Intro

ISPE has just released the second edition of Baseline Guide 5 for Commissioning and Qualification (C&Q) The objective of the 2019 C&Q Baseline Guide revision is to define and explain a simplified risk-based C&Q process in a single guide that meets present-day standards and provide focus to ensure a compliant, efficient, and cost-effective approach.  The revised Guide provides the current industry best practices for commissioning and qualification of pharmaceutical facilities and equipment.  It supersedes the 2001 publication and the two 2011 Guides covering Quality Risk Management/ASTM E2500 based approaches.

The new Guide provides an improved QRM C&Q process flow and recommended implementation practices with practical examples taken from the industry.

Overview

Key drivers of the original 2001 guide were to reduce the rising costs to bring facilities and equipment online due to inconsistent interpretations of regulatory requirements as well as understanding the importance of applying Good Engineering Practices (GEPs) in a C&Q program.  This guide defined a better understanding of baseline cGMP requirements through coordination with ISPE, industry, and global regulatory bodies.  The guide defined a flexible and innovative lifecycle approach to facility, systems and equipment design, construction, commissioning, and qualification supported by the definition of key terms for consistent interpretation and application.  The result was an improvement to an often time-consuming and costly process enabling timely and cost-effective facility C&Q.

Beginning in 2007 industry began recognizing the importance of a science and risk-based qualification approach with a focus on Quality by Design that was built around risks to product quality and patient safety.  This move was primarily influenced by the following guidance documents:

• 2007 – ASTM E2500 – defined the C&Q risk-based process as “verification”
• 2011 – ISPE Guide – Science and Risk-Based Approach for the Delivery of Facilities, Systems, and equipment
• 2011 – ISPE Good Practice Guide: Applied Risk Management for Commissioning and Qualification

The following QRM C&Q process flow diagram describes the logic of the execution process described in the new guide and also summarizes the overall content of the revised guide.

Among the improvements included in the revised guide are:

• A clear C&Q planning process, including a Document Approval Matrix for typical process deliverables
• URS Guidance Definition including “fitness for use” and how to differentiate requirements (the what) from specs (how the what is met) and distinguish between quality impact and no quality impact
• A system for the classification of systems with respect to quality impact – Direct Impact and not direct impact
• Guidance on how to incorporate a streamlined System Risk Assessment (SRA) into the C&Q process, how to identify Critical Design Elements (CDEs) which support the Critical Aspects (CAs) and their subsequent focus for qualification
• An optimized Design Review/ Design Qualification (DR/DQ) process, where DQ is performed to verify incorporation of CDEs in the system design
• A streamlined, integrated C&Q approach, on how to execute the testing, including engineering and quality differentiation and testing phase minimum requirements for completion
• Utilization of a traceability matrix as a project management tool
• Clarification of the scalable System Acceptance and Release process that can be applied to individual systems or manufacturing areas
• Establishing a Change Management processes, incorporating Engineering Change Management (ECM) necessary to support the QRM C&Q process and minimize repetitive testing
• Incorporation of current industry best practices via examples contained in appendices
• Definition of GEP documentation standards

Terminology and Retired Concepts

The revised Guide focuses on the implementation of the C&Q the process with an aim to eliminate the anxiety associated with terminology (i.e., C&Q, Verification, IV/OQ, etc.).  C&Q is used to describe the process for establishing that facilities, systems, and equipment are fit for purpose.  Verification is used to describe an activity performed during the C&Q process to establish suitability for intended use.  The terminology used for these processes isn’t critical.

The Guide defines the focus for the qualification effort as Critical Design Elements (CDEs) – Design function or feature of an engineered system that is necessary to manufacture products with the desired quality attributes consistently.

In the context of Good Engineering Practices (GEP), the guide clearly states that the C&Q process should:

• Utilize Engineering deliverables, those normally associated with the commissioning process, are used to document evidence that systems are installed and operate to meet specifications;
• align the level of the C&Q effort with the level of risk related to quality and business,
• remove artificial constraints from the execution effort.

