Inadequate process validation is one of the most common issues leading to warnings from the US Food and Drug Administration (FDA). It may also be the most difficult to address, according to Max Sherman, the editor of RAPS’ recently published second edition of The Medical Device Validation Handbook
. Unfortunately, many regulatory and quality professionals, and others involved in device compliance, lack the necessary knowledge and expertise. “People need a greater understanding of what validation consists of, as well as the process of validation itself,” says Sherman.
What Is Validation?
FDA provides several different definitions. In the introduction to the Validation Handbook
, Sherman writes that the broad definitions in 21 CFR 820 may be contributing to the problem of inadequate validation. The regulation defines process and design validation separately. “Process validation means establishing by objective evidence that a process consistently produces a result or product meeting its predetermined specifications,” and “design validation means establishing by objective evidence that device specifications conform with user needs and intended use(s).” Both definitions lack specificity, says Sherman. Adding to the confusion, FDA uses yet another definition in its 2011 Guidance for Industry: Process Validation: General Principles and Practices
Validation vs. Verification
Validation is closely associated with the related concept of verification, but it is important to understand the difference, says Sherman. Verification involves ensuring each element of a device meets the appropriate specifications and standards, while validation is concerned with the end product. Sherman offers two analogies to help illustrate the point. “Verification always comes first,” he says, just as the ingredients and recipe come before preparing a meal, or building materials and their specifications come before building a house. Validation, in terms of cooking, would be evaluating how the meal tastes. In building, it would be determining whether the house meets the residents’ needs.
Validation and the Role of the Regulatory Professional
In most companies, the team responsible for validation usually is headed up by someone in quality, such as a validation or software validation engineer, but typically, there are multiple parties involved from different departments. “Most companies have a number of disciplines reviewing the validation protocol,” says Sherman, and these should always include someone in regulatory. Regulatory personnel also are responsible for addressing 483s or Warning Letters that cite validation deficiencies.
A Common Problem
In the Validation Handbook
, Sherman writes that inadequate process validation was cited by FDA more than 119 times in 2016, but difficulty complying with FDA’s validation rules stretches back years. “There was a lack of training on validation early on,” says Sherman, “but even years later, there still is no straightforward guidance from the agency on how to do a process validation.” Validation can be confusing, he says. “It has a language all its own.”
Small companies are particularly challenged as they have fewer resources, and often use contract manufacturers that also must have properly validated processes. For these reasons, the Validation Handbook
may be especially valuable to professionals in these smaller companies.
Regulators' Increasing Emphasis on Risk
There is a much greater focus on risk analysis now, being driven by FDA and other major global regulators. FDA is increasingly looking to facilitate the process of getting innovative and promising new products to market—and to patients—more quickly, especially in instances where there is an unmet need. In Europe, where notified bodies are responsible for CE marking, they also must carefully assess risk.
In order to ensure products are not only effective but also as safe as possible, regulators need to know more about the risks and how to mitigate them. Risk management is becoming “a focal point in FDA inspections,” says Sherman. Process validation is a key element of identifying and mitigating risks for medical devices.
Pitfalls and Challenges
Today’s more sophisticated medical devices that use software to function require an entirely different type of validation than more traditional devices. “Any device with software is particularly vulnerable,” says Sherman, who adds that Internet-connected devices also can be subject to hacking. “There is a great need for software validation engineers,” he says, and the growing need to validate these types of devices is the reason there is an entire chapter of the book is devoted to software validation.
Medical Devices and Cybersecurity
Cybersecurity has now become a key concern for regulators. FDA has focused on cybersecurity risk assessment in several Warning Letters, and it isn’t hard to understand why. “You could actually hack into a pacemaker and negate the electrical properties used to control some of these life-saving devices,” says Sherman. In 2017, the high-profile “WannaCry” ransomware attack abruptly grabbed FDA regulators’ attention
when it affected several medical devices in US hospitals, underscoring the real-world threat such viruses pose.
Validation Critical for High-Risk Devices
It is critical to validate devices that carry the threat of injury or death if they were to malfunction, such as those used in surgery. “Any high-risk device is a validation challenge,” says Sherman. In a recent example of a validation failure, duodenoscopes that were not properly cleaned
resulted in the spread of deadly bacteria to multiple surgery patients, seven of whom died.
When Product Can’t Be Inspected, Process Must Be Validated
Another issue growing in importance is additive manufacturing, also known as “3D printing.” As the end products may not be able to be directly inspected or tested, regulators must rely on process validation to inform their actions and decision making. “What you have to do then is go back to the test method validation, you have to validate the equipment you use,” says Sherman
In this and other processes, such as sterilization or welding, where it is impractical or impossible to inspect the final product, regulators need to understand how the process is validated. “From an FDA perspective, if you have someone who can explain thoroughly, their validation methods and why they elected to do what they did, chances are you will avoid getting some sort of notice of non-compliance,” Sherman says. “Test method validation is a critical process and is described in two new chapters of the second edition” of the handbook.
About the Validation Handbook
The Medical Device Validation Handbook, Second Edition
is a useful resource for regulatory and quality personnel, engineers, those involved in sterilization and anybody who works in manufacturing, says Sherman, and he stresses that anyone in these fields, regardless of experience level, can and should learn more about validation. The book compiles information not available in one place from any other source and includes several chapters on topics Sherman says he hasn’t seen in any other book in his 40 years in regulatory.