| Public Health Service Food and Drug Administration |
San Francisco District |
Department of Health and Human ServicesWARNING LETTER
Via UPS
Delivery Signature Requested
May 31, 2011
Chungchiang Hsu, President and CEO
Impax Laboratories, Inc.
31153 San Antonio Street
Hayward, CA 94544
Ref: FEI 3004182921
Dear Mr. Hsu:
During our December 13, 2010 through January 21, 2011 inspection of your pharmaceutical manufacturing facility, Impax Laboratories, Inc., located at 31153 San Antonio Street, Hayward, CA, 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 CGMP violations cause your drug product(s) 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 reviewed your firm’s response dated February 11, 2011, and note it lacks sufficient corrective actions.
Specific violations observed during the inspection include, but are not limited, to the following:
1. Your firm has not established written procedures to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and drug product [21 C.F.R. § 211.110(a)]. For example:
a. Your firm failed to demonstrate that the manufacturing process for the Fenofibrate 200mg capsules is capable of controlling weight variations.
Between February and June 2010, your firm rejected validation lot T003011 and significant portions of validation lots T001006 and T002002 due to weight variability (low and high weight capsules). In June 2010, your firm also found weight variations in lot T006003. Lots T006002, T006003, and T006004 were manufactured under the same conditions as the rejected validation lot T003011. Portions of the identified lots were distributed although the process was not validated. Even though your firm has noted that micronized Fenofibrate powder sticking to the dosator pins during encapsulation may be a contributing factor, your firm has failed to identify a cause for these weight variations or to propose and implement corrective actions to address the discrepancies.
We acknowledge your voluntary recall of Fenofibrate capsules 200 mg, lots T0010061, T0020021, T0060021, T0060031 and T0060041, your commitment to revalidate the manufacturing process, and to continue your investigation into the capsule weight variations. However, your response is inadequate because it does not include details on what specific steps you are taking to conduct the investigation (e.g., whether your firm will perform a retrospective lot evaluation, the number of lots to be evaluated and the criteria for selection, or whether your firm will evaluate distributed lots).
b. Your firm does not have data to support the temperature range of (b)(4)°C used during the granulation process of Colestipol Hydrochloride 1g tablets (lots 601066, 601067, and 601068). During the validation studies for the granulation process, your firm established a temperature range of (b)(4)°C. Your process validation study does not provide any data to support the process range allowed in the Master Batch Records.
In your response, your firm states that you plan to evaluate all critical process parameters and that those results will be reviewed to determine final operating ranges. Your response, however, is inadequate in that it does not address: 1) specific details about your re-validation plans and in particular, whether you will determine the root cause to clearly demonstrate a full understanding of your products and processes before initiating the re-validations, and; 2) the controls involved with issuing, reviewing, and revising manufacturing batch records to ensure validation criteria are captured and accurate. In addition, your firm has not committed to review batch records of distributed lots of Colestipol HCl 1g tablets to ensure it was manufactured within the temperature range specified in the validation studies.
2. Your firm has not thoroughly investigated the failure of a batch or any of its components to meet its specifications, whether or not the batch has already been distributed, or extended investigations to other batches of drug product that may have been associated with the specific failure or discrepancy [21 C.F.R. § 211.192].
For example, our investigators identified up to 75% of the manufactured lots of various drug products having one or more metal-contaminated tablets. These drug products include, but are not limited, to: Oxymorphone Hydrochloride extended-release tablets 10mg; Midrodrine HCl 2.5mg tablets; Fenofibrate 160mg tablets; Pseudoephedrine Sulfate ER Core 60mg tablets; Colestipol HCl1 g tablets; Pilocarpine HCl 7.5mg tablets; Nadolol/Bendroflumethiazide 40/5mg tablets, and; Pyridostigmne Bromide 60mg tablets. Your investigations were inadequate in their scope because your firm failed to evaluate all possible sources of metal contamination (i.e., review of all components for metal content and equipment maintenance logs).
The corrective actions implemented after the April 2010 inspection, as result of the metal contamination, are ineffective as evidenced by the continuing issues observed during the most recent inspection. Your firm’s criteria of only investigating lots with over (b)(4) “second pass rejects” may limit your ability to determine the root cause during your investigations. In addition, the analysis during your review of “second pass rejects” only confirms metal contamination and leads to rejection of the product if metal is visible on the exterior of the tablet. Surface inspection by itself is not a satisfactory method to confirm or dismiss metal contamination because it limits your ability to determine a root cause.
Finally, please describe your decision making process for entire lot rejection when defects (e.g. contaminated tablets) are observed.
This is a repeat observation from the April 2010 inspection.
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. It is your responsibility to assure compliance with all requirements of federal law and FDA regulations.
You should take prompt action to correct the violations cited in this letter. Failure to promptly correct these violations may result in legal action without further notice including, without limitation, seizure and injunction. Other federal agencies may take this Warning Letter into account when considering the award of contracts. Additionally, FDA may withhold approval of requests for export certificates, or approval of pending drug applications listing your facility, until the above violations are corrected. FDA may re-inspect to verify corrective actions have been completed.
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 products, and provide the date(s) and reason(s) you ceased production.
Please send your reply to the attention:
Darlene Almogela
Director, Compliance Branch
U.S. Food and Drug Administration
San Francisco District
1431 Harbor Bay Parkway
Alameda, CA 94502
If you have any questions regarding any issue in this letter, please contact Carl Lee, Compliance Officer at 510-337-6737, or by fax at (510) 337-6703.
Sincerely,
/s/
Barbara Cassens
District Director
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