Cliff Campbell is senior consultant at KPC.

Cliff Campbell

risk management and risk assessment concept | Image Credit: © janews094 - stock.adobe.com

A published paper, titled “Quality Quartets in Risk-Based Qualification” (1), provided a review of the International Society for Pharmaceutical Engineering’s (ISPE’s) 

Baseline Guide of 2019 on Commissioning & Qualification

 (C&Q) (2). That paper introduced a concept called “Quality Quartets” as a practical means of making use of four key concepts in the Baseline Guide: critical aspects (CAs) and critical design elements (CDEs), which were newly introduced in the 2019 Baseline Guide, and the already well established critical quality attribute (CQA) and critical process parameters (CPP) concepts.

A Quality Quartet is essentially a documented expression of the knowledge that a company has about the relationship between CAs and CDEs and the associated CPPs and CQAs. It can be considered a knowledge management output, serving as a practical means of facilitating science and risk-based commissioning and qualification. In addition, the Quality Quartet concept represents a simple and concise means of capturing and communicating product and process knowledge and understanding.

This paper describes the benefits of making use of this Quality Quartet concept as a means of achieving more knowledge-driven risk-based approaches to commissioning and qualification. The International Council for Harmonisation’s (ICH) Q9(R1), which is a revised version of ICH’s 

 guideline (3), can be referred to in this regard. As outlined in the ICH Concept Paper for that revision work (4), there were four main topic areas that the revision sought to address. These were:

High levels of subjectivity in risk assessments and in quality risk management (QRM) outputs

A lack of understanding as to what constitutes formality in QRM work

A lack of clarity on risk-based decision-making

Failing to adequately manage supply and product availability risks.

Two of these four areas, subjectivity and formality in QRM, are particularly relevant to the subject matter of this paper—risk-based approaches to commissioning and qualification, and the 2019 ISPE Baseline Guide—and the guidance presented in ICH Q9(R1) in those two areas is useful to consider.

ICH Q9(R1) highlights the importance of managing and controlling subjectivity when performing QRM activities, and it discusses how subjectivity can impact every stage of a QRM process, including the identification of hazards and the estimation of probabilities of occurrence and severities of harm. It indicates that subjectivity can also impact the estimation of risk reduction and the effectiveness of the decisions made from QRM activities. The revised guideline places a heavy emphasis on the use of knowledge in supporting the application of QRM principles. For example, it states in the Introduction section that QRM “is part of building knowledge and understanding risk scenarios” and that “knowledge is used to make informed risk-based decisions, trigger re-evaluations and stimulate continual improvements.” It highlights how “all decision making relies on the use of knowledge,” and it points the reader to ICH Q10 (5) for guidance on knowledge management.

In relation to applying QRM principles when designing and executing commissioning and qualification activities, it is important to minimize any subjectivity that may be present in the risk assessments that support such activities. The authors propose that applying the Quality Quartet concept as outlined in reference 1 is a practical means toward achieving this. This is because the Quality Quartet conceptessentially links process and product understanding with the technical knowledge that a site has in relation to its facilities, systems, and equipment. When risk assessments are performed to support commissioning and qualification activities as per the 2019 Baseline Guide, that knowledge can be used to make those risk assessments more evidence-based and objective and, therefore, less subjective. To illustrate this, consider the following scenario in relation to Quality Quartets:

An active substance manufacturing site produces an active substance for which there is a CQA associated with a particular impurity (X).

This is a five-stage manufacturing process involving a number of different unit operations, which include various chemical reactions, a salt formation step, a phase separation, a precipitation step, and isolation and drying steps.

The pH of a particular hydrolysis reaction at Stage 3 of the process is known to affect the generation of impurity X.

There is pH control during this hydrolysis reaction—this is considered a CA of the process—the pH of the batch at this step is considered a CPP, and the in-line pH probe on the reactor is considered a CDE.

The impurity X level is further reduced during the isolation step near the end of the process, which occurs in a filter dryer, whereby two methanol (MeOH) additions to the filter dryer remove the impurity from the product prior to the drying step.

The first MeOH addition is made when the batch is still in slurry form and under agitation at 10 RPM. The MeOH charge volume is considered a CPP. (The filter dryer agitation rate is not considered a CPP—it is classified as a process parameter.)

The batch is then filtered under pressure, resulting in a wet cake.

The agitator is then stopped, and a second MeOH charge is made—this washes the cake to remove any residual Impurity X. This second MeOH charge is also considered a CPP. (The cake is inspected during the MeOH wash for any cracks and channels which could impact the efficacy of the wash.).

There are two in-process controls (IPCs) in the process which relate to this impurity:

A pH measurement during the hydrolysis reaction at Stage 3 of the process—as indicated previously, this is done using an in-line pH probe on the reactor.

An off-line high-performance liquid chromatography (HPLC) impurity test performed on a sample taken from the filter dryer following the second MeOH charge.

