Validation Essentials For High-Risk Medical Devices & Pharmaceuticals

Validation is a requirement for medical devices and pharmaceutical drugs. Some products are less risky and might be able to get away with “validation lite.”

Validation lite is a situation where a less-robust verification process is sufficient to ensure product safety, but what about high-risk products?

In this article, we will go over validation essentials for both medical devices and high risk pharmaceuticals.

Why Is Validation Important?

It’s important to keep in mind how often the medical device and pharmaceutical industry come with high-risk products.

A high-risk product is one that is generally life-sustaining, where it is absolutely critical that the product works properly, every time. High-risk products are usually sterile, injectable, or implantable, and have special design elements that have the potential to introduce new life-threatening situations to patients.

High Risk Product Examples

• Biopharmaceuticals, especially those that cannot endure terminal sterilization
• Radiopharmaceuticals, especially those with half-lives so short that they cannot be tested before release
• Implanted human tissues, such as bone grafts
• Implanted medical devices, especially life-sustaining ones, such as pacemakers, but including artificial joints and stents

Often, high-risk products can introduce new hazards to the patient that would not have existed if the patient did not otherwise use it. Risk is defined as the probability of injury or peril, and generally consists of two factors, the likelihood of harm and the severity of harm.

So, a high-risk product often carries some likelihood of severe harm, risks to impair human life, through death or disability. This can occur with either pharmaceuticals or medical devices.

For example, a biopharmaceutical, if nonsterile may introduce pathogens to a patient with an already-compromised immune system. Or a pacemaker might fail and cause heart failure.

In fact, the FDA began mandating validation because patient deaths in the 1970’s were found to have resulted from inadequate sterility assurance.

Understand High Risk Processes In Medical & Pharmaceutical

High-risk processes can result in critical medical issues in patients if the product has critical defects. For example, life-threatening hospital-acquired infections may result if a product purporting to be sterile undergoes an ineffective sterilization process or is not truly manufactured under aseptic conditions.

A risk assessment would identify the high-risk processes at a manufacturing site, but examples include the following:

• Sterile clean zones of Class 100 (ISO Class 5) or better
• Autoclaving/Vaporized Hydrogen Peroxide/Ethlyene Oxide SterilizationLyophilization
• Activities controlling dosage where toxicity may resultFilling/capping of sterile vials or other containers such as blow/fill/seal activities
• Terminal sterilization or depyrogenation activities for sterile/injectable/implantable products and/or their containers/closures
• Processing biopharmaceuticals that cannot receive terminal sterilization when sterilization activities reduce product effectiveness.

Ensure Product Is Sterile & Pure

Validation is just  the capstone of a larger risk management process. For example, in aseptic biopharmaceutical processing, the process must be designed with controls to ensure that the product is sterile (to prevent injecting pathogens into the patient) and pure (so the active ingredient, is unimpeded in its effect on the patient).

Validation provides the confidence that the product has these controls are consistently effective; not just when they are tested during the validation runs.

Calculate Risk

Such consistency must be calculated via mathematical models to demonstrate infinitesimal probabilities of process risk for risks involving critical human harms, thus ensuring  that harmful production risks are successfully mitigated.

This means that validation incorporates testing, but testing is not the essential part of validation.

Design Into Manufacturing Process

The FDA states clearly in its process validation guidance that quality cannot be tested into a product, it must be designed into the manufacturing process.

This is because a single contaminated vial of product in a batch would not usually be detected via product but that single vial is capable of harming another human being.  Validation for high-risk product needs to ensure that every vial from every batch meets requirements. It’s about certainty. 

How Do You Ensure Adequate Validation for High-Risk Processes? 

As stated earlier, validation is just the capstone of a larger risk management process.

Understand Risk

The first step is to understand the risks involved with the product and its manufacturing, through a risk assessment.

Create Action Plan

From there, process specifications can frame selection of appropriate facilities, utilities and equipment to implement the necessary production and process controls to ensure the product risks are acceptably minimized. Process development can then begin.

Analyze Process Design

After initial process design, characterization and/or engineering studies can help refine the process to control the variables that can lead to harm. Characterization should examine where and when the processes may fail, so such failures can be circumvented.

It is important to document the findings of these studies because the knowledge gained may be lost, either when the process is transferred to Production, or in the future as personnel move on to other jobs. 

Part of process transfer involves scale-up from laboratory quantities and includes commissioning of systems purchased to facilitate this scale-up.  Commissioning is a verification to ensure that a system, purchased from and/or installed by the vendor, meets specified criteria.

Qualify

It is the first step in qualification, which tests the system within its operational ranges to verify that the system is suitable for its intended use. Commissioning and engineering studies together help understand how the system works, and thus facilitate system qualification.

Identify System Settings

Engineering studies and commissioning also help identify fixed system settings, for example, HVAC damper settings to balance HEPA airflow to assure laminar flow in the sterile cleanroom.

Rinse & Repeat Validation Process

For such critical processes, validation is also not a one-time activity, the validation runs must be repeated at regular intervals, usually annually, to verify that the validated process continues to function properly.

What Role Does Validation Play In Your Process?

Validation, to a level of positive certainty in one’s process, is essential for high-risk products. Validation is not an experiment, but the final, repeated activity showing that the risk analysis, commissioning, process development, characterization, and qualification continues to yield proper process outputs.

The rigor is necessary because these products safeguard the most priceless of commodities: human life. This is the ethics of caring: caring for patients, their families, and medical professionals.

We at Compliance Team also care, and we have the resources and technical skills to provide support for validations, whether you manufacture high-risk products, or you have quality questions of a general nature. Ask us!