In December 2009 (12/11/09) Teva Parenterals Medicines, Inc. received a Warning Letter from the FDA for significant violations of the current Good Manufacturing Practices (cGMP) — primarily within its Propofol Injectable Emulsion product. A recent review of this almost three year old document contains many teaching points that remain valid and complement the new FDA Q&A, “Guidance for Industry Pyrogen and Endotoxin Testing: Questions and Answers” that was published in June 2012. To learn more about this extensive endotoxin Warning Letter and how it may assist your organization in minimizing this potential concern, please visit the highlights below
1) Failure to subject each lot of a component with potential for microbiological contamination that is objectionable in view of its intended use, to microbiological tests before use [21 CFR 211.84(d)(6)].
For example, your firm has not tested each lot of raw materials used in the manufacture of Propofol Injectable Emulsion finished products to determine the presence and levels of bacterial endotoxin. Such raw materials include, but are not limited to, (b)(4)
Your firm’s responses, dated August 10, September 4, and November 13, 2009, state that your firm will subject each lot of incoming raw material to full microbiological testing, including endotoxin testing. We will evaluate the implementation of this testing and verify that you are subjecting each lot of incoming raw materials to full microbiological testing during our next inspection.
2) Failure to thoroughly investigate any unexplained discrepancy or the failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed, or to extend the investigation to other batches of the same drug products or other products that may been associated with the same failure or discrepancy [21 CFR 211.192], For example:
A) Your firm’s analysis of pooled samples from customer complaint vials of finished product (Lot#(b)(4)) revealed an endotoxin concentration of (b)(4). Your firm failed to identify a root cause and failed to implement a corrective action.
Your response, dated August 10, 2009, revised the final product release specification for endotoxin levels to (b)(4) in the Propofol Injectable Emulsion product. However, reducing the release specification for endotoxin levels may not alone mitigate the potential for adverse reactions for end users of the drug. It is a CGMP requirement that you implement adequate manufacturing practices and controls to prevent bacterial endotoxin contamination.
B) Your firm was unable to determine the cause of an out-of-trend level of bacterial endotoxin contamination found in three vials of finished product (Lot #(b)(4)) of Propofol Injectable Emulsion. No corrective action was taken in response to this finding at the time of manufacture, and your firm released the lot. Subsequently, samples of Lot #(b)(4) (the finished packaging designation for Lot #(b)(4)) of Propofol Injectable Emulsion, were collected (b)(4), tested, and found to have bacterial endotoxin levels in excess of (b)(4). This lot was recalled.
Your response, dated August 10, 2009, is inadequate. Your firm committed to an increased sampling plan and testing of in-process bulk emulsion and finished product. In addition, you proposed to change the finished product release specification for bacterial endotoxin to (b)(4). You described a sample size in this response but did not include a scientific rationale for it in this response nor in the subsequent response of September 4, 2009.
For example, your firm’s finished product sampling plan for (b)(4) and (b)(4) in Propofol Injectable Emulsion is not representative of the batch produced. A total of thirteen units are sampled per lot, with three tested for bacterial endotoxin and ten tested for bioburden. This sampling of thirteen units is irrespective of lot size, which may vary from (b)(4) to (b)(4) units (vials) per lot.
Your response, dated August 10, 2009, is inadequate. You do not reference a sampling plan that utilizes basic elements of statistical analysis or provide a scientific rationale for sampling that would vary the amount of samples taken according to the lot size. Your response does not define a confidence limit to ensure an accurate and representative sampling of the product.
4) Failure to test in-process materials for quality and purity as appropriate, at the commencement or completion of significant phases of the production process [21 CFR 21I.110(c)].
For example, your firm has not tested in-process non-sterile bulk solution after the (b)(4) process, as well as, end-of-run samples (b)(4) for the presence of bacterial endotoxin.
Your response, dated August 10, 2009, is inadequate. Although you committed to testing for bacterial endotoxin, you did not include the action limits to be established for bacterial endotoxin levels and specify a timeline when such testing will be implemented. Also, the proposed testing for bacterial endotoxin does not state the sample size or reference a statistically valid sampling plan used to determine the sample size.
5) Failure to test, through appropriate laboratory testing, each batch of drug product required to be free of objectionable microorganisms [21 CFR 211.165(b)].
For example, the bacterial endotoxin test methods used for the final release of Propofol Injectable Emulsion were not adequate to ensure detection of bacterial endotoxin as described below.
A) SOP (b)(4), is deficient because there is no requirement for vortexing the finished product vials of Propofol Injectable Emulsion prior to sample preparation.
B) The pH was not checked by mixing a portion of the sample preparation with (b)(4) first before adjusting the pH of the sample preparation solution. Failure to do this may result in a pH in the sample-(b)(4) combined solution that is outside of the range specified by the reagent manufacturer.
C) There is no assurance that the (b)(4) is protected from vibration during testing of bacterial endotoxin via the (b)(4) test method.
Your response of August 10, 2009, is inadequate. Your response states that vibration absorbing material will be placed under the (b)(4), but this has not been implemented. Your corrective actions regarding vortexing and pH adjustment appear to be adequate, and these will be evaluated at a future inspection.
Additionally, your response does not address possible similar deficiencies that may exist with respect to the laboratory release testing of other drug products your firm manufactures.
6) Failure to demonstrate equipment used in the manufacture, processing, packing, or holding of drug products is of appropriate design to facilitate operations for its intended use [21 CFR 211.63]. For example:
A) The validation of Cycles #2 and # 3 for the (b)(4) Washers #1 and #2 did not include an evaluation or validation with (b)(4). Such an evaluation or validation is necessary to demonstrate that the acceptance criterion of “(b)(4)” in bacterial endotoxin is met. In addition, there was no other evidence provided, such as results from any ongoing sampling and testing of the stoppers for endotoxin.
The entire Warning Letter may be viewed at: Teva Parenterals Medicines, Inc. Warning Letter (Listed under “Warning Letters” in Right Column)