Best Practices Preparing for a Commissioning and Qualification Audit

When a company is not prepared for an audit of its commissioning and qualification (C&Q) program, or is not aware of how its program meets regulatory expectations, an audit may not go as well as expected. This article provides some guidance on how to prepare for such an audit.

Background

This article provides guidance on preparation for audits or inspections, with specific content describing the aspects to consider when preparing an introductory presentation when the scope includes C&Q, including validation maintenance activities, such as periodic validation reviews and requalification. The intent is to provide readers with some practical guidance on aspects to be included in a briefing presentation on these topics that can be given to auditors describing the process the company used, documentation deliverables, content, and how the program meets regulatory expectations.

Each company employs a unique approach to C&Q and quality management systems (QMSs), often using distinct terminology and abbreviations that new employees must learn. For both internal and external inspections in which these topics are in scope, outlining the site’s approach during the initial meeting with auditors is advisable. This explanation facilitates understanding of the company terminology, key deliverables, and their alignment with regulatory expectations. If the topic arises later in the inspection, then the introductory deck will provide the background, which can help the auditors understand the program.

There are no specific regulations defining program expectations, but there is relevant guidance in the following resources.

• The European Commission’s “Eudralex, Vol 4: EU Annex 15 Qualification and Validation EU Guidelines for Good Manufacturing Practices for Medicinal Products for Human and Veterinary Use. Annex 15: Qualification and Validation”
• International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use’s (ICH) “ICH Harmonised Guideline Q9(R1): Quality Risk Management”

ISPE Guidance

ISPE Baseline^® Guide: Commissioning and Qualification (Second Edition) was revised in 2019 to describe a science- and risk-based approach to C&Q with supporting best practices.1 These practices include conducting a system risk assessment (SRA) by defining the operational sequence or process flow of the system, identifying critical quality attributes (CQAs) and critical process parameters, evaluating their impact on the system output, and designating the controls or procedural measures that will mitigate the risks to system product quality identified in the risk assessment to an acceptable level.

Upon completion, the SRA identifies the design and the procedural risk controls and confirms that the system design proposed will have an acceptable risk profile. After qualification, the SRA will be reviewed during any significant events, such as system changes or deviations encountered during production, and updated where necessary. The outcome of the SRA also provides a basis for design qualification and becomes the focus for system qualification.

By connecting the ICH QRM Q9 (R1) methodology (see Figure 1) with the best practices in ISPE Baseline® Guide: Commissioning and Qualification (Second Edition), auditors will better understand how the QRM principles are applied to the company C&Q program.2

Source1

C&Q Process Overview

When the C&Q process is in the inspection scope, it’s recommended to introduce it to auditors during the audit kickoff meeting. The information presented should include overall C&Q process flow, company terminology, deliverables and alignment to the organization’s overall QRM program, and how the program meets the regulatory expectations relevant to the company procedures. Figure 2 graphically depicts a typical C&Q process flow with deliverables.

Good Engineering Practices

Under a science- and risk-based approach, there must be an engineering quality program to ensure that engineering deliverables meet quality unit expectations. The program is usually defined by a set of engineering Good Engineering Practice (GEP) procedures that are approved by the quality unit (see Figure 3).

Design Review

Design review (DR) is the process, usually owned by engineering, that verifies the design traceability back to the user requirements follows best practices and complies with company standards and specifications (and/or the specifications proposed by the design authority). This includes quality-impacting and quality-non-impacting requirements. ISPE Baseline® Guide: Commissioning and Qualification (Second Edition) recommends conducting DRs to confirm that design deliverables align with the user requirements specification (URS) and the mitigation control strategies developed in the SRA. The Guide also recommends that although design review and design qualification (DQ) do not need to be separate activities, they should be documented separately. DR will help support the DQ summary report for direct impact systems and the subsequent quality approval.

Engineering Change Management

To ensure that changes during construction do not impact the conclusions reached through DR/DQ or SRA and that the design intent is met, engineering change management (ECM) is applied after DR is completed and the DQ summary reports are approved.

Note that this is not the same process as site (operational) ECM. For applicable cycle development for equipment such as washers or autoclaves, engineering runs for process system may be included in the commissioning scope, i.e., before qualification under engineering change management.