It is important to note that several concepts associated with the original guide have been retired with the application of the QRM approach.  These include:

• Indirect Impact
• Component Criticality Assessment (CCA)
• “V-Model”
• Enhanced Documentation
• Enhanced Commissioning
• Enhanced Design Review

The lifecycle-based C&Q execution process, initially referred to as “leveraging,” is now referred to as an integrated commissioning/qualification execution process.

Key Chapter Concepts

User Requirement Specifications (URS)

In the new Guide’s QRM C&Q Process Flow figure, the URS is positioned as an initial document in which the process, product, system, regulatory, and quality requirements for the system are listed.  The product and process requirements provide the science-based knowledge that are the inputs to the QRM C&Q process.

The URS document describes the intended purpose of the system but does not describe how the requirements are met.  URS content separates Quality requirements from other requirements (EHS/Business) and must be written in a manner that the requirement is verifiable.

Additional information addressed for URS’s includes:

• Guidance on when URSs are needed and Identification of other sources of user requirements information
• Approval of URS’s, changes to URS’s, and changes post-approval
• URS application for modification or changes to legacy systems

System Classification

The guide establishes an updated approach for system classification, with a defined focus on product quality and expanded scope on the product manufacturing lifecycle, and provides criteria to classify systems into two categories:

• Direct Impact systems – those systems having a direct product quality impact are commissioned and qualified. Systems classified as direct impact provide the focus for the System Risk Assessments.
• Not direct impact – those systems not having a direct product quality impact. These systems are commissioned only.

System classification requires that boundaries are clearly defined to support integrated C&Q testing and to influence the construction management, document collection, turnover required to support the C&Q execution process.

Note: CAI recommends NOT performing system classification as a separate dedicated deliverable.  The process risk assessment provides the product/process knowledge (CQAs/CPPs) that can be associated with the equipment to provide the required focus (traditionally those systems deemed to be Direct Impact) for verification effort.

System Risk Assessment

The guide approach presents a System Risk-Assessment approach to establish and document the Critical Design Elements (CDEs) of the system design and operation that can impact product quality and identifies the controls (design and procedural) that mitigate the risks to product quality.  CDE identification replaces the former Component Criticality Assessment that lacked the means to rank the risk of the identified components to impact process control or CPP failure. The approach recognizes that systems used in pharmaceutical manufacturing are generally well accepted for use in manufacturing and incorporate standard design control elements.  The SRA is used to:

• Define the risks to product quality
• Define the risk controls (Critical design and automation elements – CDEs)
• Define which instruments/alarms are critical with supporting the rationale
• Link required testing to product process/quality controls
• Provide logic and scope for qualification

The guide provides a relationship diagram that shows how the System Risk Assessment fits into the C&Q process.

The following benefits are achieved by using the SRA approach:

• Focuses on the requirements that impact quality
• Establishes a quality focal point for the design review process leading to Design Qualification (DQ)
• Focuses Quality/Validation efforts on product quality impacting Critical Design Elements
• Defines the controls in place around the identified risks of process failure
• Provides a validation guide to ensure the identified controls are in place and tested
• Establishes a traceability tool from the Qualification Summary to the various lifecycle activities and testing

Design Review (DR) and Design Qualification (DQ)

The importance of DR and subsequent DQ is described as a continuous process throughout the design process of the manufacturing facility.  Guidance is provided for executing and documenting DR and DQ.

It is noted that the DR assures that the deliverables of the design meet the URS requirements and the mitigation control strategies developed during the RA.  DQ is formal documentation to show that critical aspects and CDEs have been included and addressed in the design.  DQ is not intended to be a separate activity from DR but rather is a document focused on critical aspects and is approved by quality.

