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Pre-approval cGMP inspection of API manufacturing facility. Observations include an employee cleaning equipment in a controlled area while wearing a band-aid and no other hand covering. Document contains the firm’s well-written, point-by-point response to the 483.
For cause inspection initiated as a cGMP inspection covering all products made at this facility. The firm’s compliance status was OAI (Official Action Indicated) following an inspection the previous year. This 2003 follow-up inspection found significant data integrity problems, as well as several cGMP deficiencies. A separate section of the EIR was dedicated to the data integrity concerns, which left the investigators with the feeling that they “did not have confidence in the integrity of any of the data” they were examining. It is noted that evidence of deliberate data misrepresentation was found. The EIR also noted that a plant manager apologized for management “not having been truthful”. A copy of the company’s response to the 483 (which denies any deliberate wrongdoing) is included, along with the Warning Letter and subsequent correspondence.
Pre-approval inspection was prompted by an unspecified NDA and an unspecified ANDA. The 483 lists 21 deficiencies, including an observation that none of the manufacturing equipment had been qualified. Also included in the file are the firm’s response to the 483 and a Warning Letter issued after receipt of the 483 response to the FDA.
Inspection of Active Pharmaceutical Ingredient (API) manufacturer assigned under Compliance Programs 7352.832 and 7356.002F. This inspection resulted in a recommendation for an unacceptable classification for the facility. Twelve deficiencies were noted regarding validation, instrument calibration, and impurity profile data as well as other areas. The firm’s response is included.
Inspection of medical device manufacturer which covered the firm’s MDR practices, Management Controls, Design Controls, CAPA, and Production and Process Controls. Observations included a lack of documentation for disposition of nonconforming or returned product and a lack of written procedures for reporting MDRs to FDA.
Initial inspection of Active Pharmaceutical Ingredient (API) manufacturer, which served as a pre-approval inspection for an unspecified ANDA product. The firm was deemed acceptable to manufacture, but notable deficiencies regarding documentation and SOPs were cited. In particular, the SOP for an unidentified system is said to have given no guidance as to “what should be done when any of the parameters used to monitor the system is out of specification”.
This was a follow-up inspection due to the firm being under an import alert for human and veterinary products. The import alert had been prompted after a 1999 inspection raised concerns involving data integrity and significant cGMP deficiencies. Following the 1999 inspection, the firm underwent ownership and management changes and improved the manufacturing system. Based on the previous inspection, much of this 2002 inspection focused on the impurity profile for gentamicin sulfate. Though only relatively minor observations were noted on the 483, and none regarding gentamicin sulfate, the investigators remained concerned “regarding the ability of the firm’s method to achieve adequate resolution and quantitation of certain impurities”. As noted in subsequent correspondence, the firm was recommended as acceptable for manufacture of APIs with the exception of gentamicin sulfate. Leshan Saniju-Long March’s response to the 483 is included.
Here’s an example of an inspection that went well. This was a GMP Qualifying Inspection done in accordance with CP 7356.002F. Though four observations were noted, the firm’s corrections were already noted on the 483 when it was prepared.
Pre-approval and cGMP inspection of Active Pharmaceutical Ingredient (API) manufacturer. Two significant observations regarding documentation and incomplete laboratory records were noted, and two non-483 findings were also discussed with management. Following the inspection and the firm’s response to the 483, FDA emphasized that the firms’ corrective actions would be further evaluated at the next inspection.
Follow-up compliance inspection following February 2000 Warning Letter and Import Alert that resulted from a prior inspection. This current inspection resulted in recommendations for a continued Import Alert and an Untitled Letter. Significant findings involving incomplete process validation were noted and previous objectionable conditions were found not to have been corrected sufficiently. One example is the firm’s investigation into previously returned lots, which were returned due to metallic particles. Investigators found that no attempt had been made to ensure prevention of future occurrences. File includes Tianjin Xin Xin’s response to the 483, a subsequent, seven-page December 2000 Warning Letter, firm’s response to the Warning Letter, and, finally, FDA’s response which reflects a still-incomplete satisfaction with the firm’s processes.
Compliance follow-up inspection following a June 2000 Warning Letter. Jiangsu Heingrui’s response to the previous 483 and Warning Letter were deemed “deficient”. At the conclusion of this September 2000 inspection, the firm was still listed as unacceptable for manufacturing APIs. The 21 observations on the 483 include inconsistent impurity analysis, no annual review of records or quality investigations, inadequate process validation and inadequate analytical methods validation. During discussion between management and the investigators, the QC Director admits that “there is no mechanism for quality to be notified or a controlled system for investigations”. A November 2000 Warning Letter was issued after receipt of the firm’s 483 response, requesting an Import Alert. This file includes the 483 response, the November Warning Letter, and the firm’s response to the Warning Letter.
