25/26 January 2023
The ISPE Baseline Guide Vol 5 on Commissioning & Qualification has been in place since 2001 and was thus no longer up to date. Recent developments, e.g. towards a lifecycle model, were not reflected in the document. Adjustments to the state of the art were made in the past by means of "bridges". Now, the Guide was completely revised.
The new document is very extensive with a total of 207 pages. The Baseline itself contains "only" 111 pages, though. The remaining pages contain 17 appendices with references to the regulations, sample documents, references and a glossary. Appendix 15 describes the handling of legacy systems or systems with inadequate qualification. The Baseline itself is divided into 14 chapters:
2. User Requirements Specification
3. System Classification
4. System Risk Assessment
5. Design Review and Design Qualification
6. C&Q Planning
7. C&Q Testing and Documentation
8. Acceptance and Release
9. Periodic Review
10. Vendor Assessment for C&Q Documentation Purposes
11. Engineering Quality Process
12. Change Management
13. Good Documentation Practice for C&Q
14. Strategies for Implementation of Science and Risk-Based C&Q Process
The aim and purpose of the Baseline are to present an integrated commissioning and qualification approach that is "compliant" with the regulations and enables the qualification process to be carried out efficiently and cost-effectively. The chapters 2 to 9 describe this process. The approach includes a system risk assessment that identifies critical aspects (CAs) and/or critical design elements (CDEs). The CDEs are system functions or properties that influence product quality and thus patient safety. The Baseline is applicable to human and veterinary medicinal products and to the content of medicinal products in combination products. Medical devices, on the other hand, are outside the scope of the Baseline.
User Requirements SpecificationThe integrated commissioning and qualification approach starts with the development of user requirements. They are based on product risks, critical quality attributes (CQAs) and critical process parameters (CPPs) as well as on regulatory and internal company requirements. If necessary, health and safety aspects can also be included. These user requirements must be met in order for the system to be suitable for its intended purpose.
System ClassificationIn a second step, the system is classified. Depending on its influence on product quality, the system can have a direct impact (direct impact system) or no direct impact (not direct impact system) on product quality. Direct impact systems will be commissioned and qualified. Not direct impact systems will only be commissioned. In the baseline, commissioning is not only related to initial operation, but may also be extended to the design of the systems (e.g. FAT, see below).
As part of the system risk assessment, a direct impact system is then subjected to a risk assessment in which the influence of the system on product quality is assessed and the critical design elements (CDEs) are identified. Subject matter experts (SMEs) who understand the "science" behind the manufacturing process that is to run on the system should be involved in this risk assessment. The CDEs will be identified by looking at the CPPs that need to be controlled to ensure product quality. The CPPs are in turn based on the CQAs. Unacceptable risks must be reduced within the framework of risk management, including CDEs. The CAs of the process can be derived from the CPPs. And the CDEs of the system can be identified based on CAs. This looks a bit complicated; therefore the relationship between CQAs, CPPs, CAs, CDEs and the corresponding tests is illustrated by a vivid example in the baseline.
The next step is the planning of commissioning and qualification, which can take place parallel to the design process. However, sufficient design information must be available. As an iterative process in the design phase, a design review is then carried out to ensure that all user requirements and CDEs are mapped in the design. Design aspects that influence product quality are confirmed in the Design Qualification (DQ) for direct impact systems. The quality unit releases the design qualification. After completion of the design review and the DQ, the commissioning and qualification plan can also be finalised.
Commissioning and qualification tests should start at the earliest possible stage. Of course, the prerequisites must be in place and the tests must be meaningful at such an early stage. This means that it can be started even before the design has been completed. The tests also include checking documents. In the commissioning and qualification planning, tests are also addressed which are used within the scope of qualification. These are Factory Acceptance Tests (FAT) and Site Acceptance Tests (SAT).
Once the tests have been completed, they have to be accepted and released. The release then confirms that the system is suitable for the intended purpose. Afterwards, the process validation or routine production can begin. However, process validation or Process Performance Qualification (PPQ) considerations are not part of the Baseline.
The maintenance of the commissioning and qualification status after release and also during routine operation is carried out by various systems such as change management, calibration and maintenance. In addition, a periodic review of the system is required.
Supporting processes of the actual, integrated commissioning and qualification process are described in the chapters 10 to 13. The sample examples in the appendices also serve as illustrative material for a possible implementation.
The revision of the original ISPE Baseline Vol. 5, Version 1, on commissioning and qualification includes the newer regulatory requirements of the EMA, FDA, ICH. Due to the revision, the first version of Baseline No. 5 itself as well as the following ISPE guidelines: Science and Risk-Based Approach for the Delivery of Facilities, Systems and Qualification and Applied Risk Management for Commissioning and Qualification are no longer applicable and have now been withdrawn. Also terms from version 1, such as "Component Criticality Assessment" (replaced by CDEs), "Enhanced Design Review" (replaced by Design Review leading to DQ) and the "Indirect Impacts System" are no longer included in version 2. The various roles involved in releasing the various documents are also explicitly discussed. Especially the quality unit should have an "oversight". It should be integrated in the release of test plans and documents for "direct impact systems" and in the acceptance and release documentation. The SMEs play an important role in the baseline. As an example, a document approval matrix in Chapter 6 gives suggestions regarding the signatures to be provided on various commissioning and qualification documents.
The revised Baseline No. 5 on commissioning and qualification has been available for purchase on the ISPE website since June 2019.
ECA Good Practice Guide Integrated Qualification and Validation. Last year, the ECA published a Modern Qualification Guide - a guide to effective qualification based on Customer -Supplier Partnership. The feedback on this guide is currently being incorporated into further development of the original guide. The new ECA Good Practice Guide Integrated Qualification and Validation will be presented in Berlin, Germany, on 8/9 October 2019. In the context of this presentation, comparisons/differences to ISPE Commissioning and Qualification Version 2 will also be discussed.