C&Q Planning

The guide describes the C&Q Plan as the means to facilitate a timely and cost-effective qualification effort.  Having a well-planned C&Q effort will ensure that the user, business, and patient expectations are met and include:

• Quality oversight is defined to support the integrated C&Q execution
• Equipment and systems delivered on time and within budget
• Equipment and systems meet approved requirements are fit for their intended use
• Stakeholder needs, including speed to market, are met
• Products produced from the systems meet defined quality standards.

The guide introduces the planning process, an overview of the plan content, identifies what should be included in the plan an what is not in scope, describes how to organize and write the plan.  An Approval Matrix is also provided that lists the typical documents associated with the C&Q execution effort, the pre- and post-approvers of those documents, and lists the department typically responsible for preparing the document.

C&Q Testing and Documentation

The section contains guidance on C&Q preparation and execution testing activities required to establish supporting documentation.  It outlines the scope and the purpose of the approach to testing, and the roles and responsibilities involved.  For manufacturing systems, all planned testing activities, including the integration of mechanical, electrical, and automation (control systems) components are tested to provide evidence that all acceptance criteria related to user requirements are achieved.  Documentation verification and testing demonstrate that a manufacturing system is fit for its intended use and leads to acceptance and release of the system.

The chapter uses Qualification to refer to document verification and testing for quality requirements as determined by the system risk assessment.  Commissioning refers to documentation verification and testing for all design requirements as listed within the URS, which may include Qualification testing.   Testing performed through documentation verification, vendor testing, or within a commissioning document fulfill qualification requirements as pre-approved in the C&Q plan.  Quality oversight is provided through approval of the CQAs, CPPs, CAs and CDEs, the appropriate acceptance criteria, and the C&Q Plan.

The following details the type of documentation used in the above execution strategy:

• Documentation Review – Documents, such as vendor testing documents and MOC certificates, that confirm vendor testing has been completed and recorded per previously agreed to GDP practices.
• Factory and Site Acceptance tests – Vendor testing, with technical oversight to demonstrate that conformance to design and contractual requirements.
• Test and Balance Reports – Testing conducted with technical oversight to demonstrate that conformance to design and contractual requirements.
• Qualification Testing – Testing with quality oversight, as defined in the approved C&Q Plan, to verify CDEs/CAs.

GEP should support and be applied to all phases of C&Q.  Applying GEP leads to a high degree of assurance that the system meets operational requirements while being cost-effective, compliant with regulations, and well documented.

Another key area addressed is discrepancy management.  Guidance is given on determining whether these out of specification (OOS) results are critical or not critical; those being critical require quality approval.  A discrepancy matrix is provided, indicating where quality input is and is not required.

Acceptance and Release

Acceptance and Release is where all previously completed testing is formally reviewed and accepted, and operational quality system elements are verified (for systems that are qualified) to be in place confirming that the equipment is ready to be released for GMP use.

Release may be documented within a Qualification Summary Report, Acceptance and Release Report or through a change control system.  After release, site change control replaces engineering change management and the project team transitions system ownership to operations.

The acceptance and release process is described along with the organizing and writing of summary reports.  Various figures depict several acceptance release strategies that can be utilized, ranging from individual systems/equipment to manufacturing areas.

Additional Supporting Chapters

The second edition Guide also includes several additional chapters and examples of QRM C&Q process execution documents.  Content included in the additional chapters covers:

• Periodic Review
• Vendor Verification Documentation Assessment
• Engineering Quality Process (EQP)
• Change Management
• Good Documentation Practice

About the Co-Authors

Steve Wisniewski

Steven Wisniewski has over 40 years of experience in delivering projects for design, construction, facility management and compliance of pharmaceutical facilities.  As a principal consultant, he has been involved with the management and direction of several compliance-driven projects and consulting assignments. 

Nathan Temple

Nathan Temple is a project manager and licensed Professional Engineer with twenty consecutive years of experience in the fields of start-up, maintenance, commissioning, and qualification.  He is a certified Project Management Professional.