Site Change Management

Site change management is defined in EU Annex 153 as: “Change Control. A formal system by which qualified representatives of appropriate disciplines review proposed or actual changes that might affect the validated status of facilities, systems, equipment or processes. The intent is to determine the need for action to ensure and document that the system is maintained in a validated state.” The system will transition to oversight by the company QMS, including site change management after acceptance and release.

Commissioning

This GEP has several definitions. ISPE Baseline® Guide: Commissioning and Qualification (Second Edition) defines it as: “A well planned, documented and managed engineering approach to the start-up and turnover of facilities, systems utilities and equipment to the end user that results in a safe and func-tional environment that meets established design requirements and stakeholder expectations.”

An alternative definition “is setting a mechanically complete system to work ensuring that operation meets the specifications.”3 This work is critical to ensure correct operation—it is often iterative with interim adjustments made, followed by testing to ensure the adjustment provided the desired result. For example, this includes getting the correct balance of airflow in a system or tuning a control loop to ensure smooth response and no “hunting.”

It is an engineering responsibility to ensure commissioning is adequate. Critical systems may require more tests to ensure that the specified performance is met during worst-case operating conditions. Commissioning will ensure that the system delivered is suitable for intended use and meets both quality-impacting and non-quality-impacting user requirements and business objectives. The URS and SRA alone are not adequate to define the scope of commissioning.

The Commissioning Process

EU Annex 15 offers the following information3 for factory acceptance testing (FAT)/site acceptance testing (SAT): “Equipment, especially if incorporating novel or complex technology, may be evaluated, if applicable, at the vendor prior to delivery. Prior to installation, equipment should be confirmed to comply with the URS/functional specification at the vendor site, if applicable. Where appropriate and justified, documentation review and some tests could be performed at the FAT or other stages without the need to repeat on site at installation qualification (IQ)/operational qualification (OQ) if it can be shown that the functionality is not affected by the transport and installation. FAT may be supplemented by the execution of a SAT following the re-ceipt of equipment at the manufacturing site.”

The documents delivered through these processes may support C&Q: the strategy to be used should be predefined in the change record, C&Q plan, or project validation plan. The tests and inspection required will be usually defined in local/industry and project specifications to ensure that the system is installed and operated to meet the design specifications.

Commissioning Deliverables

Note that the form of documents delivered can vary depending on the system type. For example, a heating, ventilation, and air conditioning (HVAC) testing and balancing report can provide all the necessary information to support HVAC system qualification. For an equipment system, FAT and SAT may provide the necessary information. This is described in more detail in the following sample systems.

• HVAC system: A testing and balancing report may include installation verification (IV) and operational verification (OV) in different sections of the report. There may also be engineering change records to be considered. For example, if it’s found after balancing that a fan change is required to meet the specified air flow rate with the system resistance, an engineering change record would note that.
• Lyophilizer: IV and OV may be contained within different sections of the FAT and SAT.
• Water for injection (WFI) system: IV and OV may be contained in a combination of the pretreatment generation and automation system, FAT and SAT, and a site IV and OV report. Where it is not readily apparent which sections of documents contain IV and OV, it is recommended that a way of showing the relevant content is used; tagging the relevant sections or providing a specific set of contents with IV and OV sections marked, for example.

Commissioning Summary Report

This document is produced by engineering and provides a detailed summary of the commissioning documentation, typically including the following: a) a traceability matrix, or a summary showing where URS requirements have been tested; b) ECM summary, per system or system group; c) summaries of installation verification, operational verification, any adjustable set points, and any testing issues (discrepancies); and d) rectification.

The designer (architect and engineer) is responsible for delivering a design complying with national and local standards and regulations.

The company confirms that:

• The design is fit for its intended use through DR (commissioned systems) and DQ (qualified systems).
• The SRA is typically developed at the beginning of the design process (though it may be developed later) and completed at the “issue for construction” stage when it becomes a controlled document that confirms that the proposed design has an acceptable risk profile.
• ECM will ensure any proposed changes are acceptable to the architect/engineer, to the company (commissioned systems), and to the company with the quality unit (commissioned and qualified systems) prior to allowing them to proceed. The process will also ensure that the final documentation reflects the installed commissioned system (and, where applicable, qualified system).
• Roles and responsibilities should be defined to ensure that the people with the appropriate training and experience are assigned to the relevant tasks.

