| Public Health Service Food and Drug Administration |
Silver Spring MD 20993 |
Department of Health and Human ServicesWarning Letter
VIA UPS MAIL
WL: 320-11-012
May 5, 2011
Dr. C. Joseph Kurian
President
Alpha Laboratories, Inc.
1262 Don Mills Road
Toronto, ON
Canada, M3B 2W7
Dear Dr. Kurian:
During our October 25-27, 2010 inspection of your contract testing laboratory facility, Alpha Laboratories, Inc. located at 1262 Don Mills Road, Toronto, Ontario, Canada, an investigator 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 as they apply to your contract testing laboratory facility. These violations cause drug product components tested by your facility 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 November 16, 2010, 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 or any of its components to meet its specifications whether or not the batch has already been distributed [21 C.F.R. § 211.192].
For example, (b)(4) samples and (b)(4) and (b)(4) failed to meet the assay specifications. However, no investigation was conducted. The inspection also found that your analyst did not record these out-of specification results in the OOS logbook as required by your SOP.
The inspection also documented that your Quality Control Unit reviews and approves Certificate of Analysis containing OOS results, but without conducting any investigation.
Your response states that a plan to investigate all OOS results, obtained as of November 1, 2010, has been implemented. However, there is no commitment to conduct a retrospective review of all lots tested and found OOS. Please provide a list of all OOS results obtained during the last 3 years. Include the name of the raw material or finished product, the lot number, date tested, and customer. Please indicate if all your customers were notified of these failures and date of notification.
Please include in your response the specific corrective actions taken to improve your program for handling OOS results, including ensuring that both analysts and management are properly trained on how to document and conduct investigations.
2. Your quality control laboratory has not followed written procedures for testing and laboratory controls designed to assure that the drug products you tested have the identity, strength, quality, and purity they purport or are represented to possess [21 C.F.R. § 211.160(a)(b)(3)(4)].
For example,
a. The inspection revealed that your procedure for Out-Of-specification Results (SOP-GEN-0008 Rev 4) is not followed.
The OOS procedure requires that as part of Phase (b)(4) a re-test be performed if no assignable cause has been found. The inspection found that no re-test was performed for OOS samples #542, #545, #546, #521. Your firm failed to document the reason(s) for not conducting a Phase (b)(4) investigation for an OOS results and for not documenting that your clients were notified as in your procedure.
b. The calibration program, under SOP-CAL-0000, requires that each instrument must have a written calibration procedure. The inspection found that there is no procedure approved for the calibration of the Fluorimeter used to test your raw material.
c. Your firm’s procedure SOP-GEN-0002 Rev.04, "Raw Data," requires that all raw data be permanently and legibly recorded in the laboratory notebooks.
The inspection found discrepancies regarding the (b)(4) assay data in the Atomic Absorption (AA) printout for samples (b)(4) and (b)(4) with the data recorded in the certificate of analysis (COA). Discrepancies in the absorbance values were noted. The printout for lot (b)(4) had an absorbance value of (b)(4) (original) and a (b)(4) (original) absorbance value was obtained for lot (b)(4). However, the COA included absorbance values of (b)(4) (re-test) for lot (b)(4) and (b)(4) (re-test) for lot (b)(4).
We are concerned with your firm’s response in that lacks the specific corrective actions that will be implemented to ensure that the established procedures are properly followed.
d. Your firm’s procedure, SOP-GEN-0029 Rev.1, "Master Validation Plan," requires that all instruments, whether newly purchased or already in use, be qualified prior to being release for general use.
The inspection found that your Fluorometer and Atomic Absorption have not been qualified. Your firm’s response lacks the specific corrective actions you plan to implement to ensure that Master Validation Plan is followed. In your response please provide the evaluation conducted to assure the validity of all results generated by the non-qualified Fluorometer and Atomic Absorption equipment.
We are concerned that the failure to follow established procedures is a repeat violation, also cited during the 2007 inspection.
Please note that as a contract testing laboratory, it is your responsibility to ensure the integrity of the data generated and that all test results be properly documented, maintained and reported.
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 test pharmaceutical components or drug products intended for distribution in 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 contract testing laboratory. In addition, failure to correct these violations may result in FDA refusing admission of articles tested at Alpha Laboratories, Inc., 1262 Don Mills Road, Toronto, Ontario, Canada, 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)].
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. Please identify your response with FEI # 3004058334.
If you have questions or concerns regarding this letter, contact Cesar E. Matto, Compliance Officer, at the below address and telephone number.
U.S. Food and Drug Administration
Center for Drug Evaluation and Research
Division of Manufacturing and Product Quality
International Compliance Branch
White Oak, Building 51
10903 New Hampshire Ave
Silver Spring, MD 20993
Tel: (301) 796-5339
Fax: (301) 847-8741
Sincerely,
/Carmelo Rosa/
Carmelo Rosa On Behalf of Richard L. Friedman
Director
Division of Manufacturing and Product Quality
Office of Compliance
Center for Drug Evaluation and Research
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