BR SAS MARCS-CMS 542617 —
Recipient NameMr. Pierre-Louis Delapalme
- BR SAS
28 rue de la Procession
- Issuing Office:
- Center for Drug Evaluation and Research
10903 New Hampshire Avenue
Silver Spring, MD 20993
Via UPS Warning Letter 320-18-57
Return Receipt Requested
June 8, 2018
Mr. Pierre-Louis Delapalme
Biologique Recherche (B.R.) SAS
28 rue de la Procession
Dear Mr. Delapalme:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Biologique Recherche (B.R.) SAS at 28 rue de la Procession, Suresnes, from September 18 to 22, 2017.
This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. See 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).
We reviewed your October 13, 2017, response in detail. Your response did not provide adequate corrective actions for any of the observations made during the inspection.
During our inspection, our investigator observed specific violations including, but not limited to, the following.
1. Your firm failed to have, for each batch of drug product, appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release (21 CFR 211.165(a)).
Your firm released your over-the-counter (OTC) drug product, (b)(4), without adequate testing for the identity and strength of the active ingredients, (b)(4) and (b)(4). Without this testing you cannot determine if your drug products conform to specifications.
Your response stated that you will test future batches for active ingredients. Your response is inadequate. You have not provided sufficient information regarding testing of future batches, including whether you will use a third party. You also failed to conduct a retrospective assessment of your OTC drug products that lack identity, strength, and other appropriate quality attribute tests for batches that may currently be in U.S. distribution.
In response to this letter, provide:
- all chemical and microbial test methods and specifications used to analyze each of your OTC drug products prior to a batch disposition decision;
- remediated microbiological testing methods (i.e., total counts and objectionable microbes) that conform to USP and . These methods should be capable of identifying all microorganisms in product bioburden to determine whether any are objectionable in view of the product’s intended use.62>61>
- a summary of test results obtained from testing retain samples of all OTC drug products within expiry that have been distributed in the United States. These test results should include identity and strength of active ingredients, and all other appropriate quality attributes.
2. Your firm failed to conduct at least one test to verify the identity of each component of a drug product. Your firm also failed to establish the reliability of component supplier analyses on which you rely in lieu of certain tests through appropriate validation of the supplier’s test results at appropriate intervals (21 CFR 211.84(d)(1) and (2)).
Your firm failed to test incoming raw materials, including (b)(4), for their identity, purity, strength, and other appropriate quality attributes. Instead, your firm relied on certificates of analysis (COA) from unqualified suppliers. (b)(4) contains the active ingredient (b)(4) which you use in your OTC drug products.
Your response states, “Raw materials in stock will be sampled for analysis and will be sent for characterization before October 27.” Your response is inadequate. You have not provided sufficient information regarding testing of these raw materials, including whether you will use a third party for testing.
In response to this letter, provide:
- quality control release specifications for all incoming components, and the tests you perform for each lot;
- a summary of test results obtained from full testing of all your incoming components to validate the COA from each raw material manufacturer;
- a summary of your procedures for qualifying and overseeing the adequacy of contract facilities that test the OTC drug products you manufacture;
- a comprehensive, independent review of your material system to determine whether all containers, closures, and ingredients from each supplier are adequately qualified, assigned appropriate expiration or retest dates, and incoming material lot controls are adequate to prevent use of unsuitable containers, closures, and components.
3. Your firm failed to establish written responsibilities and procedures applicable to the quality control unit (21 CFR 211.22(d)).
Your firm failed to establish written procedures for numerous functions of the quality unit. For example, there were no procedures for the following manufacturing operations:
- investigating deviations;
- conducting annual product quality reviews;
- investigating out-of-specification results;
- handling product returns;
- reprocessing and reworking;
- reconciling labels;
- creating batch records and issuing master batch records; and
- approving batch records and releasing batches.