Qualification Deliverables: URS

EU Annex 15 says the following:3 “User Requirements Specification (URS). The set of owner, user and engineering requirements necessary and suffi-cient to create a feasible design meeting the intended purpose of the system. The specification for equipment, facilities, utilities or systems should be defined in a URS and/or a functional specification. The essential elements of quality need to be built in at this stage and any GMP risks mitigated to an acceptable level. The URS should be a point of reference throughout the validation life cycle.”

Companies must have a process for defining the requirements for systems to be qualified (the process may also be used as a GEP for commissioned systems). If a typical GEP-based format is used, it needs to be modified to classify quality-impacting requirements vs. non-quality-impacting requirements. The optimum approach for these documents is to keep them concise. This means defining the specific system requirements, but not aspects that may be addressed through other project documents such a specifications/company standards, or contractual items such as specifications, documentation, training, manuals, spare parts, etc.

The URS should define the requirements but not how they are achieved. Each requirement must be verifiable. This allows the designer the freedom to produce the most effective solution. Then, the company reviews the proposed design solution during DR/DQ to ensure it is aligned with best practices and is fit for purpose. Next, by approving URS(s) associated with quality impacting systems, quality approves the quality impacting user requirements.

System Impact Assessment and System Classification

The project scope is divided into systems with clearly defined boundaries to ensure comprehensive coverage of the project scope. This process typically falls under engineering activities. Next, the systems should be assessed to determine which are categorized as a direct impact system, which will undergo C&Q, and which systems will be commissioned. The rationale for categorizing these systems should be transparent and easily explainable.

ISPE Baseline® Guide: Commissioning and Qualification (Second Edition) offers a structured method for this assessment through a set of standard questions. These questions help determine whether a system qualifies as a “direct impact system” or a “not direct impact system.” These are a system with the potential to affect product quality, which requires C&Q, or a system without that potential, which only requires commissioning. Document this information and the supporting rationale in either a change record, C&Q plan, project validation plan, or a record document that is kept in a validated system and referred to in one of these documents.

The change record, C&Q plan, or project validation plan outlines the approach the company will use for C&Q. It identifies the equipment systems in scope and specifies the deliverables for each system defined by the system boundary and impact assessment activities. The document is approved by the quality unit and will serve as the primary reference for explaining the risk-based approach during audits.

System Risk Assessment and Summary Report

The SRA considers the risks to the output of the system (considering the CQAs at each process step or stage) based on the proposed design and anticipated controls (i.e., design and procedural). It determines if the controls are adequate to provide an acceptable risk profile for that system or additional controls need to be added to mitigate unacceptable risk. Note that the risk being assessed is the potential impact to the CQA of the system product. When initial risk evaluation shows unacceptable risk, additional controls are added.

Upon completing the SRA, it must be mapped back to the URS to ensure all identified controls are incorporated in the user requirements. The design controls identified provide the focus for qualification. If the SRA process documents additional controls not included in the URS, the URS is updated to include these requirements. Note that the process focuses on potential impact to system product specifications, as this is a straightforward process from an engineering perspective; potential to impact patient safety is addressed through ensuring the process delivers product that meets the specifications.

Design Qualification

EU Annex 15 has the following content regarding DQ:3 “Design qualification (DQ). The documented verification that the proposed design of the facili-ties, systems and equipment is suitable for the intended purpose. The next element in the qualification of equipment, facilities, utilities, or systems is DQ where the compliance of the design with GMP should be demonstrated and documented. The requirements of the user requirements specification should be verified during the design qualification.”

DQ and the supporting engineering DR process ensure that quality is incorporated into the design, i.e., quality by design. Note that if the strategy adopted by the company includes the review of the design and associated specifications, quality approval of the associated specifications is not required. The DQ process is usually owned by quality, and it confirms the proposed design is fit for purpose (intended use). In contrast, the SRA determines that the proposed design has an acceptable risk profile (if the system operates according to the specifications).