The company has applied its product and process knowledge, as well as its technical knowledge about its equipment, to construct the following Quality Quartets:

CQA=% impurity X in the finished active substance

CPP–pH of the batch during the hydrolysis reaction at Stage 3 of the process

CA–Controlling pH during this hydrolysis reaction

CPP–Volume of first MeOH charge to the batch in the filter dryer, while the batch is under agitation

CA–Controlling the quantity of the MeOH addition

CDE–Flow-meter which measures the volume of MeOH charged.

CPP–Volume of second MeOH charge to the wet cake in the filter dryer while the batch is not under agitation

The above is an example of how one CQA can be part of three different Quality Quartets. This is not unusual; many CQAs relate to more than one CPP.

The above examples of Quality Quartets are illustrative only. The authors are aware that the above types of CPPs are not always registered within marketing authorisation dossiers; however, they still remain valid, when they relate to the protection or achievement of CQAs. 

Documenting Quality Quartets such as those above is considered useful, as it can help reduce the level of subjectivity in risk assessments that may be performed on a manufacturing process, and in the risk ratings that arise from such risk assessments, specifically by making the severity, probability of occurrence and detection ratings, more objective. This is illustrated by the following:

If failure modes relating to the in-line pH probe are being risk assessed, or if failure modes relating to that step of the Stage 3 process are being risk assessed, the severity ratings that are assigned to those failure modes can be informed by utilizing the knowledge represented by Quality Quartet 1. This indicates that such failure modes may directly impact upon a CQA (% Impurity X). This helps reduce any subjectivity in those ratings, because the process knowledge that Quality Quartet 1 is based on, lends objectivity to such severity ratings.

This is also the case with regard to failure modes pertaining to the isolation unit operation involving the MeOH addition steps.

Subjectivity can also be minimized when probability of occurrence and detection ratings are being assigned to failure modes pertaining to the pH probe or to the flow-meter used in the MeOH additions. This is because it is likely that there will be clearly documented good manufacturing practice (GMP) controls in place to ensure the correct functioning of those two items of equipment, given the fact that Quality Quartets have been documented which link those two items of equipment directly with a CQA (% Impurity X), and which indicate that those items of equipment are critical in nature. Thus, any probability of occurrence or detection ratings related to failure modes for the pH probe and flow-meter can be based directly on a consideration of those GMP controls and not on subjective failure rate estimates with questionable validity (6).

Overall, and as indicated above, Quality Quartets that link CQAs and CPPs with CAs and CDEs can be used to directly help minimise the level of subjectivity in risk assessment work.

ICH Q9(R1) highlights that formality in QRM is not a binary concept (i.e., formal/informal); it states that varying degrees of formality may be applied during QRM activities. It also indicates that an understanding of formality may lead to resources being used more efficiently, where lower risk issues are dealt with via less formal means, freeing up resources for managing higher risk issues and more complex problems that may require increased levels of rigour and effort.

The revised guideline refers to the following three factors that might be considered when determining how much formality to apply to a given QRM activity:

 This relates to a lack of knowledge about hazards, harms, and consequently, their associated risks, and it may be reduced via effective knowledge management in making risk-based decisions.

 The more important a risk-based decision is with regard to product quality, the higher the level of formality that may be applied, and the greater the need to reduce the level of uncertainty associated with it.

 The more complex a process or subject area is to a QRM activity, the higher the level of formality that may be applied to assure product quality. Complexity is an attribute that can be expressed in many different ways.With regard to manufacturing processes, for example, it may be characterized by the number of unit operations and steps that make up the process, the number of starting materials and isolated intermediates that may be involved, or the extent of outsourcing that is used (7). But complexity may also be characterised by the type of process that is under consideration; aseptic processes, for example, are often regarded as being more complex when compared to manufacturing processes that generate non-sterile products, and while this may be true in many cases, it may be something of an oversimplification in other cases.

These three factors are useful to consider during QRM work, because, as ICH Q9(R1) indicates, an understanding of formality can support risk-based decision-making, “where the level of formality that is applied may reflect the degree of importance of the decision, as well as the level of uncertainty and complexity which may be present.” The revised guideline states that “higher levels of uncertainty, importance or complexity may require more formal quality risk management approaches to manage potential risks and to support effective risk-based decision making” (3).

All of this is relevant when applying QRM principles to determining the extent of commissioning and qualification testing that may be required for facilities, systems, and equipment in line with the ISPE’s 2019 Baseline Guide. Furthermore, the Quality Quartet concept is also directly relevant, as illustrated by the following scenarios:

 Certain equipment components or instruments used in a manufacturing process have been classified as CDEs in line with the ISPE’s 2019 Baseline Guide. These components or instruments are considered important by virtue of their criticality designation, but their relationship to CPPs and their role in supporting the achievement of product CQAs is not well understood. There is relatively high uncertainty in this area, and there are no Quality Quartets documented that include these CDEs.

 Other equipment components or instruments have been classified as CDEs, and their relationship to CPPs and product CQAs is known and firmly established. Thus, there is lower uncertainty with regard to their relationship to CPPs and their role in supporting the achievement of product CQAs. These components or instruments are considered important.

