The US Food and Drug Administration (FDA) on Tuesday released a warning letter sent 10 April to Teva for deficiencies related to an active pharmaceutical ingredient (API) manufacturing site in Hangzhou, China.
The letter, first disclosed in an SEC filing in which the company said it would respond by 1 May, includes two observations for failing to establish written procedures to monitor the progress and control the performance of processing steps that may cause variability in the quality characteristics of API, and for failing to establish a sampling plan based on scientifically sound sampling practices.
FDA investigators said the inspection from last September found that about 10% of certain API batches produced at the site over a two-year period failed to meet an impurity limit. An additional 10% of batches also yielded out-of-trend results.
“You have reprocessed rejected out-of-specification (OOS) batches but failed to implement effective corrective and preventive actions (CAPA) to correct process design and control flaws that lead to excessive formation of this impurity during processing,” FDA said.
The agency also found Teva’s response to questions was “inadequate because it did not include the risk assessment and related scientific rationale to ensure that controls implemented for all batches will detect upstream processing variation and ensure final API quality.”
FDA is seeking information on how Teva will improve batch sampling of some APIs to ensure that intra- and inter-batch variability during commercial manufacturing is detected; how the company evaluates other APIs for adequacy of sampling plans; and how it provides overall quality system improvements to ensure all sampling performed is representative and able to detect non-uniformity of the quality attributes that may vary within a batch.
FDA also seeks an updated investigation into the root cause(s) of some OOS results and an improved CAPA plan, an explanation of Teva’s systems for incorporating reprocessing activities into Drug Master Files and more insight into the procedures that ensure reprocessed lots and process performance qualification lots are included in the site’s stability program.
Also on Tuesday, FDA released a warning letter sent 13 April to Andhra Pradesh, India-based Divi’s Laboratories, which limited access to FDA’s copying of records that its investigators were entitled to inspect, among other violations.
“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.”
FDA also posted two Form 483s for Dr. Reddy’s Laboratories.
Teva warning letter
Divi’s Laboratories warning letter