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Design Review (DR) and Quality Risk Management (QRM) are considered current industry practice and are essential as enabling processes for verification of facilities, systems, and equipment. But what is Design Review? Why is Design Review underutilized in CQV projects? What are the risks of not performing Design Review? And more importantly, aside from regulatory expectations, what are the benefits of performing Design Review?
What is Design Review
Design Review is a current industry practice and a regulatory expectation as an aspect of cGMPs. But what is it? Per ASTM E2500, Design Reviews are “planned and systematic reviews of specifications, design, and design development and continuous life-cycle of the manufacturing system. Design reviews evaluate deliverables against standards and requirements, identify problems, and propose required corrective actions.” Design Review can be considered from two perspectives: GEP and QRM.
From the perspective of GEP, the purpose of Design Review is to ensure that all requirements, including product and process user requirements and general user requirements, federal, state, and local regulatory code compliance requirements, are satisfied by the design; that health, safety, and environmental (HSE) risks are identified and appropriately mitigated by the design; and that business needs, energy efficiency, total cost of ownership, constructibility, and other similar considerations are addressed by the design.
From the perspective of QRM, the purpose of Design Review is to ensure that product and process requirements are satisfied by the design, that Critical Aspects are appropriately addressed by the design, that risks to product quality or patient safety posed by the design are identified, and that unacceptable risks to product quality or patient safety are mitigated by the design.
Per the ISPE ARM GPG: “The effort, formality, and documentation of these reviews should follow the ICH Q9 of being commensurate with the level of risk. Design review documentation may take the form of engineering meeting minutes or notes. For highly critical, novel systems, design reviews and stage approvals may be extensive and generate significant project documentation.”
Design Review as a Verification-Enabling Process
So, how does Design Review enable Verification?
To answer that question, let’s first look at Verification. Per ASTM E2500, Verification is “a systematic approach to verify that manufacturing systems, acting singly or in combination, are fit for intended use, have been properly installed, and are operating correctly. This is an umbrella term that encompasses all types of approaches to assuring systems are fit for use such as qualification, commissioning and qualification, verification, system validation, or other.” As such, Verification, like Design Review, can be considered from the same two perspectives: GEP and QRM.
From the perspective of GEP, Verification includes fitness for intended use for all aspects of a system and encompasses both requirements that impact product quality, PURs, and requirements that do not, General User Requirements (GUR). From the perspective of QRM, Verification includes fitness for intended use for Critical Aspects of a system and encompasses PURs only. As with Design Review, the effort, formality, and documentation of Verification activities should also be commensurate with the level of risk.
First, Design Review helps prevent implementation of systems that fail verification testing by ensuring that the design satisfies user requirements prior to procurement or fabrication of the system. As a result, changes, re-designs, and rework during system commissioning are minimized.
Second, Design Review helps ensure that user requirements are well-defined and appropriate. In order to perform Verification, user requirements, and therefore the design aspects that satisfy those user requirements, must be specific, realistic, measurable, and verifiable. Verifying these aspects of the design through Design Review supports and facilitates verification of the system once implemented.
Third, and most importantly from the QRM perspective, Design Review supports definition of the process risk control strategy and identification of Critical Aspects of the system. Design Review identifies process risks to product quality posed by the design and determines the acceptability of those risks. Where identified risks are unacceptable, Design Review ensures that the design acceptably mitigates those risks. Thus, the features of the design that mitigate risk to product quality are identified as Critical Design Elements, which combined with Risk Assessment, directly inform the verification strategy to ensure that testing is commensurate with risk.
Therefore, robust Design Review combined with Risk Assessment becomes the key enabler for implementing a science-based, risk-based verification of facilities, systems, and equipment.
Current Industry Design Review Practices
In practice, Design Review is often not performed, performed as an afterthought, or otherwise seen as a non-value-added hindrance to project progress.
Suppliers develop designs from an unclear design basis due to missing or inadequate user requirements, which prevents meaningful Design Review. In the absence of clear user requirements, suppliers follow their own procedures and design standards. In the absence of structured Design Review, suppliers follow their own change management procedures for continued design development.
Pharmaceutical firms may lack a formal Design Review process or may simply fail to follow their formal process due to competing priorities and constraints, and a lack of understanding of the value of Design Review. When Design Review is performed, roles and responsibilities are often unclear, the appropriate SMEs may not be involved, and everyone assumes others are performing needed reviews.
Data from CAI C&Q benchmarking reveals that most firms do not perform Design Review. Those that do perform Design Review typically have Design Review required per SOP; however, in practice, it tends to be a checkbox activity required by Validation (i.e. as Design Qualification “light”) and not seen as adding value. The same perception generally holds true for DQ, with most firms performing DQ as part of Design Review activity, or as EDR that is used as an exercise to meet EU Annex 1 requirements.
Opportunity Cost of Failure to Perform Design Review
So, what happens as a result?
Critical design features fail to meet specification. Product-contact materials of construction are designed incorrectly or with incorrect surface finishes. Components are sized incorrectly. Instrument ranges or accuracy are designed incorrectly. Hygienic piping (dead legs, slope, drainage, etc.) is designed incorrectly. Systems are designed with operability, physical, mechanical, or automation integration issues. These issues lead to system implementation and commissioning failures that directly impact risk to product quality, resulting in often extensive and time-consuming re-design and re-implementation. Verification costs and
schedule increase. Quality oversight increases.
Important maintenance, environmental, safety, and ergonomic features fail to meet specifications, because they were not considered adequately during Design Review. These issues lead to implementation changes or remediation.
Issues that would otherwise be simple are missed, such as incorrect P&ID component or instrument tags. Such issues may lead to multiple drawings and documents that require revision post-implementation, resulting in considerable issue management and document control overhead.
All of these outcomes adversely impact overall project cost and schedule, causing costly delays that were entirely preventable and implementation changes that are far more expensive than if they had been resolved during the Design phase.
How CAI Can Help
How significant is it to your success to deliver a large project two months earlier?
CAI had four authors on the original ASTM E2500 standard, published in 2007, and CAI has two authors on ISPE Baseline Guide Volume 5 2nd Edition, expected to be released later this year. CAI has executed multiple projects using a QRM-based integrated C&Q approach per the principles defined in ASTM E2500, ICH Q9, and the upcoming ISPE Baseline Guide Volume 5, 2nd Edition. Leverage our experience to optimize your C&Q program and deliver your projects more quickly with increased compliance and reduced costs. Design Review is an essential GEP and an enabling process for QRM-based integrated C&Q. CAI can help
you develop your GEPs and a QRM-based integrated C&Q approach using the latest industry practices.
FDA 21 CFR 211.42: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=211.42
FDA Pharmaceutical cGMPs for the 21st Century: https://www.fda.gov/media/77391/download
ICH Q8: http://www.ich.org/products/guidelines/quality/quality-single/article/pharmaceutical-development.html
ICH Q9: http://www.ich.org/products/guidelines/quality/quality-single/article/quality-risk-management.html
FDA Guidance for Industry – Process Validation (2011): https://www.fda.gov/downloads/drugs/guidances/ucm070336.pdf
Eudralex Volume 4: https://ec.europa.eu/health/documents/eudralex/vol-4_en
EU Annex 15: https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-4/2015-10_annex15.pdf
ASTM E2500: https://www.astm.org/Standards/E2500.htm
ISPE Baseline Guide Volume 5: https://ispe.org/publications/guidance-documents/baseline-guide-vol-5-commissioning-qualification-2nd-edition