- Delivery Method:
- VIA UPS
Recipient NameMr. Vishnukant Chaturbhuj Bhutada
Recipient TitleManaging Director
- Shilpa Medicare Limited
#12-6-214/A1 Hyderabad Road
- Issuing Office:
- Center for Drug Evaluation and Research | CDER
Warning Letter 320-21-01
October 9, 2020
Dear Mr. Bhutada:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility at Shilpa Medicare Limited, Unit-IV, FEI 3009876430, Plot No. S-20 to S-26, Pharm, Formulation SEZ, TSIIC, Green Industrial Park, Polepally (Village), Jadcherla (Mandal), District Mahabubnagar (Telangana), from February 13 to 20, 2020, and February 24 to 25, 2020.
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).
In addition, the inspection revealed that your firm failed to submit an (b)(4) Field Alert Report (FAR) to FDA within three working days of receipt of information concerning significant chemical, physical, or other change or deterioration in a distributed drug product, as required by section 505(k) of the FD&C Act, 21 U.S.C. 355(k) and stipulated by the regulation 21 CFR 314.81(b)(1)(ii).
We reviewed your March 17, 2020, 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 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 firm manufactures (b)(4) sterile injectables and solid dosage drug products. You failed to conduct adequate out-of-specification (OOS) and complaint investigations, including the identification of the root cause and timely implementation of effective corrective action and preventive action (CAPA) plans.
a. On June 29, 2019, (b)(4) Tablets batch (b)(4) obtained OOS results for impurity-(b)(4).
Your Phase I investigation confirmed the initial OOS result when the original sample was re-injected and re-filtered. No probable root cause was identified. Also, you did not thoroughly investigate an unknown chromatographic peak observed adjacent to the impurity (b)(4) peak in the High-Performance Liquid Chromatographic (HPLC) run.
You attributed the unknown chromatographic peak to sample contamination or HPLC column load problem, without supporting documentation. You made no meaningful effort to determine if the sample was contaminated. The initial HPLC run that generated the OOS result met the method system suitability requirements and no column or equipment malfunction was reported. Your analyst also reported that the column had been properly flushed. Based on your investigation, the unknown peak was not observed in either the blank or the placebo injections.
During your Phase II laboratory investigation, the HPLC column was reconditioned (i.e., washed for (b)(4)). With no explanation of your rational, on July 9, 2019, you retested batches (b)(4), (b)(4), and (b)(4) using the reconditioned column. The three batches complied with the specification for the impurity-(b)(4). However, you did not include batch (b)(4), which had the original OOS result, in the retest.
Later, batch (b)(4) was retested using a new sample preparation with the reconditioned column. However, this chromatographic run was aborted: reportedly, there was a system communication error. You again reconditioned the HPLC column by washing it with water for (b)(4), followed by (b)(4) washing (b)(4). Batch (b)(4) was retested after the HPLC column was reconditioned multiple times. The impurity-(b)(4) met the specification and product was released.
Your response is inadequate. You did not provide sufficient scientific justification to demonstrate the HPLC column was the root cause of the original confirmed OOS. You did not explain why the unknown chromatographic peak was not observed in the blank or standard solutions. Your investigation is unclear as to why the original sample was not retested using a new HPLC column to rule out sample contamination as the root cause. Your investigation also lacked information about the history and use of the HPLC column, and an evaluation of the analytical method and equipment-column performance.
b. You obtained OOS assay results in three different batches of (b)(4) Injection. The specification is (b)(4)-(b)(4)% for both solution and suspension assay.
i. On April 30, 2018, you reported an OOS assay result for batch (b)(4), which failed to meet the (b)(4) solution and suspension specifications. The OOS results reported were (b)(4)% in solution and (b)(4)% in suspension. You concluded that the most probable cause was an error in the preparation of the stock solution, and released the batch based on the average of a (b)(4) retest.
ii. On October 12, 2019, you obtained an OOS assay result for batch (b)(4), which failed to meet (b)(4) solution specifications. The OOS result reported was (b)(4)%. You concluded the OOS was “due to analytical error” and the batch was released.
iii. On October 16, 2019, you obtained an OOS assay result for batch (b)(4), which failed to meet (b)(4) solution specification. The OOS reported was (b)(4)%. You concluded the OOS was due to analytical error, and the batch was released.
In all three investigations you concluded, without adequate scientific justification, that analytical error was the most probable root cause for the original OOS results. Your firm opened CAPA where analysts were retrained to avoid reoccurrence. Your investigations lacked sufficient details of the CAPA implemented and how you will measure the effectiveness of the CAPA. Although you conducted a Phase 2 production review, you did not conduct a comprehensive evaluation of the product development, manufacturing validation, previous failing results obtained, and analytical test method. All three batches were released based on passing retest results.
Your response is inadequate. Although you suggested possible root causes, you provided no scientific evidence to support your conclusions that laboratory errors had occurred. Your firm also failed to provide details of the CAPA implemented and how you measure the effectiveness of CAPA.
c. Your complaint investigation related to (b)(4) Injection (b)(4) mg/(b)(4) mL, batch (b)(4), produced in January 2019 with an expiration date of (b)(4), was inadequate.
