Inspections, Compliance, Enforcement, and Criminal Investigations
Tedec-Meiji Fanna, S.A. 4/24/12
Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
Silver Spring MD 20993
VIA UPS MAIL
April 24, 2012
Dr. Guillermo Tena Quintero
Tedec-Meiji Farma, S.A.
Caretera M-300, KM 30.500
Alcala De Henares, Spain
Dear Dr. Tena Quintero:
During our July 18, 2011, through July 22, 2011, inspection of your pharmaceutical manufacturing facility, Tedec-Meiji Farma, S.A. located at Caretera M-300, KM 30.500 Alcala De Henares, Spain, investigators from the Food and Drug Administration (FDA) identified significant violations of Current Good Manufacturing Practice (CGMP) regulations for Finished Pharmaceuticals, Title 21, Code of Federal Regulations, Parts 210, and 211. These violations cause your drug products to be adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. § 351(a)(2)(B)] in that the methods used in, or the facilities or controls used for, their manufacture, processing, packing, or holding do not conform to, or are not operated or administered in conformity with, CGMP.
We have reviewed your firm’s response of August 4, 2011, and note that it lacks sufficient corrective actions.
Specific violations observed during the inspection include, but are not limited, to the following:
1. Your firm has not thoroughly investigated the failure of a batch to meet its specifications whether or not the batch has already been distributed [21 C.F.R. § 211.192].
For example, your firm failed to conduct a timely, adequate out-of-specification (OOS) investigation into Lot # (b)(4) of (b)(4) tablets (b)(4) mg, which failed (test result (b)(4)% label claim) to meet the established specification for assay ((b)(4)% to (b)(4)% label claim) during stability testing at the 24 months stability station. You did not detect the out-of-specification result until approximately 28 days after your laboratory obtained the OOS result. Your firm then tested another sample four times and obtained the following results: (b)(4)%, (b)(4)%, (b)(4)%, and (b)(4)%. Your firm averaged these retest results to obtain a passing result of (b)(4)% label claim. Although you did not find a root cause, and you were unable to invalidate the initial OOS result, you concluded your investigation based on the fact that this was the expiration date stability station. Your firm did not extend your investigation to other batches that may have been associated with the specific failure, nor did you conduct a review of your production operations (review of incoming raw material variability, deviations or discrepancies in manufacturing records, etc.).
In your response, you stated that you revised your procedures. However, you failed to include your scientific rationale for invalidating the initial OOS result or identify the root cause of the OOS result. Your response should include a comprehensive review of the OOS investigations conducted by your firm to determine the adequacy of these investigations (e.g., evaluating the cause of the OOS result, corrective actions).1 Your response should also include an evaluation of retain samples for all product lots within expiry. Also include your plans if any retain sample does not meet specifications or is projected to fail before expiration. This should include the action to be taken for any such lot(s) distributed to the US.
2. Your firm has not established the reliability of the supplier’s analyses through appropriate validation of the supplier’s test results at appropriate intervals [21 C.F.R. § 211.84(d)(2)].
For example, your firm has not adequately qualified your drug component suppliers used in the manufacture of (b)(4) tablets ((b)(4) and (b)(4) mg). You failed to verify the accuracy of the certificate of analysis (COA) provided by the suppliers, conduct (b)(4) testing during qualification of drug component suppliers, and conduct validation of the (b)(4) test results at appropriate intervals.
Your response is inadequate in that you continue to rely on unqualified vendors. The data you used to conduct (b)(4) content of your drug products was based solely on unverified (b)(4) content provided by your vendors. As a drug product manufacturer, you must adequately qualify drug component suppliers (followed by periodic verifications at appropriate intervals) to be able to use their COAs in the manner described in your response to calculate (b)(4) content in your drug products.
3. Your firm has not established scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that drug products conform to appropriate standards of identity, strength, quality, and purity [21 C.F.R. § 211.160(b)].
Your firm failed to perform adequate calibration of the semiautomatic dissolution apparatus. Examples of the lack of mechanical calibration of the dissolution apparatus used to perform the dissolution assay for (b)(4) tablets ((b)(4) and (b)(4) mg) include the following:
A. Your firm failed to verify the distance between the inside bottom of the vessels and the bottom of the paddles.
B. Your firm failed to verify that the timing devices on the semi-automatic dissolution equipment are calibrated and performing as intended. Therefore, there is no assurance that your firm takes the aliquots at the required time during dissolution testing of samples.
