Plenary 7: Quality Considerations for Combination Products and Device
Specialty applications for drug delivery systems and devices continue to evolve; providing fit for use criteria remains a challenge for suppliers. Compliance with national and international standards is a starting point but cannot encompass all uses. A set of baseline requirements and documentation of risk to drug of changes can support suitability studies along with providing insight on quality expectations. The last plenary session examined these areas, beginning with Kesley Gallagher, Senior Regulatory Affairs Manager, Amgen Inc., who discussed change control for marketed combination products from a device perspective. Gallagher’s presentation covered device change control and subsequent filing considerations of combination products where the drug is the primary mode of action.
She discussed change control and assessment based as measure of the risk to the drug of those changes. When assigning risk, she outlined the following some questions to ask when assigning risk (Figure 16). For instance, are clinical data needed? What level of design verification and validation testing will be needed? Are there any new biocompatibility concerns due to the proposed changes? Is there a new sterilization method being introduced? Does the change necessitate a change in the way the device will be used? Is there a substantial impact on the drug product because of the change?
Figure 16 Questions to Ask When Assigning Risk
Gallagher also made the following points about change control: a change control process should be documented in an SOP and reassessed often, drug constituent parts and device constituent parts shoudl be distinguished from each other and define types of changes for the device and create a process flow chart as a decision tree. She concluded that it is all about defining the levels of risk and reporting in an organized manner that is easy to follow.
Four takeaways from her presentation were:
- Design of a device is often changed based on internal and external needs as part of device life-cycle management.
- Pharmaceutical companies marketing combination products need to accommodate design changes as required by cGMP for Combination Products 21 CFR Part 4.4 and, subsequently, design control per 21 CFR 820.30.
- Device change control procedures can include a decision tree to a) understand if the change impacts the drug product, b) aid the assessor’s understanding of the ramifications of the change on the safety and effectiveness of the device constituent part and c) to help document and justify the filing strategy for the change when needed (Figure 17).
- The combination product change control procedure needs to accommodate device change reportability from a global perspective. Submission strategies for device changes may vary by country/region.
Figure 17 CMC Decision Tree
Lee Nagao, PhD, Science Advisor, Drinker Biddle, then discussed partnering across the supply chain to develop and communicate risk-based requirements for material quality. Orally inhaled and nasal drug products (OINDPs) are drug/device combination products falling under CDER as the primary review division in the FDA. Nagao’s presentation focused on recommendations summarized in the new International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS) Baseline Requirements for Materials used in Orally Inhaled and Nasal Drug Products. Originally published 2011, IPAC-RS chose to revise the document in 2017 due to the evolving regulatory landscape. The revised IPAC-RS baseline requirements document seeks to integrate and bring structure and hierarchy to the many global quality requirements expected for inhalation and nasal product device and container closure system materials and components. The guidance specifically covers the rationale, development, and baseline requirements for materials quality, as well as discusses how best to engage with suppliers and consider differences one may expect to see in quality requirements during the lifecycle of the inhalation/nasal product.
Lee explained that the baseline requirements guide can be used as a communications and technical tool by both upstream and downstream suppliers, as well as final product manufacturers. The guideline emphasizes the following key elements of the OINDP Supplier and Manufacturer Communication Strategy:
- Early and often business communication
- Early and often discussions about requirements
- Early and often technical communication
- Design of quality into the product up front
And she emphasized that all of the activities should be applied within a risk-based framework – that is the agreed to tests should be performed and requirements set based on an risk analysis of material or component application. The following tests are recommended in the guide: Biocompatibility: based on product use (patient contact and duration), e.g., ISO 10993, parts 5 and 10 (sensitization, irritation), or USP <87>; classification of plastics per USP <88> preferred; Physicochemical testing: compliance with, e.g., EP Chapter 3; USP <661>; <381>, JP XV, Controlled extraction studies and minimum requirements based on best practices, e.g., PQRI, as well as Routine extractables testing and testing for foreign particulates.
Nazia F. Rahman, Biomedical Engineer, CDRH, FDA, and M. Isabel Tejero del Rio, MD, PhD, Lead Consumer Safety Officer, CDRH, FDA both offered regulatory insight on supplier controls for quality of delivery systems. They began their presentation with a review of selected definitions, such as Combination Product, Constituent and Modes of action, all from 21 CFR. These definitions formed the foundation for a review of combination product regulation history and CGMP regulatory requirements for supplier control. They followed with a discussion of how these requirements may be applied, and included definitions of what is a manufacturer, specification developer and contract manufacturer, since confusion can exist considering the complexity of these delivery systems.
Perhaps the most interesting and informative part of their presentation also included a useful case study on prefilled syringes which covered design controls, purchasing controls, risk analysis and CAPA. The scenario is described in Figure 18.
Figure 18 Prefilled Syringe Scenario
Based on their combined experience, the authors concluded with the following points.
- 21 CFR part 4 does not introduce new or eliminate existing regulatory requirements associated with combination products.
- The sponsor, owner, of the combination product is responsible overall for all regulatory requirements.
- When considering what’s necessary to show compliance to applicable 21 CFR part 820 regulatory requirements, think about how those regulations apply to the finished combination product.
- The owner of the combination product is responsible for the quality of any part, service, material, design, manufacturing, etc., associated with the finished combination product outsourced to 3rd party outfits.
- 21 CFR 820.50 is the regulatory environment governing supplier controls for medical devices, and is applicable to combination products with a device constituent part. Applicability extends to any part, service, material, design, manufacturing, etc., associated with the finished combination product whether is directly associated to the device constituent part or not.
All of the presentations at the 2017 PDA Container Closure, Devices and Delivery Systems: Compatibility and Material Safety Workshop illustrated the complexity around container closure systems and offered a look at how both industry and regulatory agencies can work together to bring awareness to these issues and develop solutions. Any one interested in further discussion around this topic is encouraged to attend the 2018 PDA Container Closure Performance and Integrity Conference in June.