On October 2, 2019, a complaint received reported that the “(b)(4) enclosure” system separated from the glass vial. During the manufacture of this batch an unplanned deviation was initiated due to several filled vials showing sealing defects. About an hour after the filling operation started “bad cap rejections” (improper (b)(4)) was observed. The deviation record indicated that the (b)(4) were misplaced/misaligned and that the (b)(4) was not properly locked. According to your complaint investigation a breakdown of the sealing machine had occurred when the product was manufactured and “there might be the probability that few vials with loose sealing might have missed out during visual inspection.” Despite this you released the batch.
We acknowledge that your firm conducted a study after the inspection to assess the integrity of the seal of vials as part of assessment into this issue.
Your response is inadequate. You provide no justification for having released the batch of (b)(4) Injection batch #(b)(4), including the portion filled during the first hour of sealing, when a machine breakdown occurred. In addition, your investigation is silent regarding the vials filled prior to noting the equipment breakdown.
d. You received multiple consumer complaints for batches of (b)(4) Injection related to the presence of foreign particles; these complaints have not been properly evaluated to prevent reoccurrence.
Your investigation concluded, with no scientific evidence, that the root cause was related to the use of a (b)(4) by the end user. You indicated that you evaluated the drug product using (b)(4) and observed no problem, while the complainants used an (b)(4). You do not have sufficient scientific data, including but not limited to functionality test data, to support your root cause that the foreign particles and stopper separations or “seal coring” defects are caused by the use of a (b)(4).
Inadequate OOS investigations is a repeat CGMP violation from the 2017 FDA inspection.
We acknowledge your efforts to remediate your investigation program and your decision to initiate a protocol-based study to evaluate the (b)(4) used by the end user on Shilpa-supplied products.
However, your response lacks adequate details regarding the scope and extent of the remediation.
In response to this letter, provide the following:
• 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.
• Provide your market action plan for the batches referenced in this letter and other batches found out of compliance as part of your independent retrospective assessment.
• An independent assessment and remediation plan for your CAPA program. Provide a report that evaluates if staff with proper investigation competencies effectively conducts root cause analysis, assures CAPA effectiveness, regularly reviews investigations trends, implements improvements to the CAPA program when needed, ensures appropriate quality assurance unit decision rights, and is fully supported by executive management.
• A management strategy including the 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 batches to your stability programs to assure stability, drug application actions, and enhanced complaint monitoring.
• A retrospective, independent review of all invalidated OOS (including in-process and release/stability testing) results for U.S. products irrespective of whether the batch was ultimately distributed in the U.S. and a report summarizing the findings of the analysis, including the following for each OOS:
o Determine whether the scientific justification and evidence relating to the invalidated OOS result conclusively or inconclusively demonstrates causative laboratory error.
o For investigations that conclusively establish laboratory root cause, provide rationale and ensure that all other laboratory methods vulnerable to the same or similar root cause are identified for remediation.
o For all OOS results found by the retrospective review to have an inconclusive or no root cause identified in the laboratory, include a thorough review of production (e.g., batch manufacturing records, adequacy of the manufacturing steps, suitability of equipment/facilities, variability of raw materials, process capability, deviation history, complaint history, batch failure history). Summarize potential manufacturing root causes for each investigation, and any manufacturing operation improvements.
• A comprehensive review and remediation plan for your OOS result investigation systems. The CAPA should include but not be limited to addressing:
o Quality unit oversight of laboratory investigations
o Identification of adverse laboratory control trends
o Resolution of causes of laboratory variation
o Initiation of thorough investigations of potential manufacturing causes whenever a laboratory cause cannot be conclusively identified
o Adequately scoping of each investigation and its CAPA
o Revised OOS investigation procedures with these and other remediations
For more information about handling failing, OOS, out-of-trend, or other unexpected results and documentation of your investigations, see FDA’s guidance document Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production at https://www.fda.gov/media/71001/download.
2. Your firm failed to follow adequate written procedures describing the handling of all written and oral complaints regarding a drug product including the review by the quality control unit of any complaint involving the possible failure of a drug product to meet any of its specifications and, for such drug products, a determination as to the need for an investigation in accordance with 21 CFR 211.192 (21 CFR 211.198(a)).
Your procedure QAD/GEN/049-05 titled “handling of market complaints” indicates if a compliant is assigned a rank of 3 in severity, the complaint should be treated as critical, irrespective of the risk priority number. None of the complaints related to the presence of particles found in your (b)(4) Injection or potential breach of vial integrity of (b)(4) Injection were assigned rank 3. Extrinsic particles or integrity breach could be an indicator of loss of sterility. Instead, the complaints received during the past two years were classified as minor even though some of them were determined by your client as critical complaints and could lead to serious adverse events. You classified the above complaints as minor and no CAPA were implemented.
In your response you acknowledged that complaints associated with particulate contamination, coring, and seal integrity, originally classified as minor, should have been classified as major.
