Read expert advice on how to implement FDA’s rule on current Good Manufacturing Practices for combination products.
Mary C. Getz, PhD, Olivia Wong, D. Michelle Garrett, and W. Ben Shand
In January 2013, the FDA’s Office of Combination Products (OCP) released the final rule for 21 CFR Part 4 to address current Good Manufacturing Practices (cGMPs) for combination products. This regulation was followed up by a companion draft guidance published in January 2015 to further clarify the final rule and to provide additional recommendations on the application of cGMPs to combination products.
However, judging by the amount of industry-led workshops and seminars available for combination products, manufacturers continue to be unsure about how to approach gaps in their quality systems, and questions still remain on how to implement and maintain a successful and compliant quality system for combination products.
As background, a combination product can be defined as “single entity” (e.g., drug eluting stent or pre-filled syringe), “co-packaged” (e.g., first aid kit), or “cross-labeled” (e.g., drug cartridge used with dedicated injector pen). Each constituent part of the product (the drug, device, and/or biologic) that makes up the combination product must meet its respective set of regulatory requirements.
One important aspect to the draft guidance that OCP reiterates is that 21 CFR Part 4 did not bring forth any new requirements: “The final rule clarifies that the CGMP requirements that apply to each of the constituent parts apply to the combination product they constitute.”
However, manufacturers remain fully responsible for ensuring that appropriate, often significant, considerations are given to the manner in which these constituent parts interact with one another to ensure compatibility, stability, and overall product quality.
Integrating GMPs and QSRs into Combination Products
Manufacturers of single entity or co-packed combination products are given the option of adopting a streamlined approach in meeting certain pre-prescribed aspects of the complementary device or drug regulations. The alternative approach is to ensure compliance with all cGMP requirements relevant to the constituent parts.
Companies that have been in the pharmaceutical arena for quite some time are now struggling with how to integrate specific medical device 21 CFR 820 Quality System Regulation (QSR) requirements such as design controls and CAPA/medical device reporting (MDR). On the flip side, traditional medical device companies are learning how to navigate the pharmaceutical 21 CFR 210 and 211 Good Manufacturing Practices (cGMPs) and wondering how to address requirements such as stability and theoretical yield.
The challenge lies in knowing how to apply and implement the regulations without duplication of effort or even worse, a noncompliant quality system. This results in a common refrain among combination product manufacturers: Do we have to create all new procedures? If not, how do we integrate the two regulations to have one compliant quality system?
In an ideal world, companies involved with combination product(s) would be well-versed in both cGMPs and QSRs. However, in the real world, firms may not have the resources to hire, develop, and most importantly, retain this type of expertise. Instead, firms can focus on developing this knowledge base by reviewing their product portfolio and developing a risk-based strategy that involves evaluating and prioritizing their product pipeline, including its supply chain. Things to consider would be a) how the drug and device interact with one another, b) whether the constituents are manufactured or further processed by a third party, and c) how the combination product will be used (i.e., human factors), to name a few.
Manufacturers need to develop an effective quality risk management program and demonstrate their ability to identify and control product and patient risks throughout the product lifecycle, starting from development and continuing to post-market activities. Having a well-thought-out risk management plan is the first step toward characterizing the risk profile of the combination product and its associated manufacturing process. Conducting a thorough risk-based analysis indicates the manufacturer has performed its due diligence to ensure the safety and efficacy of the product for the user population while also demonstrating the manufacturer is in control of its processes.
Note that having a third-party contract manufacturer (CM) or original equipment manufacturer (OEM) does not preclude manufacturers from their accountability in meeting the 21 CFR Part 4 regulations. Additionally, if a manufacturer sources an off-the-shelf component from an external supplier, the manufacturer is still ultimately responsible for determining whether there are any adverse effects from the joining of constituent parts to form the combination product. Via supplier quality agreements, a manufacturer may choose to adopt a supplier’s quality documentation as evidence of development work performed, but these records must be properly identified, reviewed, and easily retrievable from the manufacturer’s own quality system.
By gaining a more heightened understanding of its combination product, a manufacturer can experience a host of benefits, including better decision making within the company, transparency with FDA, and greater regulatory assurance of the company’s capabilities to be aware of and mitigate risks. Since the FDA has stated there are no new regulations due to 21 CFR Part 4 and the final guidance is not yet available, manufacturers are in a position to take a more proactive stance in the wake of this gray area while working through their implementation and/or remediation strategies.
The risk-based approach gives a company the opportunity to identify critical areas to devote more attention and resources, instead of spreading the same amount of resources across the entire supply chain, where deficiencies might be missed. Using the proper tools and methodologies to identify and classify product safety risks is a crucial step when taking this approach.
