Inspections, Compliance, Enforcement, and Criminal Investigations
Banner Pharmacaps, Inc. 28-Sep-06
Department of Health and Human Services
Public Health Service
Atlanta District Office
September 28, 2006
VIA FEDERAL EXPRESS
September 28, 2006
Roger E. Gordon
President and CEO
Banner Pharmacaps, Inc.
4100 Mendenhall Oaks Parkway
High Point, NC 27255
Dear Mr. Gordon:
On April 18 through May 17, 2006, the Food and Drug Administration (FDA) conducted an inspection of your manufacturing facility located at 4125 Premier Drive, High Point, North Carolina. The inspection revealed significant deviations from Current Good Manufacturing Practice (CGMP) regulations (Title 21 Code of Federal Regulations (CFR,Parts 10 and 211) in the manufacture of drug products such as [redacted], and [redacted]. These CGMP deviations were listed on an Inspectional Observations (FDA 483) form issued to your Plant Manager, Jeff Thompson, at the close of the inspection (a copy is enclosed for your review). These CGMP deviations cause your drug products 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)(13)).
Examples of the deficiencies observed are as follows:
1. The failure to have adequate laboratory facilities for the testing and approval (or rejection) of components, drug product containers, closures, packaging materials, In-process materials, and drug products available to the Quality Control Unit as required by [21 CFR 211.22(b)] and as demonstrated by the following examples:
a) The failure to appropriately test each batch of drug product to determine satisfactory conformance to final specifications, Including the identity and strength of each active ingredient, prior to release [21 CFR 211.165(a)]. Products which had failed analytical testing were noted to have been released for distribution. These failing results were deliberately changed by your analyst and falsified results indicating that the product had passed all testing were recorded in the batch records. Some examples of this include [redacted] Batches 25030655, 25101150, 25101146, 25101915, and 26022117 which had failing content uniformity results. These failing results should have prompted failure of the lot or additional testing. Your firm initiated recent recalls of three of these lots as a result of these findings.
b) Laboratory records failed to Include complete data derived from all tests necessary to assure compliance with established specifications and standards [21 CFR 211.194(a)]. Our investigator noted numerous instances where your firm failed to record the appropriate analytical results failed to include all calculations and data with the records, and intentionally manipulated data. In addition to the lots discussed above, other examples of manipulated data include [redacted] lot 24122208 (stability assay), [redacted] lot 25030657 (dissolution), [redacted] lot 25030526 (dissolution and content uniformity), [redacted] lots 24090819 and 24091063 (dissolution), [redacted] lot 25020699 (content uniformity), [redacted] lots 25101063 and 25101065 (in process assay ), [redacted] lots 25061636 and 25070172 (content uniformity), [redacted] lot 24110990 (in process assay), and [redacted] lots 26031583, 26031585, 26031587 (dissolution). This intentional data manipulation included using standards from a different run, changes to the concentration of the standards, changes to the number of capsules tested, changes In multipliers, changes in sample weights, and changes in dissolution volumes.
c) Laboratory records failed to include the Initials or signature of a second person showing that the original records have been reviewed for accuracy, completeness, and compliance with established standards [21 CFR 211.194(a)(8)]. The above discussed manipulations were performed by analysts using the [redacted] Chromatographic Data System [redacted] CDS). Although the audit function is discussed in your procedures, there is no specific requirement regarding any review of the audit trails, and your records failed to include documentation that a second person had conducted such a review. In fact, our investigator was told that no such audit had ever been performed. However, a second person must review these audit trails, particularly given the lack of controls for preventing data manipulation. Such an audit may well have detected the data manipulation which was occurring at your facility.
d) Failed to assure that each person responsible for supervising the manufacture, processing, packing or holding of a drug product had the education, training, and experience, or any combination thereof, to perform their assigned functions in such a manner as to provide assurance the drug products have the Identify, strength, quality, and purity that they purport to possess [21 CFR 211.23(b)]. The analysts reviewing the release and stability testing performed by another analyst did not have sufficient training and experience to identify the above situations where analysts had failed to follow procedure or had intentionally manipulated results.
