Mr. Yongjun Tu
Chief Executive Officer and Chairman of the Board
Jiangkou Development Zone
Zhejiang Sheng, 318020
Warning Letter 320-22-23
August 17, 2022
Dear Mr. Yongjun Tu:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Zhejiang Tianyu Pharmaceutical Co., Ltd, FEI 3010972581, at Jiangkou Development Zone, Huangyan Taizhou City, Zhejiang from February 28 to March 4, 2022.
This warning letter summarizes significant deviations from current good manufacturing practice (CGMP) for active pharmaceutical ingredients (API).
Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your API 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 March 24, 2022, 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 to extend investigations to other batches that may have been associated with a specific failure or deviation.
Your investigation of the (b)(4) impurity in (b)(4) active pharmaceutical ingredient (API) is deficient. Though you identified at least four lots that failed your (b)(4) impurity specification, you did not extend your investigation to all lots manufactured prior to August 2018 after you identified (b)(4) had a higher risk of forming. Your investigation was limited to testing eight lots out of (b)(4) lots manufactured in 2018 using the non-optimized manufacturing process. Furthermore, from the time your risk assessment revealed (b)(4) could form until you had a validated analytical method, which was approximately three months, you continued to release and distribute (b)(4) API lots without implementing mitigating controls.
In your response, you acknowledged not all API lots were tested for the presence of (b)(4) within their retest period. Your response lacked the reason for the delay in testing (b)(4) batches manufactured using the non-optimized process that were within their retest period.
We acknowledge additional retrospective testing for (b)(4) was conducted after our inspection for the remaining lots manufactured in 2018. This retrospective testing identified four additional lots from 2018 exceeding your (b)(4) impurity specification. You did not perform your investigative testing in a timely manner and API lots manufactured as early as 2017 using the non-optimized process were not considered and included within the scope of your investigation.
In response to this letter, provide:
- A comprehensive assessment of the overall system for investigating deviations and discrepancies. Provide a detailed action plan to remediate this system to include, but not be limited to, significant improvements in investigation competencies, scope determination, root cause evaluation, corrective action and preventive action effectiveness, quality oversight, and written procedures. Address how your firm will ensure that all phases of investigations are appropriately conducted.
- A summary update on investigations and corrective action and preventive action plans initiated to identify, evaluate, and address the presence of all impurities.
- An assessment and testing results for the (b)(4) impurity in (b)(4) API batches manufactured prior to 2018 that remain within the established retest or expiry date.
2. Failure to establish an impurity profile for identified and unidentified impurities.
Your firm failed to conduct a comprehensive evaluation of the manufacturing process to identify all potential impurities.
A. (b)(4) impurity (b)(4)
Your firm failed to perform a systematic evaluation of the manufacturing process of (b)(4) API and have robust procedures to identify the potential formation of (b)(4) impurity. On July 6, 2021, you were notified of the presence of the (b)(4) impurity by a customer complaint and on July 9, 2021, you received a deficiency letter from European Directorate for the Quality of Medicine (EDQM) which identified (b)(4) can form as a by-product in the route of synthesis. Your subsequent investigation confirmed the presence of this impurity at unacceptable levels and determined that it is a byproduct of your manufacturing process. Prior to the risk assessment, you did not identify (b)(4) could form from your manufacturing process.
Your lack of systematic evaluation prevented you from identifying (b)(4) in 39 lots intended for the U.S. market with levels between (b)(4) ppm and (b)(4) ppm. Despite having procedures for performing a systematic evaluation of potential existing mutagenic impurities, your firm had not anticipated the presence of the (b)(4) impurity based on your assessment of the API manufacturing process.
Your response states the impurities were not identified at the time as these were discovered in the process of continuous research which also resulted in the improvement of the sensitivity and detectability of your test methods. You are responsible for developing and using suitable methods to detect impurities when designing, and making changes to, your manufacturing processes. If new or higher levels of impurities are detected, you should fully evaluate the impurities and take action to ensure the drug is safe for patients.
In response to this letter, provide:
- A retrospective review of (b)(4) batches released without having undergone appropriate testing for impurity (b)(4) and how that may impact finished drug quality.
- A plan to address any product quality or patient safety risks for out of specification (OOS) batches of API in U.S. distribution, including recalls.
- Specifications, including test methods, used to release the API. Your response should address capability to detect and quantify a wide array of potential impurities or contaminants, including but not limited to (b)(4) impurities.