Using Tools for Risk Management
Typical tools for risk management include failure mode effects analysis (FMEA) to highlight the occurrence probabilities of anticipated failure modes and a risk management report to determine the overall product risk profile and risk-benefit analysis. To demonstrate a proactive approach, manufacturers may also elect to perform a similar analysis for currently marketed legacy combination products under the direction of a company-approved quality plan.
The quality plan outlines the strategy for evaluating legacy product documentation and assessing the state of compliance for development products. This risk-based strategy demonstrates how familiar a manufacturer is with its products and processes. Within the quality plan, a manufacturer documents the previously identified critical parameters and linkages within its processes for evaluation.
For example, a manufacturer takes its FMEA a step further and includes a criticality analysis, which enables the manufacturer to weigh the probability of a failure mode against the severity of an anticipated outcome. The quality plan establishes the sequence for correction or remediation, based on those higher priority items (high probability, high severity). The manufacturer uses this information to determine which areas within its quality systems or processes warrant additional monitoring and/or control for compliance to the regulations.
If a manufacturer does not have a solid understanding of its products and processes, it cannot develop a robust quality plan. As Winston Churchill reminded us, “He who fails to plan is planning to fail.”
Building in Continuous Improvement
As with any robust system, a feedback loop is necessary for continuous improvement. Whether a firm adopts all elements of both cGMPs and QSR regulations, or follows the streamlined approach, having a quality system capable of providing the appropriate data to track and trend is invaluable when it comes to maintaining control and compliance. Since so many firms still have confusion as to how to integrate and implement Part 4 guidelines, a manufacturer who can identify problem or high-risk areas is already a step ahead of everyone else.
The risk management process is intended to be a reiterative system where potential risk events are monitored, analyzed, and then reduced or mitigated. Additionally, during the assessments that take place as a part of the quality plan, manufacturers may detect trends in the types of observations noted during the compliance checks. These trends can be used as part of a root cause analysis to determine why there are compliance issues or gaps within the existing systems. Having the correct root cause identified is key to correcting cGMP issues and for implementing the right solutions to prevent future occurrences.
This once again highlights the importance of a manufacturer understanding its own products and processes to enable more efficient and better-informed decision making that takes product/patient risk into account.
Another area where many manufacturers struggle is proper implementation of cGMP corrections once the solutions are identified. Since quality systems are linked, changing one area may have more widespread implications than initially thought.
For instance, 21 CFR 820.30 Design Controls is a common remedial space for combination product manufacturers. However, since design controls encompass so many different subparts from design and development planning to design validation, remediating one may lead to the need to update other quality system elements as well, such as change control or risk management. A traditional pharmaceutical company may not be fully aware of these interdependencies so new gaps may occur within the quality system or existing gaps may no longer be completely addressed.
Combination product manufacturers need to recognize these nuances and adjust accordingly. No longer are manufacturers simply looking at their products as a drug or a device, but as an integrated product whose constituent parts may be altered due to their interactions.
In the absence of having a subject matter expert on the streamlined portions of the drug or device cGMPs (or the entire sets of both regulations), combination product manufacturers should consider engaging with external resources familiar with 21 CFR Part 4 to proactively develop a more thorough characterization of their products. There will be a smoother transition during implementation of any new guidelines or regulations if a manufacturer takes active steps to define their impact on its operations versus merely cobbling together requirements that are difficult to follow or understand.
A solid comprehension of its products and processes, coupled with the cGMP compliance that is already expected from combination product manufacturers, positions a company more favorably when FDA decides to release the final guidance for 21 CFR Part 4.
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Mary C. Getz, PhD, is the vice president of Quality Systems & Compliance for NSF Health Sciences Medical Devices. She has over 25 years of industry experience, including extensive expertise in developing quality, compliance and regulatory affairs strategies and solutions.
Olivia Wong is the director of Quality Systems for NSF Health Sciences Medical Devices. She has over 13 years of industry experience, including extensive expertise in project management and in developing quality/compliance strategies and solutions.
D. Michelle Garrett is an operations manager for NSF Health Sciences Medical Devices. With over 20 years’ experience as a project and quality associate for the medical device, pharmaceutical and biotechnology sectors, she has significant experience coordinating and managing compliance strategies, corrective action plans and process optimization projects to enhance operations and mitigate risk.
W. Ben Shand is a practice manager for NSF Health Sciences Medical Devices. His responsibilities include development of proposals for and the management of consulting projects including quality system development and remediation engagements, cGMP and due diligence assessments, and training programs around FDA regulations.
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