| Public Health Service Food and Drug Administration |
| Silver Spring MD 20993 |
Department of Health and Human ServicesWarning Letter
VIA UPS MAIL
WL: 320-10-10
September 30, 2010
Mr. Vyangesh Choksi, Director
Choksi Laboratories, Ltd.
6/3 Manoramaganj
Indore 452001 (MP)
India
Dear Mr. Choksi:
During our April 21-24, 2010 inspection of your contract testing laboratory facility, Choksi Laboratories, Ltd., located at Plot 362, Industrial Area Phase II, Panchkula, Haryana, India, 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, 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 note that you did not provide a written response to the Form FDA-483, Inspectional Observations.
Specific violations observed during the inspection include, but are not limited, to the following:
1. Your firm has not established scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that tested products conform to appropriate standards of identity, strength, quality, and purity [21 C.F.R. § 211.160(b)].
For example,
a) The gas chromatographic analysis performed and the data provided to the application sponsor is not traceable to raw data. The original chromatograms could not be located during the inspection.
b) In-house laboratory procedures for various laboratory tests were either non-existent or inadequate. For example, the entire GC and HPLC test procedures address only a few precautions to be taken in running the instruments. Routine practice consisted of performing test procedures provided by customers, and then destroying these procedures as soon as the analyses were completed.
c) Your firm's standard operating procedure #CLL-PKL-SOP-10, “Maintenance of Integrity of Sample,” is inadequate in that it does not assure complete integrity of documentation related to sample analysis. It specifies the assignment of a “booking number” to each sample, but no further procedures regarding subsequent documentation are included. Certain elements of sample integrity are addressed in other SOPs, but none of the procedures explicitly call for maintaining sample integrity throughout the testing of the sample.
d) Performance of test methods such as loss on drying, residue on ignition, and sulfated ash is not adequately documented. Certain steps such as time in and time out of the oven are not recorded, and the laboratory record does not provide a format for recording such data.
e) Method verifications for compendial tests are not performed. Any method, including compendial methods, must be verified as suitable under actual conditions of use. This has not been done for any method provided by your clients.
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 [21 C.F.R. § 211.192].
For example,
a) Your firm's out-of-specification (OOS) procedure #CLL-PKL-SOP-01, Ver. #3 is inadequate in that the procedure for invalidation of an OOS result is inappropriate. The procedure does not specify re-analysis of the original sample solution or stock solution before re-sampling of a new portion of the original sample, or using a fresh sample obtained from a client. Additionally, the procedure specifies invalidation of an OOS result if the results of (b)(4) subsequent analyses of a new sample portion or of a fresh sample from the client are within specifications.
b) Documentation is not maintained for every OOS event. Your firm only conducts OOS investigations when the client provides additional payment for such an investigation.
3. Your quality control unit has not approved or rejected all procedures or specifications impacting the identity, strength, quality, and purity of the drug product; all procedures applicable to the quality control unit are not in writing, and all procedures are not followed [21 C.F.R. § 211.22].
For example,
a) SOP revisions are not performed and documented appropriately. For example, for SOP #CLL-PKL-SOP-01, the recorded history shows that version 02 was issued on March 10, 2009, version 03 on April 2, 2009, and version 02 again on March 14, 2009.
b) Records are issued from the record storage room without any written checkout procedures, and instead upon verbal direction by the QA manager.
c) The document control SOP lists “quality manager” and “technical manager” under“Responsibility” for document control, but does not clarify the individual roles of each.
4. Your firm has not established procedures for investigation of complaints, and for initiation of corrective and preventive actions based on results of such investigations [21 C.F.R. § 211.198].
For example,
a) Five complaints received in 2009 were related to the reporting of incorrect batch numbers. Root cause was attributed to unintelligible handwriting, but no preventive actions were taken.
b) Five complaints received in 2008 were based on incorrect or missing information on the customer analysis reports, but no corrective or preventive actions were taken.
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, this office will recommend withholding approval of any new applications or supplements listing your firm as a contract testing laboratory.
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 these violations. Include an explanation of each step being taken to prevent the recurrence of violations and copies of supporting documentation. If you cannot complete a 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 # 3008299032.
If you have questions or concerns regarding this letter, contact Thomas Savage, 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) 796-3193
Fax: (301) 847-8741
Sincerely,
/s/
/Richard L. Friedman/
Richard L. Friedman
Director
Division of Manufacturing and Product Quality
Office of Compliance
Center for Drug Evaluation and Research
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