FDA warning letter: dissolved non-conforming can not just modify the standard.

On July 21, the FDA's official website published a warning letter against a U.S. drug company.
one of the company's capsule products in the stability study and sample inspection period, there have been multiple batches of dissolved test failure results.
, the company eventually used a lax quality standard.
the standard was approved in advance by the FDA, the FDA said it was unacceptable because the company had not determined the root cause of the change in solubility and had not implemented the appropriate CAPA, and that there were still many failures after the revision of quality standards.
the main content of the warning letter: July 8, 2020 Dear Mr. Fan: The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing plant in Irvine from October 3 to 25, 2019.
the warning letter summarizes serious breaches of CGMP regulations.
see 21 CFR Sections 210 and 211.
your medicine is considered adulterated under Section 501(a) (2) (B) of The FD?amp;C Act because the methods, facilities or controls you use to produce, process, package or hold are not in conformity with CGMP.
We have reviewed your details of November 18, 2019, which responds to our FDA Form 483, and we confirm receipt of your follow-up letter.
During our inspection, our investigators observed specific violations, including but not limited to the following.
multiple batches of delucation seisquid, undetermined cause1. Your company is unable to thoroughly investigate the batch, or any unexplained discrepancies or non-conformitys in any of its components, regardless of whether the batch has been distributed (21 CFR 211.192).
for temozolomide capsules, your company cannot guarantee that the solubility standard will be met throughout the life period.
during stability research and sample-keeping testing, multiple batches of dissolved outtest (OOS) results appeared.
you surveyed some OF the OOS results and finally approved a loose quality standard.
However, you have not determined the root cause of the solutization change, nor have you implemented an appropriate CAPA to prevent future failures due to the use of new quality standards.
for example, the temorine capsule, batch number 18J043B, stability at a certain point in time, the solubility test (the average result of the phase 3 test) is not qualified.
new quality standards that the batch failed to pass, even if it was relaxed.
we know that the batch has been recalled.
However, your investigation of non-conformity is inadequate because it lacks the ability to determine the root cause and prevent the recurrence of CAPA.
you initially suspect that the product is over-drying due to changes in strong desiccant and sealing performance, and then you study other desiccants.
However, stability data from these studies show that reducing the absorption of desiccants does not improve solubility.
we acknowledge that the FDA did approve your lax solubility quality standards.
However, your answer is inadequate because, after revising the quality standards, there are many times when the degree of dissolution is not up to scratch, and you do not identify the root cause.
We also acknowledge that your company continues to research to find alternative desiccant.
, however, your company can't prove that the failure to dissolve is indeed due to excessive drying of the capsules.
your answer is inadequate because you do not provide sufficient details about the new desiccant study being initiated or the formulation modification being evaluated.
you have not provided a research plan, or a new CAPA (19-020) that you have initiated.
In addition, your company does not have adequate interim measures to address cleaning issues, including the challenges posed by a failed cleaning confirmation, after producing methotrexate tablets.
in response to this letter, please provide the following information: 1) a comprehensive assessment of the system as a whole, to investigate deviations, discrepancies, complaints, OOS results and non-conformity.
provide a detailed action plan to remedy the system.
your action plan should include, but is not limited to, significant improvements in investigation capabilities, scope determination, root cause assessment, CAPA effectiveness, quality unit oversight and written procedures.
explain your company's how it will ensure that proper investigations are conducted at all stages.
2) Complete your root cause survey and CAPA to understand the insoluble non-conformity observed during release, stability, or any other test.
this should include, but is not limited to, the study of desiccants and preparations, and the need to address whether batches have been added to the annual stability plan to monitor the decline in the solute performance of the temylyamine capsules during the life of the life.
3) From 2017 to the present, all pyromine capsule seones are summarized and collated.
the table should contain the following parameters (slightly).
4) In the validity period of all batches of pyridine capsules, the retention of samples for the solubility test.
5) A comprehensive assessment of the production process of the timozola capsules, including but not limited to the evaluation of active ingredients, accessories, raw materials, containers/closed containers, suppliers, suitability of equipment (e.g. mixing, drying, compression) and process variables.
includeany supplier or other production changes that may cause solubility problems, with particular emphasis on the potential impact of formula composition differences (physical and chemical properties) on solubility behavior.
6) A summary of the current standard operating procedures (SOP) to ensure that appropriate procedures are in place to validate and confirm the cleaning procedures for new products, processes and equipment.
detail how your company responds to deviations when using production equipment for new products during clean validation studies.
also provides updates on the latest methotrexate cleaning validation and confirmation results, and is concerned about any changes to cleaning procedures and practices.
Data Integrity 2. Your company does not exercise proper control over computers or related systems to ensure that only authorized personnel can change master production control records or other records (21 CFR 211.68(b)).
your company lacks the necessary controls to ensure the integrity of electronic verification data.
specific, you don't have enough control to support data integrity, or to ensure that only the right individuals have administrative authority.
note, the demonstrations conducted during the inspection showthat the computer operating the spectrometer (ID:L-563) is out of control and therefore the data file can be deleted.
the instrument is used for the release and stability of several drugs.
your answer is inadequate because it does not include a comprehensive review of all laboratory instruments to determine whether all user roles are appropriate.
you acknowledge that your software is not working as expected and that you lack the necessary knowledge or experience to resolve the issue.
you indicate that you are repairing the spectrometer.
your response is inadequate because it lacks a retrospective assessment of how system vulnerabilities affect data integrity.
your quality system does not adequately ensure the accuracy and completeness of your data and does not support the safety, effectiveness and quality of the drugs produced.
for CGMP data integrity, please refer to the FDA guidelineS Drug Data Integrity and CGMP Compliance.
in response to this letter, please provide the following information: 1) a comprehensive, independent assessment and CAPA program for the security and integrity of your computer system.
includes a report that identifies vulnerabilities in design and control, as well as appropriate remedies for each lab computer system.
should include, but is not limited to, (slightly).
2) a complete evaluation of the documentation systems used in the entire production and laboratory operations to determine which local documentation practices are inadequate.
includes a detailed CAPA plan that comprehensively revises the company's documentation practices to ensure that you achieve attribution, clarity, complete, original, accurate, and synchronized records throughout your operations.
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