2. You failed to conduct a thorough investigation Into the failure and the unexplained discrepancies associated with the nine months stability assay testing results of a lot [redacted] already distributed [21 CFR 211.192]. This lot was subsequently recalled by your firm. This stability failure was the subject of a field alert in March 2006. Your investigation revealed that the lot had actually failed at the six month assay. You also determined that the analyst used standards from a previous run to calculate the results. By using this incorrect raw data, the analyst recorded the results as passing. However, when you recalculated the results with the correct raw data, the lot failed. You failed to initiate an additional investigation at that time to determine if this was an isolated incident, or if there were other instances in which this analyst had used erroneous data to calculate results. The investigation was not extended to other analytical testing done by this analyst until our investigator noted other instances of data manipulation and discrepancies in the documented results.
We are in receipt of your May 26, 2006, update of your Quality Control Audit Plan, your June 14, 2006, response to the FDA 483 observations, and your June 28, 2006, plan for the Review and Disposition of Marketed Products Identified as Questionable. The CGMP violations discussed above have not been adequately addressed by your responses. We acknowledge that you have initiated a recall on four lots, out of the 500 lots distributed, that you have identified as questionable. We are especially concerned that as of July 10, 2006, you had not implemented your plan for disposition of other distributed lots with questionable data and therefore have not addressed the potentially adulterated products that remain in the market.
We also acknowledge that your proposed corrective actions include reviewing all the notebooks used by the three suspect analysts in the last two years and their associated entries in the [redacted] CDS, a one day presentation on data integrity issues for all the staff, closing of all laboratory notebooks in use at the time the manipulated results were discovered, training quality control staff on data review, and reclassification of authorization levels and privileges to staff members with access to the [redacted] CDS. However, for the remaining [redacted] analysts you proposed to review a random sample of their laboratory data corresponding to approximately 16 pages out of a completed 200 page notebook that should include one chromatographic data entry. There is no specific proposal for reviewing data associated with other types of analyses/instruments (e.g. Ultraviolet (UV)) or data generated by systems other than the [redacted] CDS. Please provide your rationale for selecting this limited sampling scheme or how reviewing random pages of analytical results generated by the remaining analysts could assure with a considerable degree of certainty that the data that supports the quality characteristics of drug products are accurate.
In addition, in your response dated May 26, 2006, you stated that you have conducted interviews with all of your quality control staff members, which includes analysts. However, during a telephone conversation with the District on July 10, 2006, you stated that you have not interviewed or reviewed any of the notebooks of the analyst who performed the testing on [redacted]capsules lot 25071736A, which was found to have discrepancies with the content uniformity testing results. We wish to be apprised of ongoing results from your audit of data generated by all of your analysts. You could include this in your monthly updates. The second monthly update dated September 14, 2006, has been received and is currently under review.
Neither this letter nor the observations noted on the Form FDA 483 are intended to be an all-inclusive list of the deficiencies that may exist at your facilities. It is your responsibility to ensure that all drug products manufactured and distributed by your firm comply with the Act and the regulations. You should take prompt action to correct these violations, and you should establish procedures whereby such violations do not recur. Failure to do so may result in regulatory action without further notice, including seizure and/or injunction.
Federal agencies are advised of the issuance of all Warning Letters pertaining to drugs so that they may take this information into account when considering the award of contracts. In addition, any pending New Drug Applications, Abbreviated New Drug Applications, or export certificate requests submitted by your firm may not be approved until the above violations are corrected.
Please respond to this office in writing within fifteen (15) working days of receiving this letter. Your response should describe the specific actions, in addition to those already submitted, you will take, or have taken, to correct the violations described above and include an explanation of how each action being taken will prevent recurrence of similar violations. If corrective action cannot be completed within fifteen (15) working days, state the reason for the delay and the time within which corrections will be completed.
Your response should be sent to Philip S. Campbell, Compliance Officer, at the address noted in the letterhead. If you wish to discuss this letter or our continuing concerns with your facility, you should contact Mr. Campbell at (404) 253-1280.
Mary H. Woleske, Director