The SRA can help focus DQ, by defining the design risk controls, allowing the team to assess the reliability of the design of those risk controls. Therefore, DR, DQ, and SRA together confirm that the final version of the proposed design (i.e., issue for construction) is optimized from an engineering perspective, fit for intended use from a quality perspective, and has an acceptable system product quality risk profile.

Installation Verification and Qualification

IQ is described in EU Annex 15 as the following:3 “Installation Qualification (IQ); The documented verification that the facilities, systems and equip-ment, as installed or modified, comply with the approved design and the manufacturer’s recommendations. IQ should be performed on equipment, facilities, utilities, or systems. IQ should include, but is not limited to the following: Verification of the correct installation of components, instrumenta-tion, equipment, pipe work and services against the engineering drawings and specifications; ii. Verification of the correct installation against predefined criteria; iii. Collection and collation of supplier operating and working instructions and maintenance requirements; iv. Calibration of instrumentation; v. Verification of the materials of construction.”

Operational Verification and Qualification

OQ is described in EU Annex 15 as the following:3 “Operational qualification (OQ); The documented verification that the facilities, systems and equip-ment, as installed or modified, perform as intended throughout the anticipated operating ranges. OQ normally follows IQ but depending on the com-plexity of the equipment, it may be performed as a combined Installation/Operation Qualification. OQ should include but is not limited to the following: i. Tests that have been developed from the knowledge of processes, systems and equipment to ensure the system is operating as designed; ii. Tests to confirm upper and lower operating limits, and /or “worst-case” conditions. The completion of a successful OQ should allow the finalization of standard operating and cleaning procedures, operator training and preventative maintenance requirements.”

Note that, as defined in ISPE Baseline^® Guide: Commissioning and Qualification (Second Edition), installation and operational verification is a process, not an activity. This commissioning process provides the documented evidence that the system installation and operation meet specification. Installation and operational qualification refers to this documentation process as one that provides the supporting documented evidence developed by engineering (i.e., subject matter experts [SMEs]). Although, historically, the validation department was responsible for generating IQ/OQ after commissioning. The ISPE Baseline^® Guide: Commissioning and Qualification (Second Edition) process has only one set of documents. Typically, engineering will summarize the commissioning in a commissioning summary report.

It is worth noting the following content from Annex 15:3 “3.6: Where appropriate and justified, documentation review and some tests could be performed at the FAT or other stages without the need to repeat on site at IQ/OQ if it can be shown that the functionality is not affected by the transport and installation.” And “3.7: FAT may be supplemented by the execution of a SAT following the receipt of equipment at the manufacturing site.”

Qualification Summary Report/Acceptance and Release

The qualification summary report provides a concise summary of typical commissioning documentation, including:

• Summary of commissioning and any associated discrepancies
• Traceability showing where design risk controls have been tested based on SRA
• Traceability showing where procedural risk controls are included based on SRA
• Engineering change management summary (per system or system group)
• Confirmation of a parts and spares list
• List of operational and maintenance procedures
• List of personnel trained in the procedures
• Confirmation that the system is incorporated in the maintenance and calibration programs
• Handover certificate

Acceptance and Release

Per ISPE Baseline^® Guide: Commissioning and Qualification (Second Edition), if defined appropriately in the company procedures, approval of the qualification summary report by operations and quality readies the system for the next required step, which is operation/performance qualification.

Requalification

Equipment, facilities, utilities, and systems should be evaluated in accordance with a defined program to confirm that they remain in a validated state. Where requalification is considered necessary, it can be done to ensure maintenance of the validated state. Guidance on a science- and risk-based approach for this is provided in ISPE Baseline^® Guide: Commissioning and Qualification (Second Edition).

Conclusion

Using the best practices presented in this article will enable companies to be prepared for audits or inspections, especially for C&Q. The knowledge shared will assist companies in understanding the points to consider during the development of materials. This will help them prepare to explain their approach to commissioning, qualification, and validation maintenance. Being prepared for audits and inspections will ensure companies complete successful audits.