Warning Letter: Audit trail functionality enabled the day before inspection (ucm554576)

Our investigators observed that the software you use to conduct high performance liquid chromatography (HPLC) analyses of API for unknown impurities is configured to permit extensive use of the “inhibit integration” function without scientific justification.  For example, our investigator reviewed the integration parameters you used for HPLC identification of impurities in release testing for [redacted].  These parameters demonstrated that your software was set to inhibit peak integration at four different time periods throughout the analysis.  Similarly, in the impurities release testing you performed for [redacted], your HPLC parameters were set to inhibit integration at four different time periods throughout the analysis.

Inhibiting integration at various points during release testing for commercial batches is not scientifically justified.  It can mask identification and quantitation of impurities in your API, which may result in releasing API that do not conform to specifications.

2. Failure to prevent unauthorized access or changes to data and failure to provide adequate controls to prevent manipulation and omission of data.

During the inspection, our investigators discovered a lack of basic laboratory controls to prevent changes to and deletions from your firm’s electronically-stored data in laboratories where you conduct CGMP activities.  Specifically, audit trail functionality for some systems you used to conduct CGMP operations was enabled only the day before the inspection, and there were no quality unit procedures in place to review and evaluate the audit trail data.  For example, you used standalone HPLC (2-RD HP/SM/32) to conduct analyses for Drug Master File (DMF) submissions and investigations, such as characterization of a starting material for your [redacted] DMF.  You also used uncontrolled systems to conduct out-of-specification (OOS) investigations for in-process materials used to manufacture [redacted] API.

3. Limiting access to or copying of records

Your firm limited access to or copying of records that our investigators were entitled to inspect.  For example, our investigators requested records of your audit trail data from all chromatographic systems used to test drugs for the U.S. market at your facility.  The files you ultimately provided (in the form of Excel spreadsheets rather than direct exports from your chromatographic software) were not the original records or true copies, and showed signs of manipulation.  The records you did provide contained highlighting, used inconsistent date formats, and lacked timestamp data; these features are inconsistent with original data directly exported from chromatographic testing software.

Our investigators and their supervisor explained at least twice that the data you provided was not representative of actual audit trail data from the chromatographic systems, and requested that you provide the original, unmodified records.  Your firm stated, without reasonable explanation, that you could not provide the requested audit trail records.  When our investigators explained that your failure to provide the requested records would be documented as a refusal, you acknowledged the refusal.

Our investigators documented other instances in which your firm limited the inspection by providing some, but not all, of the records requested by the FDA investigator that FDA had authority to inspect.  At multiple times during the inspection, FDA requested records of CGMP activities performed in your R&D laboratories at the behest of your quality unit.  However, you limited the inspection by providing only a subset of the requested records, and our investigators also found at least one of the requested records shredded in the trash.  Finally, our investigators requested chromatograms to substantiate your claim that you had identified and quantitated the impurities in [redacted], but you never provided the records that our investigators asked for to support your claim.

When an owner, operator, or agent delays, denies, limits, or refuses an inspection, the drugs may be deemed adulterated under section 501(j) of the FD&C Act.

View the original warning letter.