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Testing, Commissioning, Validation, Qualification, or Verification? A Brief History – Part 3

In Part 3 of my history of Testing, Commissioning, Validation, Qualification, and Verification, I’ll describe the intent and reality of ASTM E2500 along with some practical advice for implementing an ASTM E2500 risked based approach to qualification of Biopharmaceutical and Pharmaceutical manufacturing systems.

The 2006 draft of Science and Risk-Based Approach to Qualification of Biopharmaceutical and Pharmaceutical Manufacturing Systems contained some great ideas which I really liked. I believe that it spelled out key factors necessary for a sane approach to qualification of life sciences manufacturing systems. I paraphrase them like this:

1. Keep Quality Assurance and Validation organizations away from pure engineering functions.
2. Change control for projects is a different beast than change control for operations.
3. Don’t do the same work twice.
4. Test run your process for real.

To help make the case for point one, the draft guidance created the concept of GEP – Good Engineering Practice. The idea is to use GEP in all areas where GMP is not required. Please remember that the “M” in GMP stands for manufacturing! Where in Part 211 does it describe requirements for engineering? Even in the 820 regulations where design controls are required, they are for the end product itself, not for the supporting equipment, utilities, and facilities. Pushing quality systems and oversight too far upstream into the engineering realm is counterproductive. The draft further states that “Technical experts will self-manage”. Wow, just imagine stepping back and trusting an organization’s professional engineering group to do its job. The guidance does recommend that quality assurance be brought into the loop when critical control elements are affected. The final guidance document also references GEP and leaves things very open regarding quality assurance’s role in equipment commissioning. I believe that this gives industry some leeway to decide where best to focus the quality assurance group’s efforts.

ASTM E2500 definitely distinguishes between change control for projects vs. change control of operations. Project based change control is termed change management and is to be run by engineering. Once all verification testing is complete, the system is managed under operational change management, and quality assurance would then resume its role in pre-approving all changes. Making this distinction can have a major impact on how smoothly projects run.

How is this for radical? The draft guidance states: Commissioning is an engineering activity. Furthermore it calls or the elimination of the IQ/OQ, replacing it with a well-documented, professional-run commissioning program. While this approach was not explicitly called for in the final guidance, it points to the group’s thinking in terms of how to reduce redundant work. The final document simply calls for manufacture’s to perform verification on systems, but again intimates at Engineering having the primary role in verification testing and change control; reducing the quality unit’s role in the project until the systems has been turned over to operations.

Verification—A systematic approach should be defined to verify that manufacturing systems, acting singly or in combination, are fit for intended use, have been properly installed, and are operating correctly. This verification approach should be defined and documented. The extent of verification and the level of detail of documentation should be based on risk, including those associated with product quality and patient safety, and the complexity and novelty of the manufacturing system.

ASTM E2500 is very clear on encouraging the use of vendor documentation in the verification process; the guidance states that, vendor documentation, including test documents may be used as part of the verification documentation, providing the regulated company has assessed the vendor. This statement shows the intent of streamlining the verification process and goes to my third point of don’t do the same work twice! I would further stipulate that for complex, highly automated systems leveraging vendor documentation is not only encouraged but required. In most cases it is not practical or even feasible to reverse engineer complex systems in order to create a thorough verification and testing program. This means that working with reliable and trustworthy vendors is critical to a project’s success. However, it may take more than a quality systems self-survey form to ensure that one is working the right OEM.

For many years one of my pet peeves has been the lack realistic test runs on equipment prior to equipment turn over to operations. The protocols look great, instruments are calibrated, drawings are updated, and SOPs are in place, but has anyone really run the equipment? It seems so basic. The draft guidance, Science and Risk-Based Approach to Qualification of Biopharmaceutical and Pharmaceutical Manufacturing Systems, did a great job defining the role of a Performance Qualification (PQ); Testing shall demonstrate reliable performance and should be performed on the fully integrated system. In other words, let the operators run the system. Unfortunately, I feel the final version of ASTM E2500 falls short on this point. There is no specific recommendation for a PQ. The document instead chooses to focus on more fashionable things such as Quality Risk Management and Design Review. Those are great, but I don’t see how anyone can turn over a system in good faith without first doing a solid test run under real-world conditions.

Although the principles outlined above can help to streamline and ensure project success, calling an IQ/OQ a commissioning document or using a punch list instead of deviations to manage change control does not change the “physics” of a project nor does it remove the human element. If a project is underfunded, if a project is based upon an unreasonable schedule, if a project is not properly staffed, no approach to specification, design, and verification is going to work.

ASTM E2500 is not a license to create an engineering silo or a special projects team which cuts itself off from the rest of the organization or is disrespectful to quality assurance and/or operations. These groups are still critical to project success. Bringing quality assurance into the project early will help ensure that qualification activities are included in the project schedule in a realistic way; it can help ensure that the project doesn’t have to chase after material certifications a year too late; it can help ensure that data integrity concerns are addressed at the conceptual stage of systems design. As with any endeavor, it’s humans all the way down.

Nels Hackl

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