C. Your firm failed to verify that the temperature probes on the dissolution equipment are calibrated and are performing as intended. Therefore, there is no assurance that your firm maintains the dissolution medium temperature within the required specification.
In addition, your firm failed to conduct the degasification of the dissolution medium. The degasification step is critical to control dissolved gases in the dissolution medium that affect the dissolution test results. Please provide your scientific rationale for not degassing.
We also note that your firm operates the semi-automatic dissolution apparatus using the governing procedure entitled “PI-A335210/0, ANALISIS DE (b)(4) mg COMPRlMIDOS DOSIFICADOS (b)(4).” This procedure does not include instructions on how to use the semi-automatic instrument.
In your response, you committed to revising the analysis sheets to include the instructions to degas the dissolution medium and verify the stir blade height in the dissolution vessels during the dissolution analysis. Your response is inadequate in that you provided no documentation to show how you have implemented your commitments and did not address the calibration of the temperature probes or the timing devices.
In addition, you failed to assess the impact that the above violation had on the quality of (b)(4) lots of (b)(4) mg tablets, (b)(4) lots of (b)(4) mg tablets, (b)(4) lots of (b)(4) mg tablets, and (b)(4) lots of (b)(4) mg tablets, all manufactured between 2008 and 2011 and distributed to the U.S. In response to this letter, please indicate the corrective actions that you have implemented to prevent recurrence of these violations and how you have ensured the quality of the released product.
The violations cited in this letter are not intended to be an all-inclusive statement of violations that exist at your facility. You are responsible for investigating and determining the causes of the violations identified above and for preventing their recurrence and the occurrence of other violations. If you wish to continue to ship your products to the United States, it is the responsibility of your firm to ensure compliance with all U.S. standards for CGMP and all applicable U.S. laws and regulations.
Until all corrections have been completed and FDA has confirmed corrections of the violations and your firm’s compliance with CGMP, FDA may withhold approval of any new applications or supplements listing your firm as a drug product manufacturer. In addition, failure to correct these violations may result in FDA refusing admission of articles manufactured at Tedec-Meiji Farma, S.A., Caretera M-300, KM 30.500, Alcala De Henares, Spain into the United States. The articles are subject to refusal of admission pursuant to section 801(a)(3) of the Act [21 U.S.C. § 381(a)(3)], in that the methods and controls used in their manufacture do not appear to conform to Current Good Manufacturing Practice within the meaning of section 501(a)(2)(B) of the Act [21 U.S.C. § 351(a)(2)(B)].
If, as a result of receiving this Warning Letter or in general, you are considering making a decision that will result in a decreased number of finished drug products or active pharmaceutical ingredients produced by your manufacturing facility, FDA requests that you contact CDER’s Drug Shortages Program immediately, as you begin your internal discussions, at email@example.com in order to ensure that your action(s) does not adversely affect the public health.
Within fifteen working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to correct violations. Include an explanation of each step being taken to prevent the recurrence of violations and copies of supporting documentation. If you cannot complete corrective action within fifteen working days, state the reason for the delay and the date by which you will have completed the correction. Additionally, your response should state if you no longer manufacture or distribute (b)(4) mg tablets, (b)(4) mg tablets, or (b)(4) mg tablets, and provide the date(s) and reason(s) you ceased production. Please identify your response with FEI # 3003184440.
If you have questions or concerns regarding this letter, contact Joseph Duran, Compliance Officer, at the below address and telephone number.
U.S. Food and Drug Administration
Center for Drug Evaluation and Research
Office of Manufacturing and Product Quality
Division of International Drug Quality
White Oak, Building 51
10903 New Hampshire Ave
Silver Spring, MD 20993
Tel: (301) 796-0491
Fax: (301) 847-8741
Office of Manufacturing and Product Quality
Office of Compliance
Center for Drug Evaluation and Research
1 We recommend you review the FDA guidance for industry entitled, "Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production," for some basic principles regarding conduct of OOS investigations.