and the products manufactured conform to FDA requirements.
The role of senior management leadership is critical to ensure successful functioning of a robust and effective quality system. See FDA’s guidance document Quality Systems Approach to Pharmaceutical CGMP Regulations for help implementing quality systems and risk-management approaches to meet the requirements of CGMP regulations 21 CFR, parts 210 and 211, at https://www.fda.gov/media/71023/download.
CGMP Consultant Recommended
Based upon the nature of the violations we identified at your firm, we strongly recommend engaging a consultant qualified as set forth in 21 CFR 211.34 to assist your firm in meeting CGMP requirements.
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.
The violations cited in this letter are not intended to be an all-inclusive list of violations that exist at your facility in connection with your products. 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 email@example.com, 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 your firm on Import Alert 66-40 on December 7, 2022.
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 admission of articles manufactured at Sun Pharmaceutical Industries Ltd, Halol, 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. We request you email CDER-OC-OMQ-Communications@fda.hhs.gov, within five days of receipt of this letter to schedule a regulatory meeting.