Issue link: https://www.e-digitaleditions.com/i/1462155
Pharmaceutical Technology QUALITY AND REGULATORY SOURCEBOOK EBOOK MARCH 2022 9 of the medical device component. While this would be ideal, it is not always possible. In the case of prefilled drug delivery systems or co-packaged products, de- vices are purchased from a third party who files all the appropriate regulatory documentation and provides the combination product sponsor a letter of reference to the device master file. The sponsor's requirement is to demonstrate compatibility with their product. In more complex devices such as a drug-coated stent, it is necessary to validate many of the drug product-related methods because they are used to manufacture the finished product and are inf lu- enced by it. Not validating methods used to test at- tributes during verification and validation can result in deficiencies or 483 observations. Therefore, product and quality engineers must pay particular attention to methods used to test combination products that are outsourced to third- party vendors. While third-party vendors have ex- pertise in performing the testing, they may not have the full understanding of the combination product under development and may miss critical aspects that should be captured during the validations. This would result in the data not supporting the method as suitable for its intended purpose. If changes to the product or methods are to be made after verification and validation studies for the combination studies are complete, it is important to evaluate the risks and their impact on the integrity of the data generated up to the change. It may be neces- sary to repeat the verification and validation with the changed product and methods. With combination products, there are risks inherent in validating meth- ods too early in the life cycle because products may change during the clinical phases. Validating meth- ods late in development may require a significant amount of additional work if verification and valida- tion studies need to be repeated. With complex com- bination products, it will be important to meet with regulatory bodies early and often to get their buy-in on the verification/validation and method validation plan. It is helpful to establish a clear communica- tion plan within the overall regulatory strategy that defines when the communication with regulatory bodies will take place. Conclusion: consider method appropriateness Method validation for combination products is not as straightforward as it would be for a drug or de- vice alone. There are multiple approaches to method development and validation for combination prod- ucts. With proper application of validation timing and suitability, a clear understanding of the methods' appropriateness for the final combination product's intended use can be ensured. The importance of get- ting buy-in from regulatory authorities early in the development process is critical in order to establish meaningful specifications. Any improper validation of methods is likely to re- sult in regulatory agency deficiencies that can range in degree of severity. These insufficiencies will be detailed in part two of this series, "Common FDA 483 Observa- tions for Combination Products." References 1. CFR Title 21 (Government Printing Office, Washington, DC), ecfr.gov/current/title-21, accessed Feb. 23, 2022. 2. ICH, Q8 (R2) ICH Harmonised Tripartite Guideline: Pharma- ceutical Development, Step 4 version (2009). 3. FDA, CFR Title 21, Part 820 (Government Printing Office, Washington, DC), FDA.gov, accessed Feb. 23, 2022. 4. ICH, Q2 (R1) Validation of Analytical Procedures: Text and Methodology, Step 4 version (1994). 5. USP, USP General Chapter <1225>, "Validation of Compendial Procedures," USP29-NF24 (Rockville, MD, 2017). 6. Eurachem, The Fitness for Purpose of Analytical Methods: A Laboratory Guide to Method Validation and Related Topics, (2nd ed., 2014). 7. Australian Pesticides and Veterinary Medicines Authority, Vali- dation of Analytical Methods for Active Constituent, Agricul- tural and Veterinary Chemical Products (2004). PT