Warning Letter Analysis: FDA Asks for Notification of Impending Drug Shortages in Newest Citations
| Posted: 23 May 2012
By Alexander Gaffney
The US Food and Drug Administration (FDA) released a new batch of warning letters on 23 May, citing two pharmaceutical manufacturers and two medical device manufacturers for a series of regulatory infractions including current good manufacturing practice (CGMP) deficiencies, adulterated products, quality system regulation deficiencies and sterility issues.
In a new development, FDA is also asking for companies served with warning letters to keep in informed about future drug shortages. As part of its warning letters to two pharmaceutical companies this week, FDA requested notification of impending actions if either company is considering actions that would result in “a decreased number of finished products.”
FDA’s 24 April warning letter to Spain-based Tedec-Meiji’s President, Dr. Guillermo Tena Quintero, cites the company for “significant violations of CGMP regulations for Finished Pharmaceuticals.”
During a July 2011 inspection of the facility, FDA said it found that the company failed to investigate out-of-specification (OOS) batches despite not knowing whether the batch had been distributed or not.
More troubling, FDA alleges after detecting the failure of a particular lot—28 days after obtaining the lab result—Tedec Meiji then re-tested a sample from the failed lot four times, averaging the re-test results to ensure the sample passed.
Further, FDA said the company “did not extend its investigation to other batches that may have been associated with the specific failure, nor did you conduct a review of your production operations.”
Tedec-Meiji was also slammed with a litany of other regulatory violations, including failure to validate its suppliers’ analyses, failure to establish scientifically sound specifications or test procedures, failure to calibrate production equipment, and failure to assess the effects of batch failure on product quality.
Interestingly, FDA expressed an additional concern of its own: drug shortages.
“If, as a result of receiving this Warning Letter or in general, you are considering making a decision that will result in a decreased number of finished drug products or active pharmaceutical ingredients produced by your manufacturing facility, FDA requests that you contact the Center for Drug Evaluation and Research’s (CDER) Drug Shortages Program immediately […] in order to ensure that your action(s) does not adversely affect the public health.”
B.M.P. Pharma, a German manufacturer of active pharmaceutical ingredients (APIs), was cited for “significant deviations” from CGMP practices in a 4 May warning letter from FDA.
B.M.P. Pharma’s Norderstedt facility was found to be manufacturing adulterated APIs as the result of several manufacturing deficiencies resulting in the potential for cross contamination.
In particular, FDA cited B.M.P Pharma for failing to designate production areas for the operation of high-risk tasks. “For example, your firm performs sampling, an open operation involving powders, on both several products in a shared facility, using shared equipment and a shared dust collection hood,” explained FDA. “The procedures in place at your facility, as discussed in your response, are insufficient to prevent” cross-contamination between the two product types, concluded FDA.
Due to the serious potential for product contamination, FDA asked the company to “commit to cease” all production until the issue is addressed through an approved operational plan.
Like Tedec-Meiji, B.M.P. Pharma was asked by FDA to alert the agency to any impending drug shortages—a development Regulatory Focus has not seen in previous warning letters.
FDA’s 7 May warning letter to CareFusion Corporation’s Mexican manufacturing subsidiary Urólogos de México cites the company for manufacturing several adulterated products.
The products, which FDA alleges are in violation of US Quality System Regulations (QSRs), were found to be deficient as the result of two specific violations.
FDA alleges the company failed to establish and maintain adequate procedures for implementing corrective and preventive action (CAPA) after it filed numerous extensions on an initial corrective action and failed to adequately fix the problem in a timely manner.
FDA also cited the company for failing to adequately ensure the validation of testing processes after the company neglected to document validation activities or maintain consistent testing standards.
A warning letter sent to the President of Italian Manufacturer BTS S.p.A., Bruno Ros, alleges the company is manufacturing devices in violation of US Quality System Regulations (QSRs).
FDA notes eight deficiencies in its 10 May warning letter:
- Failure to establish adequate device validation procedures and maintain evidence of the procedures in the Design History File.
- Failure to conduct regular design review procedures.
- Failure to establish internal audit systems such that complaints could be received, reviewed and evaluated.
- Failure to establish and maintain procedures for the acceptance of inspections, tests and other verification activities.
- Failure to establish and maintain adequate document control procedures.
- Failure to maintain Device History Records for each batch and lot.
- Failure to establish adequate procedures for quality audits.
- Failure to ensure all staff is adequately trained and assigned appropriate responsibilities.