WARNING LETTER Cosmaceutical Research Lab Inc. - MAY 29, 2020
1. Your firm failed to ensure that laboratory records included complete data derived from all tests necessary to ensure compliance with established specifications and standards (21 CFR 211.194(a)).
Your firm performed extra injections without a clearly identified purpose and using ambiguous nomenclature.
You injected samples with the intention of obtaining an “unofficial” result and/or failed to clearly indicate if the single injections were standards to determine whether high-performance liquid chromatography (HPLC) instruments were fit for use. For example:
a) On April 25, 2019, at 3:37pm, you performed an HPLC injection with a blank “sample name” field. Afterwards, you ran a sample set of (b)(4), lot (b)(4), at (b)(4). Both the initial injection and the (b)(4) sample set had similar chromatograms and retention times. Only the results from (b)(4) were reported as the final results.
b) On September 19, 2019, at 2:52pm, you performed an HPLC injection with a name of “(b)(4)” in the “sample name” field. Afterwards, you ran (b)(4) for (b)(4) pain reliever (b)(4), lots (b)(4), at 4:19pm and (b)(4). All (b)(4) in this series of injections performed that day had similar chromatograms and retention times. Only the results from 4:19pm and (b)(4) were reported as the final results.
We also found torn documents in the trash related to quality and production...
2. Your firm failed to establish laboratory controls that include scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity (21 CFR 211.160(b)).
You lacked impurity testing and used deficient testing methods for your products. For example:
a) You lacked impurity testing for your products, including, but not limited to, (b)(4) and (b)(4). (b)(4) may contain a potentially carcinogenic impurity called (b)(4). Because you did not test for (b)(4), you do not know the amount of (b)(4) in the final product to which a user might be exposed.
b) Your analytical test methods were deficient, including but not limited to, AM-011 Determination of (b)(4) in Raw Material and (b)(4) by HPLC, for your (b)(4). Range was not evaluated adequately with respect to accuracy and precision. It did not appear that accuracy was conducted on spiked placebo formulations. Accuracy testing was conducted on standard solutions whose composition is not representative of the final product. Furthermore, precision was not reported for the low or high concentrations used to determine the calibration function for range analysis...
4. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).
Your investigations into out-of-specification (OOS) results were inadequate. For example, you obtained OOS results for active pharmaceutical ingredient (API) assay during raw material testing for both (b)(4). In your OOS Number 169 investigation report, you attributed the root cause to assumed dilution error, prepared new sample solutions, and performed new tests. The new tests for (b)(4) API passed and you used the (b)(4) to manufacture (b)(4) for the U.S. market. Before performing the new tests, you noticed that the (b)(4) on the original sample had been damaged during testing. Yet you did not test the original sample or investigate the damaged (b)(4). Your investigation did not involve hypothesis testing to scientifically show dilution error was the root cause of the OOS results.
Re-analysis of the actual solutions, test units, and glassware is an integral part of an investigation to determine whether a laboratory error may have occurred. This assessment, in tandem with hypothesis testing if initial re-examinations do not reveal a root cause, is instrumental in determining whether there was a causative laboratory error. Whenever an investigation lacks conclusive evidence of laboratory error, a thorough investigation of potential manufacturing quality causes must be conducted either internally or with your supplier, depending on the source of the material being tested...