Your response is inadequate. Your response did not provide a scientific justification or rationale for not classifying these complaints as “critical.” Your response also failed to explain the discrepancy between your sponsor’s and your own complaint risk assessment classification.
In response to this letter, provide the following:
• An independent assessment and remediation plan for your complaint handling program. Provide a report that evaluates all CAPA implemented. Include an evaluation of staff competencies, root cause analysis, CAPA effectiveness, regular reviews of investigation trends, improvements to the CAPA program when needed, and review of decisions made by the quality unit to ensure they are scientifically based and supported by executive management.
• An independent retrospective review of all complaints and associated investigations for batches within expiry. This review should focus on the completeness of the investigations and analysis of complaint or reserve samples, particularly for investigations involving more than one complaint.
Field Alert Reporting Violations
The NDA/ANDA Field Alert reporting requirements in 21 CFR 314.81(b)(1)(i) and (ii), effective since May 23, 1985, require holders of NDAs and ANDAs to submit information concerning any bacteriological contamination, or any significant chemical, physical, or other change or deterioration in the distributed drug product, to the appropriate FDA district office within three working days of receipt by the applicant. The intent of the 21 CFR 314.81(b)(1) regulation is to establish an early warning system so that significant problems are brought to the FDA’s attention by applicant holders in order to prevent potential safety hazards from drug products already in distribution and also to prevent potential safety hazards with drug products manufactured in the future. FARs must be submitted for confirmed and unconfirmed problems meeting the definition of the regulation within three working days of a firm’s becoming aware of the problem.
From this inspection, in addition to the aforementioned CGMP violations, your firm is in violation of the Field Alert reporting requirements set forth in 21 CFR 314.81(b)(1)(ii). During 2017 and 2018, FARs related to (b)(4) solution were not provided to FDA within three working days. Specifically, you received several complaints related to extrinsic particles observed in vial(s) of several batches of (b)(4) Injection (b)(4) mg/vial and no FAR was submitted to the agency:
1. On December 5, 2018, you received a customer complaint for batch (b)(4). On December 5, 2018, you acknowledged the complaint and determined that an initial FAR was not required. You investigated the complaint and closed the investigation on February 11, 2018.
2. On November 21, 2018, you received a customer complaint for batch (b)(4). On November 21, 2018, you acknowledged the complaint and determined that an initial FAR was not required. You investigated the complaint and closed the investigation on January 18, 2019.
3. On October 3, 2018, you received a customer complaint for batch (b)(4). On October 3, 2018, you acknowledged the complaint and determined that an initial FAR was not required. You investigated the complaint and closed the investigation on December 3, 2018.
4. On September 10, 2018, you received a customer complaint for batches (b)(4) and (b)(4). On September 11, 2018, you acknowledged the complaint and determined that an initial FAR was not required. You investigated the complaint and closed the investigation on November 2, 2018.
5. On August 31, 2018, you received a customer complaint for batches (b)(4) and (b)(4). On August 31, 2018, you acknowledged the complaint and determined that an initial FAR was not required. You investigated the complaint and the investigation on November 2, 2018.
6. On July 27, 2018, you received a customer complaint for batch (b)(4). On July 27, 2018, you acknowledged the complaint and determined that an initial FAR was not required. You investigated the complaint and closed the investigation on September 22, 2018.
7. On January 6, 2018, you received a customer complaint for batch (b)(4). On January 7, 2018, you acknowledged the complaint. On January 8, 2018, you determined that no initial FAR was required. You investigated the complaint and closed the investigation on February 23, 2018.
8. On December 15, 2017, you received a customer complaint for batch (b)(4). On December 16, 2017, you acknowledged the complaint and determined that an initial FAR was not required. You investigated the complaint and closed the investigation on February 16, 2018.
We are concerned with the CGMP violations demonstrated at your facility and failure to submit FAR-related events within three days of becoming aware of a problem. Please include in your written response the corrective action you plan to take regarding distributed products manufactured at your facility that may be affected by the violations.
CGMP Consultant Recommended
Because you failed to correct the repeat violation from previous inspection, we strongly recommend engaging a consultant qualified to evaluate your operations 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. You are responsible for investigating and determining the causes of these 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 firstname.lastname@example.org, 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.
Until you correct all violations completely and we confirm your compliance with CGMP, FDA may withhold approval of any new drug applications or supplements listing your firm as a drug manufacturer.
Failure to correct these violations may also result in the FDA refusing admission of articles manufactured at Plot No. S-20 to S-26, Pharm, Formulation SEZ, TSIIC, Green Industrial Park, Polepally (Village), Jadcherla (Mandal), District Mahabubnagar (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 may be subject to refusal of 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).
After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done since our inspection to correct your violations and to prevent their recurrence. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.
If you believe that your products are not in violation of the FD&C Act (or you have complied with FDA regulations), include your reasoning and any supporting information for our consideration.
Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.gov. Identify your response with FEI 3009876430 and ATTN: Rafael E. Arroyo.
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research