Issue link: https://www.e-digitaleditions.com/i/1462155
14 Pharmaceutical Technology QUALITY AND REGULATORY SOURCEBOOK EBOOK MARCH 2022 P h a r mTe c h . c o m Quality: Validation issues can have a cascade effect that compromises all parts of the marketing applications. Common observations Citations for method validation for combination products relate to relevant regulations for the con- stituent components, as in Table III. In this case, FDA 483 observations from 2018– 2020 for medical devices and combination prod- ucts were reviewed by the Pharmatech Associates team for issues related to method validation. In all, 29 different observations were found, with ex- amples provided in Table IV. Citations came primar- ily from US manufacturers. However, a number of citations were from non-US suppliers. While a review was not provided, EMA has launched a new version of the EudraGMDP database Table III. Constituent components of combination products and relevant FDA regulation. Constituent component FDA regulation Medical device 21 CFR 820.30 Design Controls Drugs 21 CFR Part 211, Subparts E, F, and I Biologic 21 CFR Part 610 – General Biological Standards HCT/Ps (human cells, tissues or cellular or tissue-based products) 21 CFR Part 1271 Table IV. Examples of 483 observations related to combination product method validation. FDA center FDA issues Relevant observations Medical devices and rad health Methods validation, data integrity, equipment qualification, process validation • You have not conducted a test method validation for(b) (4)~~~ of sterile packaged products. • A process whose results cannot be fully verified by subsequent inspection and test has not been adequately validated according to established procedures. Medical devices and rad health Methods validation • The acceptance status of the product was not identified to indicate conformance or nonconformance with acceptance criteria. Medical devices and rad health Methods validation, equipment qualification, process validation • A process whose results cannot be fully verified by subsequent inspection and test has not been adequately validated according to established procedures. Human drugs, medical devices, and rad health Methods validation, process validation • There is no documented validation of the needle tip deflection test. This test is used in the production environment to monitor needle deflection or needle straightness during the filling of (b)(4)~~~ units. • Functionality testing of next-generation auto-injectors (NGAs). Test method validation for functionality testing is included in document Title: Test Method Validation Summary Report: NGA EpiPen/EpiPen Jr., (b)(4)~~~ Method Functionality Testing, which provides test method validation for the consistency amongst tester/appraisers but does not justify and/or validate the test (b)(4)~~~ to support how this parameter represents use of the product. There is also no evaluation to see if (b) (4)~~~ has any effect on the recorded activation force or other functional product requirements. To ensure that functional testing results adequately reflect actual use(b)(4)~~~ should be adequately validated to demonstrate that the test (b)(4)~~~ reflects actual use or the test (b)(4)~~~ used does not affect the functional testing results, including activation force. Human drugs, medical devices, and rad health Methods validation, laboratory controls, procedures Established test procedures are not followed. Animal drugs and feeds, human drugs, medical devices, and rad health Methods validation, environmental; monitoring, facility design and construction, facility general The accuracy, sensitivity, specificity, and reproducibility of test methods have not been established. Human drugs, medical devices, and rad health Methods validation The accuracy and reproducibility of test methods have not been established. Sources: b (4)~~~ - Indicates text redacted by the FDA and published on the FDA website. https://www.fda.gov/combination-products 483 data is sourced from the Redica Systems database (formerly Govzilla).