Your response stated, “A procedure describing the responsibilities of the quality service will be drafted by the end of November.” Your response is inadequate. You failed to describe how this procedure will ensure that your firm will establish and maintain a robust quality system.
In response to this letter, provide a comprehensive assessment and a corrective action and preventive action (CAPA) plan to ensure that you establish an effective quality unit with appropriate authority, responsibilities and resources. Your response should also include a detailed procedure describing your remediated quality unit’s responsibilities.
4. Your firm failed to establish and follow an adequate written testing program designed to assess the stability characteristics of drug products and to use results of such stability testing to determine appropriate storage conditions and expiration dates (21 CFR 211.166(a)).
You did not have adequate stability data to demonstrate that the chemical and microbiological properties of your drug products remain acceptable throughout their labeled expiry period. For example, your firm performed an accelerated stability study on (b)(4) lot ((b)(4)) but did not test for assay or impurities during this study.
Your response stated you would undertake “to restart stability tests.” Your response is inadequate. You have not provided details regarding your stability testing program, including which tests you will perform, whether you will use a third party for testing, and where products will be stored during testing.
In response to this letter, provide your standard operating procedure (SOP) describing your firm’s ongoing stability program. Also, provide stability data demonstrating that each OTC drug product distributed by your firm to the United States meets all specifications throughout its expiry.
5. Your firm failed to establish adequate written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess (21 CFR 211.100(a)).
You have not validated the processes you use to manufacture your drug products. For example, you did not conduct process performance qualification studies, and you lack an ongoing program for monitoring process control to ensure stable manufacturing operations and consistent drug quality. See FDA’s guidance document, Process Validation: General Principles and Practices, for general principles and elements of process validation at http://www.fda.gov/downloads/Drugs/.../Guidances/UCM070336.pdf.
In your response, you provided a timetable for the (b)(4) system qualification, and cleaning and manufacturing validation processes. Your response is inadequate. You did not provide sufficient details describing your qualification and validation program.
In response to this letter, provide the protocols for your validation and qualification activities. Also, describe how you will monitor sources of variability in your operation throughout the drug lifecycle to minimize batch variation and assure consistent product quality.
Your response also failed to evaluate the impact of manufacturing your products using unvalidated processes and procedures.
In your response to this letter, conduct an assessment into distributed batches of your OTC drug products. Provide your plans for addressing product quality and patient safety risks for any OTC drugs still in distribution, including customer notifications or market withdrawals.
Quality Unit Authority
Significant findings in this letter indicate that your quality unit is not able to fully exercise its authority and responsibilities. Your firm must provide the quality unit with the appropriate authority and sufficient resources to carry out its responsibilities and consistently ensure drug quality.
CGMP consultant recommended
Based upon the nature of the violations 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. We also recommend that the qualified third party perform a comprehensive audit of your entire operation for CGMP compliance, including the quality assurance system, materials system, facility and equipment system, laboratory system, production system, and packaging and labeling system. Your CAPA should then be evaluated by the third party to help ensure systemic remediation before you pursue resolution of your firm’s compliance status.
Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for fully resolving all deficiencies and ensuring ongoing CGMP compliance.
Violations cited in this letter are not intended as an all-inclusive list. You are responsible for investigating these violations, for determining the causes, for preventing their recurrence, and for preventing other violations.
FDA placed your firm on Import Alert 66-40 on January 17, 2018.
Until you correct all violations completely and we confirm your compliance with CGMP, FDA may withhold approval of any new applications or supplements listing your firm as a drug manufacturer.
Failure to correct these violations may also result in FDA continuing to refuse admission of articles manufactured at Biologique Recherche (BR SAS) at 28 rue de la Procession, Suresnes, into the United States under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Under the same authority, articles 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.
Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.gov or mail your reply to:
U.S. Food and Drug Administration
White Oak Building 51, Room 4359
10903 New Hampshire Avenue
Silver Spring, MD 20993
Please identify your response with FEI 1000373305.
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research