Inspection of API manufacturer for pharmaceutical and veterinary products conducted in accordance with CP 68001 and CP56002F. The investigators compliment the firm’s preparation for the inspection, but do note 9 deficiencies regarding degradation studies, product annual review, and integrity testing, among other areas.
Surveillance GMP inspection. This was the initial inspection of this API manufacturer and revealed that the firm was operating with no process validation, no documentation of investigations into out-of-specification results, no impurity profile, and deficient analytical methods, among other issues. The 483 lists 11 observations. Upon finding the firm’s 483 response inadequate, FDA issued a Warning Letter in December 2000. Both follow-up documents are included in this file.
Pre-approval and cGMP inspection of a firm with a history of significant deficiencies and warning letters. This inspection was a follow-up to a 2000 inspection and Warning Letter. The EIR details the current inspection and findings, as well as a good deal of the previous observations and corrections. Investigators found that most of the 2000 deficiencies had been corrected, and noted the firm’s positive attitude toward compliance, but cited continuing problems with inadequate test methods. No Warning Letter was issued and the firm was declared acceptable for manufacture of the relevant APIs.
Pre-approval inspection of this large Active Pharmaceutical Ingredients (APIs) and finished product manufacturer, for an unspecified ANDA. Twelve cGMP deviations were noted on the 483, including problems with change control procedures, incomplete batch record entries, and incomplete process validation reports. FDA deemed the firm’s corrective actions to be adequate following receipt of their 483 response (also included).
Pre-approval inspection for Gentamicin sulfate; also served as a cGMP inspection. The firm is a government-owned facility. Observations include incomplete and inadequate raw data worksheets and problems with temperature and humidity control. It is noted in the EIR that the temperature in the long-term stability chamber room was out-of-specification for a month without any action being taken. The firm’s 483 response is included.
Pre-approval inspection for an unspecified ANDA, as well as a Bulk Pharmaceutical Chemicals Drug Process Inspection. Observations included problems with instrument calibration, an incomplete Drug Master File (DMF), inadequate written records, and problems with raw data and batch records. The firm was using calibration standards from the Chinese Instruments Calibration Agency.
This cGMP inspection was the third consecutive inspection of the firm which resulted in observation of numerous significant deficiencies. Brief discussion regarding the previous inspections is included. The remainder of the lengthy EIR details the current observations. The 5-page 483 lists 16 observations which include significant concerns over batch records, lack of product-specific information in process validation reports, and deficiencies regarding process control. Regarding batch records, it is noted in the EIR that the observation “brings into question the validity of data reported in any executed batch record” reviewed during the inspection. Following receipt of the firm’s 483 response (included), FDA requested further clarification on several points (this correspondence is also included).
While the EIR is not immediately available from this inspection that has generated an enormous amount of publicity, this document contains the 483 as well as the subsequent April 2008 Warning Letter issued to Changzhou SPL. Baxter Healthcare’s recall of injectable heparin made headlines in 2008. Production of the product was temporarily stopped and, until March 2009, monthly reports on the results from screenings tests on the active ingredient were required to be submitted to FDA. Changzhou SPL was the manufacturer of the Active Pharmaceutical Ingredient for Baxter’s version of Heparin Sodium and, as such, was inspected as part of FDA’s investigation into the Heparin concerns. The 483 lists 11 observations which include the lack of an impurity profile, incomplete manufacturing instructions, and inadequate investigation into failed lots, among others. The April 2008 Warning Letter was issued following FDA’s receipt of two Changzhou responses to the 483, both of which were deemed inadequate. The Warning Letter discusses continued concerns regarding assurance of impurity removal, inadequate evaluation of suppliers, unverified test methods, and unsuitable equipment.
Here is the Memoranda of Understanding (MOU) between U.S. and China outlining the agreement on cooperation with regard to monitoring and regulating the safety of drugs and medical devices. The agreement focuses on prevention and control of counterfeit products. A Work Plan is discussed which would identify products at risk for counterfeiting, require a chain-of-custody system ("pedigree") for the identified products, emphasize information sharing, and develop activities to encourage regulatory cooperation.
Pre-approval inspection for an unspecified Active Pharmaceutical Ingredient for an injectable drug product. cGMP deviations involving batch production records, inventory control, and standard operating procedures. The well-received company response to the 483 is also included in the file.