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This inspection of an API manufacturer was initiated in response to an assignment from HFD-322, Foreign Inspection Team, requesting a compliance follow-up at this firm. It revealed significant GMP deficiencies, including: inadequate laboratory instrument calibrations, inadequate systems review and management of laboratory data, and uninvestigated “unacceptable” calibration results.
Inspection of this Active Pharmaceutical Ingredient (API) manufacturer was conducted as per an HFD-324 assignment to cover the drugs Cefaclor and Cephalexin. A separate limited assignment was also issued by HFD-322, which requested an examination of the firm’s equipment for components containing lead. The inspection found a number of deficiencies cited on a 16-observation 483, including: objectionable conditions with regard to the lack of product specific protocols for working standards qualification, lack of a written protocol for acceptance and rejection of raw data, and the Quality Control Laboratory’s failure to establish system suitability "which gives no assurance that results obtained are even accurate".
Inspection of this Active Pharmaceutical Ingredient (API) manufacturer was initiated by HFD-322 to cover the drug substance Amoxicillin and another unspecified drug product. Subsequently, an October 1997 inspection covered several APIs including Ranitidine HCl, Docycycline Hyclate, and Cephalexin Monohydrate; a 483 was issued. The inspection found a number of deficiencies cited on a 9-observation 483, including: failure to include in-process testing to insure completion of a critical Amoxicillin processing step, failure to conduct documented periodic checks throughout several critical steps, and failure to quantitatively measure an intermediate in the process where the firm had set a specific limit as being critical.
This inspection revealed numerous deficiencies in laboratory protocol, process validation, and sterility testing. Validations of sterility test methods were not performed with all USP required microorganisms, which when done correctly, “demonstrates the ability of the test system to support the growth of a variety of different microorganism types”. Laboratory controls for sterility test analysts were not established to assure that drug products conformed to appropriate standards of purity during testing. Microbial contamination prevention procedures were deficient. Environmental monitoring samples were not collected on January 27, 2004 when a maintenance staff worker entered, then exited, the sterile area. There was no approved protocol for mapping studies conducted for the stability storage chamber. The temperature of the storage chamber was observed to be “out of specification” but there was no record of this failure in the log book, and no follow-up testing was performed. Several process study reports were approved using outdated and irrelevant data. The inspection of the firm resulted in a warning letter, in which FDA concluded that several drug products were adulterated.
This inspection revealed significant GMP deficiencies, many cited on the lengthy 483 and discussed with management. The firm was cited for shipping products to the US market for an entire year prior to the initiation of process validation. The FDA investigator explained to the firm that it is “unacceptable to ship product to the US that has not been manufactured under current GMPs, which includes validation”. Most documentation related to processing and/or manufacturing operations was not prepared, and when available it was deficient. Review of test results revealed that on several occasions samples during product changeovers were either not collected or not tested as specified in the firm’s SOP. The firm was also cited for the lack of impurity testing for several batches of finished APIs. The inspection resulted in the issuance of a 26-observation 483 and the deviations cited caused the APIs to be considered adulterated.
This inspection of an API manufacturer was initiated in response to an assignment from HFD-322 and was conducted under active pharmaceutical guidelines. The inspection revealed significant GMP deficiencies, including: quality systems failed to detect calculation errors that negatively affect validation data; recovered solvents not fully evaluated for purity/impurities, and inadequate laboratory instrument calibrations.
Inspection of this manufacturer of sterile & non-sterile Active Pharmaceutical Ingredients (APIs) was initiated by HFD-324. The inspection found a number of deficiencies, including lack of SOPs to require investigation of failing test results, analysts conducting testing did not wear gloves, and lack of documentation for the preparation of standard solutions for testing.
This inspection of an API manufacturer was initiated in response to an assignment request from HFD-323 and was conducted under CP 7356.002F. The inspection revealed several deficiencies, including omission of stability study failures from the firm’s most recent response to a deficiency letter, no documentation that calculations have been reviewed/verified by a second person, and studies have not been done for swab samples taken during cleaning validation.
Inspection of this manufacturer of non-sterile APIs was conducted on request from HFD-324 and covered Famotidine, Ranitidine HCL; and an unspecified API. The investigator found a number of deficiencies, which were cited on a six-observation 483. The list of deficiencies included: failure to conduct out of specification investigations for failing test results for numerous batches of raw material, failure to investigate numerous borderline and “out of trend” results for another test conducted on the same raw material, the SOP for supplier qualification allows for a "failure ratio of nearly 50% of raw material as acceptable".
