Les Produits Chimiques B.G.R., Inc. Receives FDA Warning Letter (07/24/2018) for Failure to Perform Laboratory Testing. The U.S. Food and Drug Administration (FDA) inspected Les Produits Chimiques B.G.R., Inc., Pointe-Claire, Quebec, from September 25 to 27, 2017. A Warning Letter was issued which contained significant deviations from current good manufacturing practice (CGMP) for active pharmaceutical ingredients (API).
Because the methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your Company’s 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).
During the FDA inspection, the investigator observed specific deviations including, but not limited to, the following:
- Failure to perform laboratory testing of API to ensure conformance to specifications and to accurately report results on certificates of analysis (COA).
Your firm distributed multiple lots of (b)(4) powder USP API without completing required release testing for identity. Your COA reported that these drugs met all required specifications. We reviewed your firm’s COA and laboratory notebooks for (b)(4) powder USP lot #(b)(4), as well as for multiple lots of this product dating back to at least 2015. The laboratory notebooks lacked the analytical data to support the information on your COA. Your firm confirmed to our investigator that, although your COA states that the identity tests “Passed,” you did not perform the tests. Although you never performed the required testing, you distributed these API lots to the U.S. market with false information on the COA.
In your response, you provided the identity test results for lots produced since 2015; you conducted these retrospective analyses only after our inspection identified that you had never performed the tests in the first place. Your response is inadequate. While you tested lots identified during our inspection that were manufactured since 2015, you did not test all distributed lots within expiry. In addition, you did not conduct a thorough review of all release records to determine whether the test results for other drug quality attributes were falsely reported.
Customers and regulators rely on certificates of analysis for critical information about the quality and source of their ingredients. Unreliable information on a COA compromises supply-chain accountability and quality assurance, and may put consumers at risk.
In response to this letter, provide the following.
- A comprehensive investigation into the extent of the inaccuracies in data records and reporting. 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 data integrity deviations on the quality of your API. Your assessment should include analyses of the risks to patients caused by the release of drugs affected by a lapse of data integrity.
- A management strategy for your firm that includes the details of your global corrective action and preventive action 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 laboratory data and manufacturing records.
COMMENT:
Retrospective analyses were conducted on all product API that were reviewed during the FDA visit from 2015 forward. However, the Client did not test all distributed lots within expiry. In addition, the Client did not conduct a thorough review of all release records to determine whether the test results for other drug quality attributes were falsely reported.
- Failure of your quality unit to exercise its responsibility to ensure the API manufactured at your facility are in compliance with CGMP.
Your quality unit failed to perform a number of critical functions to ensure that the (b)(4) powder USP API was manufactured according to CGMP. For example, your quality unit failed to ensure that the records it reviewed included complete data derived from all tests conducted to ensure compliance with established specifications and standards prior to the distribution of an API batch. Your quality unit did not document details such as sample weight and preparation for tests such as (b)(4) content, (b)(4), (b)(4) or (b)(4) and (b)(4) content.
Your quality unit also failed to ensure that samples intended for stability studies are stored with controlled temperature and humidity. Your firm kept retain and stability samples of (b)(4) USP in a cabinet in the quality control laboratory without monitoring temperature and relative humidity.
In addition, your quality unit did not ensure the cleanliness of buildings and facilities used to manufacture API. You lacked sufficient controls to prevent the presence of pests in your packaging material storage area. At least twice, our inspector observed insects and spider webs in and on plastic-wrapped stacked containers used for packaging API.
Your quality unit also did not ensure that your cleaning validation records are accurate and contain appropriate documentation. For example, you did not document rinse times in your study to validate cleaning of the (b)(4) you use to manufacture API.
In your response, you stated that you would:
- update your documentation procedure to clarify the information that is to be recorded in laboratory notebooks;
- purchase a stability chamber and improve your stability program;
- clean and transfer packaging materials to a location in the warehouse where you prevent entry of pests, and train personnel on packaging material inspection requirements;
- repeat your cleaning validation with documented rinse times, and update corresponding cleaning procedures and checklists.
Your response did not provide sufficient detail or evidence that your proposed corrective actions and preventive actions (CAPA) will bring your operations into compliance with CGMP.
In response to this letter, provide the CAPA plans and procedures you have implemented to ensure that the roles and responsibilities of the quality unit are clearly defined and established. This should include but not be limited to assuring your quality assurance unit has the appropriate authority and resources needed to carry out its responsibilities.
Also provide:
- a revised documentation procedure that specifies the detailed information that must be recorded in laboratory notebooks;
- evidence to demonstrate that you have purchased and qualified a stability chamber, as well as your updated stability protocol;
- your procedures for appropriate storage and inspection of raw materials;
- the report that summarizes your new cleaning validation studies; and
- your revised cleaning procedures and checklists.
COMMENT:
The Client indicated to the FDA that they would provide a variety of materials in response to the Form FDA 483. However, it appears that the firm did not follow-up with periodic updates to the FDA as they anticipated. As a consequence, a Warning Letter was issued which requested that the Client provide the CAPA plans and procedures that they have implemented to ensure that the roles and responsibilities of the quality unit are clearly defined and established. This should include, but not be limited to, assuring your quality assurance unit has the appropriate authority and resources needed to carry out its responsibilities.
Also provide:
- a revised documentation procedure that specifies the detailed information that must be recorded in laboratory notebooks;
- evidence to demonstrate that you have purchased and qualified a stability chamber, as well as your updated stability protocol;
- your procedures for appropriate storage and inspection of raw materials;
- the report that summarizes your new cleaning validation studies; and your revised cleaning procedures and checklists.
Further, as noted in the four bullets, the FDA is requesting “proof” that a variety of activities were accomplished as promised.
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