For a medical device manufacturer, one of the most challenging aspects of compliance is understanding whether a manufacturing process must be verified or validated in order to ensure its alignment with regulations.
The answers to the process validation vs. process verification conundrum are found in 21 CFR 820, otherwise known as the Quality System Regulation (QSR), which is enforced by the U.S. Food and Drug Administration (FDA). However, device manufacturers often lament the lack of specificity in the QSR guidelines in terms of which activities require process verification or process validation, so a deeper examination of the regulation’s intent and background is warranted.
The FDA defines process verification as “confirmation by examination and provision of objective evidence that specified requirements have been fulfilled.”(1) Conversely, the agency defines process validation as “establishing by objective evidence that a process consistently produces a result or product meeting its predetermined specifications.”(2)
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There is an adage in the manufacturing world that verification activities are focused on asking the question, “Are you building the thing right?” Validation, on the other hand, asks, “Are you building the right thing?”
In manufacturing environments in general, verification is approached from a systemic level while validation is applicable to the user level. From that perspective, a medical device manufacturer’s process verification should be concerned with confirming that specifications are correctly implemented by the system while process validation activities must be geared toward meeting the needs of the user.
Process verification isn’t testing to confirm a process or medical device product actually works. It’s confirming whether specifications are being met according to predetermined parameters. But when a manufacturer is confronted with parameters that can’t be measured, validation comes in to play. Process validation corroborates that intended performance yields consistent results.
Process verification is used throughout the life cycle of a medical device, from design development to upscaling production. But since the QSR stipulates the existence of objective evidence that specs are met, it is contingent upon quantifiable metrics that serve as key performance indicators (KPIs). If a process’ KPIs can be measured, it can be verified.
Nevertheless, few processes are measurable with 100% accuracy, even with the most stringent controls. That’s why the “fully verified” clause in the QSR is cause for concern to many medical device manufacturers. It’s also the reason why process validation is always prudent whenever it’s a cost-effective option.
The QSR, which was first published in the Federal Register in 1996 and most recently revised in April 2019, has never explicitly defined what it means for a process to be fully verified. However, the agency’s chief of the postmarket and consumer branch of the Center for Devices and Radiological Health (CDRH), Joseph Tartal, frames its meaning and context in an FDA Industry Basics Workshop Series informational video.
He defines a fully verified process as “being able to confirm with high confidence all of the key quality attributes.”(3) Verifiability is reliant on objective evidence, according to Tartal.
“By objective evidence, we mean supporting the existence or truthfulness of it,” he said. “Objective evidence may be an observation, a measurement or a test. For example, I can measure an item on a scale to verify how much it weighs.”
When objective evidence cannot be measured in a process, however, it cannot be fully verified and QSR guidelines call for a validation approach. As Part 820.75(a) states, “Where the results of a process cannot be fully verified by subsequent inspection and test, the processes shall be validated with a high degree of assurance and approved according to established procedures.”(4)
Galileo Galilei allegedly once said, “Measure what is measurable, and make measurable what is not so.” Making the unmeasurable measurable is an apt description of the aim of process validation.
For some processes, outputs are not quantifiable, or inspection and testing are insufficient. To meet FDA requirements in such instances, validation “with a high degree of assurance” is the only viable option. Such is the case for products in which issues can’t be detected until they are in use. For example, it is impossible to verify the longevity of a hip replacement component until after it has been surgically implanted in a patient and repeatedly used over time. In other circumstances, verification may not be plausible without taking the device apart, which makes testing cost prohibitive.
Using the example of injection molding, Tartal explained how fully verifying certain processes is untenable.
“If I am performing an injection molding process, I need to look at all of the molded pieces as well as all their key quality attributes,” he said. “These may be dimensional measurements, which may be fully verifiable, and also strength specifications that may require impact-resistant testing, which I cannot fully verify since it is destructive. Therefore, the process must be validated.”
He recommended validating all automated processes whenever possible, but each medical device manufacturer must determine whether to validate a process on a case-by-case basis.
Other than four processes identified in the preamble of the QSR (sterilization, injection molding, aseptic processing and welding), the FDA does not provide guidelines for specific processes that require validation. Instead, the agency defers to the Global Harmonization Task Force (GHTF) Process Validation Guidance as the best resource for advice on meeting regulatory expectations for process validation.
A decision tree provided in the GHTF guidelines identifies two fundamental questions device manufacturers should first ask to determine if process validation is required: (5)
If neither criterion is met, the GHTF guidelines indicate that the process should be validated, or perhaps that the process and/or product should be redesigned.
In many scenarios, a medical device manufacturer’s decision to validate a process up front is the most cost-effective measure. Process validation enhances control over factors like variations, which typically results in streamlined operations, increased yields and less scrap, among other benefits. Based on these types of tangible impacts that directly correlate with the bottom line, the relative cost of validating a range of different processes may outweigh, or perhaps even help reduce the cost of inspection in many cases.
“You may have a process that can be fully verified, but the test is cost prohibitive, which is not an FDA concern but still is your concern. Therefore, you may want to validate,” Tartal said.
Process validation isn’t necessarily about proving the excellence of your process capabilities. It’s about demonstrating to the FDA your understanding of why your process capabilities are satisfactory. That means the criticality of process validation is a factor across the entire product life cycle, so the earlier a manufacturer engages in validation activities the better.
The FDA has made a notable shift toward a more life cycle-centered approach to process validation since the agency’s first guidance on the matter was issued in 1987. The “Process Validation: General Principles and Practices” guidance published in 2011 advises that process validation should extend to activities occurring across the life cycle of a product.(6) It specifies that a life cycle approach to process validation involves three phases of activities:
The life cycle approach helps manufacturers improve control and enables them to effectively secure quality, according to Grace McNally, FDA senior policy advisor and co-author of the process validation guidance. In a presentation at the 4th European GMP Conference shortly after the guidance was published, McNally noted that taking a life cycle approach should lead manufacturers to address three key questions when engaging in process validation activities: (7)
Even if you believe McNally’s process validation questions have been satisfactorily answered, compliance isn’t assured. There are four fundamental directives a device manufacturer should continually observe to ensure sustained compliance.
The FDA recommends companies take a risk-based approach to controlling processes that can’t be verified. In doing so, it may be helpful for device manufacturers to analyze process risk according to the guidelines set forth in the ISO 14971 risk management standard, since it’s imperative they understand the impact of risk on their manufacturing processes and specifications, particularly for essential design outputs.
The QSR does not mandate the use of a master validation plan, but it is recommended in the GHTF guidance and by FDA officials.
“I highly recommend using a master validation plan as it helps you develop a roadmap for what needs to be done, how it will be done and who will do it,” said CDRH’s Tartal. “It becomes extremely important when you have multiple processes and multiple process validations going on all at the same time.”
As with any regulatory process, the documentation of activities and results is requisite for FDA audit preparedness. That includes documenting justifications as to why a company believes processes do not justify revalidation. The requirements for documenting process validation are outlined in QSR 820.75(a).(8)
Even after process validation is completed, a manufacturer is required to establish sufficient monitoring and controls of validated processes to ensure specified requirements can be met on an ongoing basis.(9)
For a deeper analysis of process validation goals and requirements, visit our Process Validation for Medical Devices page.