- Delivery Method:
- VIA UPS
Recipient NameMr. Praj Srichandra
Recipient TitleFactory Division Manager, Board Member of Saha Group
- S & J International Enterprises Public Company Limited
600/4 Moo.11 Sukaphiban 8 Road
Nongkharm, Si Racha
Chon Buri 20230
- Issuing Office:
- Center for Drug Evaluation and Research | CDER
Warning Letter 320-24-17
January 26, 2024
Dear Mr. Srichandra:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, S & J International Enterprises Public Company Limited, FEI 3005979923, at 600/4 Moo.11 Sukaphiban 8 Road, Nongkharm, Si Racha, from July 17 to July 21, 2023.
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 product is 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).
Furthermore, during the inspection you delayed or limited access to or copying of records requested. Due to your delay and limiting access to or copying of records during the inspection, the drug products you manufacture are also deemed adulterated within the meaning of section 501(j) of the FD&C Act, 21 U.S.C. 351(j).
We reviewed your response1 to our Form FDA 483. Your response is inadequate because it did not provide sufficient detail or evidence of corrective actions to bring your operations into compliance with CGMP.
During our inspection, our investigator observed specific violations including, but not limited to, the following.
1. Your firm’s quality control unit failed to exercise its responsibility to ensure drug products manufactured are in compliance with CGMP, and meet established specifications for identity, strength, quality, and purity (21 CFR 211.22).
Your quality unit (QU) did not provide adequate oversight and control over your drug manufacturing operations. Specifically, your QU did not implement adequate controls to prevent the alteration of production records, to ensure the complete documentation of laboratory preparation, and to ensure the review of raw analytical data. For example, production staff are able to alter master batch records, including modifying batch formulations and other parameters or formulations before printing. Laboratory sample preparation is not documented, and weight print-outs are not retained. Lastly, your QU only reviews analytical results entered into your enterprise system and does not review raw analytical data before releasing quarantined materials or finished drug products.
An adequate QU overseeing all manufacturing operations is necessary to consistently ensure drug quality. 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.
In response to this letter, provide 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:
- A determination of whether procedures used by your firm are robust and appropriate.
- Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices.
- A complete and final review of each batch and its related information before the QU disposition decision.
- Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all products. Also describe how top management supports quality assurance and reliable operations, including but not limited to timely provision of resources to proactively address emerging manufacturing/quality issues and to assure a continuing state of control.
2. Your firm failed to prepare batch production and control records with complete information relating to the production and control of each batch of drug product produced (21 CFR 211.188).
You recorded production data on laminated sheets using erasable markers that could be easily altered or lost. These logs were used to record (b)(4) weight verification checks for balances and scales, room cleaning checklists, employee health and hygiene checks, operator shoe cleaning, pest control checks, facility and equipment checks, and (b)(4) temperature and humidity monitoring in manufacturing areas. You stated that these temporary records are scanned and retained. However, you could not provide the permanent version of these records and stated that only production staff and production supervisors, and not the QU, have access to the scanned sheets and logs. Without adequate and complete batch records, you cannot assure the uniformity of your drug products from batch to batch and may impact your ability to adequately investigate any product deviations.
In response to this letter, provide a complete assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are insufficient. Include a detailed corrective action and preventive action (CAPA) plan that comprehensively remediates your firm’s documentation practices to ensure you retain attributable, legible, complete, original, accurate, contemporaneous records throughout your operation.
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 strongly recommend that you retain a qualified consultant to assist in your remediation. In response to this letter, provide:
- A comprehensive investigation into the extent of the inaccuracies in data records and reporting, including results of the data review for drugs distributed to the United States. Include a detailed description of the scope and root causes of your 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 CAPA plan. The detailed corrective action plan should describe how you intend to ensure the reliability and completeness of all data generated by your firm including microbiological and analytical data, manufacturing records, and all data submitted to FDA.
Delaying, Denying, Limiting, or Refusing a Drug Inspection
You delayed and limited access to or copying of records requested during the inspection. During the inspection, our investigator provided a list of requested documents and made numerous repeat requests during the inspection for these documents. Yet, your firm only provided or allowed access to a limited number of documents.
For example, upon request for the current labeling for your United States (U.S.) drug product, you provided a single photograph of the primary and secondary drug product packaging on the last day of the inspection, which was of poor quality and not legible.
Additionally, upon request for a list of all laboratory non-conformances and investigations during the inspection, your staff initially stated that there were no out-of-trend, out-of-specification (OOS), incidents, non-conformances, or investigations, and provided blank logs for years 2021-2023. However, later during the inspection, our investigator observed logs for these years on an electronic drive that contained non-conformance report numbers, dates, descriptions, and close-out dates, and appeared to include a raw material OOS entry for (b)(4), the active ingredient in your U.S. drug product. Only after discovery by our investigator were these logs provided to our investigator.
When an owner, operator, or agent delays, denies, limits, or refuses an inspection, the drugs may be deemed adulterated under section 501(j) of the FD&C Act. See FDA’s guidance document Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug Inspection at https://www.fda.gov/media/86328/download.
CGMP Consultant Recommended
Based upon the nature of the violations we identified at your firm, you should engage a consultant qualified as set forth in 21 CFR 211.34 to evaluate your operations and to assist your firm in meeting CGMP requirements if your firm intends to resume manufacturing drugs for the U.S. market. The qualified consultant should also perform a comprehensive six-system audit2 of your entire operation for CGMP compliance and evaluate the completion and efficacy of your corrective actions and preventive actions 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.
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.
FDA placed your firm on Import Alert 66-40 on January 23, 2024.
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 continuing to refuse admission of articles manufactured at S & J International Enterprises Public Company Limited, 600/4 Moo.11 Sukaphiban 8 Road, 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.
Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.gov. Identify your response with FEI 3005979923 and ATTN: Christina Capacci-Daniel.
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research
1 Response provided by email on December 19, 2023 following the July 17 to July 21, 2023 inspection.
2 i.e., Quality System, Facilities & Equipment System, Materials System, Production System, Packaging & Labeling System, and Laboratory Control System per FDA’s guidance document Quality Systems Approach to Pharmaceutical CGMP Regulations.