The testing of a medicinal product before its release for distribution is one of the most important manufacturing steps and a core function of quality control. There is no inspector, neither with the FDA nor with one of the European supervisory agencies who won't take a close look at the quality control department responsible for this final test. In fact, an inspector will want to make sure that the staff members of this department perform their tasks in exact compliance with GMP regulations. It is therefore surprising that serious GMP violations occurring in this sensitive area, which directly affects the safety of end users, are amongst the most common described in FDA warning letters. Most cases are not just about singular misconduct of laboratory personnel or an unassessed deviation in an analysis result, but fundamental GMP deficiencies. An analysis of the warning letters of the past 24 months emphasises this fundamental flaw in the quality management system, because of which finished medicinal products are released into the market without their compliance with final specifications being tested. In many cases, this does not only concern content determinations, but also absent tests for microbiological contamination.
The legal basis regulating the final testing and product release can be found in 21 CRF 211.165, subsection (a)-(f). The corresponding description of defects in warning letters mostly sounds like this:
"Your firm does not have, for each batch of drug product, appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient and freedom from objectionable microorganisms, prior to release …"
"Your firm failed to establish and document the accuracy, sensitivity, specificity, and reproducibility of its test methods …"
The following compilation of findings from several warning letters issued between October 2016 and September 2017 (fiscal year 2017) contains details about the type of GMP violation. It is representative for a period of 24 months (fiscal years 2016/2017).
|OTC||Neither content determinations nor microbiological testing have been performed before release. Records of further chemical analyses do not exist.|
|Pharmco Laboratories, Inc.; Titusville, USA||Products for topical application||The method of content determination for benzoyl peroxide and salicylic acid has not been validated, nor was the equivalency of these methods with the procedures described in the USP proven.|
|Zhejiang Bangli Medical Products Co., Ltd.; Yongkang City, China||Transdermal patches||No testing for identity, purity and strength of the active components.|
|Howard Phillips, LLC; Millerton, USA||Sterile products for topical application||There was generally no final testing performed before the release, neither identity and content determination nor tests for sterility and microbiological integrity.|
|Yusef Manufacturing Laboratories, LLC; Clearfield, USA||Products for topical application||No testing for identity and strength of active ingredients or microbiological quality. A post-analysis by the FDA showed that the active substance level was too low.|
|ChemRite CoPac, Inc.; Lannon, USA||OTC||No tests for compliance with microbiological specifications. Results for analysis of the objectionable organism P. aeruginosa was declared with 1 CFU/ml in the batch protocol, even though there were no tests performed by the company or the contract manufacturers.|
|Sage Products, Inc.; Cary, USA||OTC||The procedure used for testing the bioburden is unsuitable. An attempt to validate the method failed. Products were released regardless. A post-analysis of several batches in accordance with USP methods after various customer complaints showed a high bioburden.|
|Foshan Flying Medical Products Co., Ltd.; Foshan City, China||Finished medicinal products||No testing for identity or strength stated on the label; testing for absence of objectionable microorganisms was never performed.|
As mentioned before, this type of fundamental violations of GMP rules has not only appeared in the most recent warning letters. In fact, their number has been on a high level for at least two years.
An analysis of further GMP violations frequently found in warning letters will follow shortly.