This inspection of a pharmaceutical manufacturer was conducted under CP 7356.002 (Drug Process Inspections) and 7352.832 (Pre-Approval Inspections). The inspection revealed several GMP deficiencies, including inadequate cleaning validation studies, failure to perform an investigation into a problem identified during the manufacture of Ranitidine tablets, and no systematic employee training program.
This inspection of an API manufacturer was initiated in response to an assignment from HFD-322 to conduct a Pre-Approval and an API Inspection. The inspection of the firm found minor deviations in laboratory operations. Deviations included lack of adequate system suitability for related substances and assays, and lack of a timely review of laboratory records. The firm corrected all deviations prior to conclusion of the inspection.
This GMP Qualifying Inspection was done in response to a September 2001 request from CDER after the filing of an ANDA by an unspecified drug company for ophthalmic solution for glaucoma to eventually be manufactured in the USA. Although it will not be sold in the USA until the patent term expires, there are plans for the product to be marketed in four countries where this patent is not recognized. At the conclusion of the inspection a 483 was issued, which cited failure to perform installation qualification and operational qualification, and system suitability test and reference standard procedures were not addressed on SOPs.
This was the initial GMP inspection of an intermediates and API manufacturer. The inspection was prompted to cover the synthesis of the API in conjunction with the review of an unspecified new ANDA. The inspection revealed a number of GMP deviations, including inadequate control of raw material, in-process and finished product identification, inadequate protection of bulk liquid unloading lines, and errors in calibration in two different production buildings.
This inspection was conducted as the pre-approval of several ANDA products manufactured at this facility. The inspection of the firm found several GMP deviations which resulted in the issuance of a 483, which cited such deviations as potential for cross-contamination of penicillin, amoxicillin and cephalosporins with other products manufactured at the site. Additionally, the annual product reviews did not cover non-US distributed product and the firm had a “skip testing” standard operating procedure (SOP) judged to be inadequate for the circumstances. Finally, there was no scientific rationale recorded for the frequency of calibration of certain equipment.
Inspection was conducted for the pre-approval of an unspecified ANDA product. October 2001 inspection of the firm was classified as NAI (no action indicated); this 2003 follow-up inspection found the firm to have no major cGMP deviations. However, Inspectional Observations were issued and the firm was classified as VAI (voluntary action indicated). The observations pertained to distribution of active pharmaceutical ingredients, computer audit trails for Active Pharmaceutical Ingredient quality assurance instrument calibration, and process validation issues.
The inspection of this API manufacturer was performed at the request of HFD-322 in response to an abbreviated new drug application filed with FDA. Dr. Reddy’s supplies the API for the application holder and has filed the Drug Master File (DMF) for disclosure to FDA. The firm was inspected in 1999 in relation to another pre-approval inspection of an unspecified drug product when no objectionable conditions were observed and the firm was operating in compliance with cGMP. This follow-up inspection, however, found several deviations from GMP guidelines, including lack of adequate investigation procedures to handle deviations and “abnormal events,” failure to appropriately evaluate anomalies and develop the necessary corrective actions, and inadequate data evaluation for batches subject to additional reprocessing steps.
The inspection of this manufacturer of solid oral finished drug products was initiated by HFD-332 to cover Ciprofloxacin Tablets). A 1997 inspection covered Ranitidine HCL Tablets; this October 2000 follow-up found a number of deficiencies serious enough to be cited on a 483. Observations included failure to provide documented training of personnel involved in analytical method transfer, failure to conduct method validation prior to initiation of release and sample stability testing, and acceptance of validation data despite inconsistent response data.
This inspection was conducted for the pre-approval of an unspecified ANDA product. The investigator found several cGMP deficiencies and cited that process validation did not address the elimination of impurities from the finished bulk drug product, as well as a lack of identification testing of raw materials.
This was a GMP inspection of an API manufacturer, conducted in accordance with current bulk drug and Active Pharmaceutical Ingredient guidelines. The inspection revealed major deficiencies in nearly every area examined, including: questionable and missing laboratory data, failure to follow Laboratory SOPs, and pervasive maintenance and equipment deficiencies in both laboratory and production areas.