- Provide improvements to procedures for performing a systemic evaluation for identifying impurities and establishing a control strategy from the process development stages.
B. (b)(4) impurity (b)(4)
You manufactured (b)(4) starting material to be used in API manufacturing. On November 25, 2021, you received a customer complaint that stated (b)(4) was present in your (b)(4) starting material. Your firm failed to identify (b)(4) in (b)(4) as a by-product from starting materials. Your initial risk assessment titled “(b)(4) Quality Risk Assessment Report” approved on September 23, 2020, did not evaluate all (b)(4) source impurities that may carryover from starting materials which could impact the efficacy or safety of the drug product.
In response to this letter, provide:
- Test results for (b)(4) API, intermediates and (b)(4) starting material that remain within the established retest or expiry date for the presence of (b)(4), (b)(4), (b)(4), (b)(4) and other potentially mutagenic impurities.
- Updated risk assessments for the potential presence of impurities in (b)(4) API, intermediates and (b)(4) starting material manufactured at your facility. Include your program for ongoing lifecycle evaluation for impurity profiles of all drugs and starting materials you produce.
- Identify corrective actions to ensure adequate quality oversight of establishing appropriate impurity/degradant limits for all drugs, including starting materials you produce, using well-studied, scientifically based impurity profiles specific to their own manufacturing processes.
3. Failure to clean equipment at appropriate intervals to prevent build-up and carryover of contaminates and degradants where equipment is assigned to continuous production or campaign production of successive batches of the same intermediates and API.
A. Equipment cleaning
(b)(4) used in the (b)(4) synthesis were observed with brownish rust like spots on the upper walls of the (b)(4) with layers of thick black spots above the brownish spots. These layers of black and brown residues were on product contact surfaces. The status of the equipment was ready to be used for the next batch.
A complaint investigation reported a (b)(4) lot was returned due to the (b)(4) impurity (b)(4) being out of specification. Your retention samples of (b)(4) were tested and (b)(4) was out of specification with a result of (b)(4) ppm (Limit: < (b)(4) ppm). Your investigation identified the most probable root cause to be damaged or worn-out (b)(4) equipment used in production leaching metal (b)(4) into the (b)(4) production synthesis.
In your response to this observation, you subsequently analyzed the discoloration for (b)(4) and (b)(4) starting material. You provided chromatograms to demonstrate the spots contained (b)(4) and (b)(4) starting material. Your response did not address whether you assessed the brown and black residue on your manufacturing equipment for (b)(4) as well as other (b)(4) impurities such as (b)(4) and (b)(4) which may also be present in the residue.
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 summary of updated SOPs that ensure an appropriate program is in place for verification and validation of cleaning procedures for products, processes, and equipment.
- Your corrective action and preventive action 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.
B. Cleaning validation is a repeat deviation from the 2019 FDA inspection.
Your firm failed to complete cleaning validation studies prior to release and distribution of (b)(4) batches of (b)(4) starting material from 2020 to 2022. You acknowledged your cleaning validation was not completed before the batches were distributed. Although the (b)(4) is manufactured on dedicated equipment trains, there was no assurance your cleaning methods were adequate and that no contamination was carried over from batch to batch during production campaigns.
Your response is inadequate. You state a cleaning verification for residual (b)(4) was being performed prior to validation being completed. You did not provide documentation of cleaning verification results for (b)(4) manufacturing process (b)(4), from November 2020 to April 2021. You lack assurance that equipment used to manufacture the (b)(4) batches of (b)(4) were clean and that no contamination was carried over from batch to batch during production campaigns.
In response to this letter, provide:
- A risk assessment of (b)(4) batches manufactured using process (b)(4) and released without cleaning validation or verification.
- Describe the steps that must be taken in your change management system before introduction of new manufacturing equipment or a new product.
Repeat Observations at Facility
In a previous inspection, dated April 8 to 12, 2019, FDA cited similar CGMP observations. You proposed specific remediation for these observations in your response.
Repeated failures to address deficient operations demonstrate that executive management oversight and control is inadequate.
Based upon the nature of the deviations 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 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 [email protected], 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 deviations promptly. Failure to promptly and adequately address this matter may result in regulatory or legal action without further notice including, without limitation, seizure, and injunction. Unresolved deviations may also prevent other Federal agencies from awarding contracts.
Failure to address deviations may also cause FDA to withhold issuance of Export Certificates. 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 address any deviations.
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 [email protected] Identify your response with FEI 3010972581 and ATTN: Erika V. Butler.
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research