 Certain process parameters have been classified as critical by virtue of the process knowledge that is in place in terms of their relationship to one or more CQAs. These process parameters have been designated as CPPs, and they are considered important to control. These CPPs have been listed in a number of Quality Quartets, as in the pH and MeOH charge examples discussed previously, and the equipment components or instruments that support those CPPs are known. Thus, there is low uncertainty here.

 For certain other process parameters, their relationship to any CQAs is not well understood; there is significant uncertainty in this area. The relative importance of such process parameters is also not understood, and these parameters have not been included in any Quality Quartets to date.

In Scenario A—important equipment components or instruments, but significant uncertainty in their relationship to CQAs, and no Quality Quartets documented—it may be useful to apply a higher degree of formality to any risk assessments that will be used to help determine the extent of commissioning and qualification testing that is required. Doing this can be beneficial because, given the level of uncertainty that is present, higher efforts can be made when assessing risks to ensure that appropriate risk controls are identified which mitigate those risks.

In Scenario D—process parameters of unknown importance, where their relationship to CQAs is uncertain and no Quality Quartets have been documented—more effort will likely be needed when applying QRM principles to determine the extent of commissioning and qualification testing that may be required. Thus, a higher level of formality may be needed in any risk assessments that are performed to help determine the extent of commissioning and qualification testing that is required. The extra effort may yield increased process understanding in relation to the role that those process parameters have in risk control, if any. This should serve to reduce the level of uncertainty that is present and, thus, it should lead to risk reduction as knowledge increases.

In Scenarios B and C, there are important equipment components/instruments and process parameters in place, there is a low level of uncertainty about their relationship to CQAs, and documented Quality Quartets are also in place. Any risk assessments that are performed to help determine the extent of commissioning and qualification testing that is required will likely be more straightforward and easier to perform, given the extent of equipment and process knowledge that is in place.

Overall, and as indicated above, the concept of Quality Quartets is useful to consider when determining how much formality to apply when performing risk assessments and when applying QRM principles to commissioning and qualification activities. The presence (or absence) of documented Quality Quartets for a manufacturing process and its associated facilities, systems, and equipment can help a site understand the degree of uncertainty that may be present as well as the relative importance of various process parameters and items of equipment (or their components). This understanding can inform risk assessment and QRM activities.

But uncertainty and importance are not the full picture; complexity considerations are also useful to think about, and as noted above, complexity is a key factor that ICH Q9(R1) refers to when one is determining how much formality to apply to a given QRM activity. ICH Q9(R1) indicates that the more complex a process or subject area is to a QRM activity, the higher the level of formality that may be applied to assure product quality. Thus, with scenarios A through D, it is useful to also consider the level of complexity that is associated with the facility, system, or equipment that may be subject to QRM activities.

This paper illustrates the benefits of applying the concept of Quality Quartets, as introduced in reference 1, to the risk-based commissioning and qualification of manufacturing facilities, systems and equipment, and it discusses how the guidance in ICH Q9(R1) in relation to subjectivity and formality in QRM can be applied in practical terms.

All commissioning and qualification activities involve making important decisions. For example, decisions need to be made about which items of equipment require qualification and which don’t. Related decisions concern how much leveraging can be made of factory acceptance testing, and how much in-house qualification testing will be required. The 2019 ISPE Baseline Guide places a heavy emphasis on the use of QRM principles when commissioning and qualifying facilities, systems, and equipment.ICH Q9(R1) states that “effective risk-based decision making begins with determining the level of effort, formality, and documentation that should be applied during the QRM process” (2). The guideline also indicates that addressing “uncertainty through the use of knowledge” not only facilitates informed decisions, it also helps recognize “where uncertainty remains, so that appropriate risk controls may be identified.” The scenarios discussed in this paper illustrate how those concepts in ICH Q9(R1) can be directly applied when developing risk-based approaches to commissioning and qualification. This is through the use of a knowledge management construct called a Quality Quartet, which is a construct of a site’s knowledge about the relationship between certain CQAs, CPPs, CAs, and CDEs.

To maximize the usefulness of the 2019 C&Q Baseline Guide, and taking into account the new guidance that the 2023 ICH Q9(R1) guideline provides, the authors suggest that the Quality Quartet concept would be useful to consider when manufacturing sites are working towards achieving true risk-based commissioning and qualification of their facilities, systems, and equipment.

The views expressed in this paper are those of the authors and should not be taken to represent the views of the Health Products Regulatory Authority (HPRA).

Campbell, C. Quality Quartets in Risk-Based Qualification. 

Baseline Guide Vol 5: Commissioning & Qualification

ICH. Concept Paper on the revision of ICH Q9, November 2020, 

O’Donnell, K.; Zwitkovits, M.; Greene, A.; Calnan, N. Quality Risk Management–Putting GMP Controls First. 

., 2012 May/June, Vol. 66, No. 3. pp 243-261.

A Recommended Model for Risk-based Inspection Planning in the GMP Environment

Kevin O’Donnell is Market Compliance Manager at Ireland’s Health Products Regulatory Authority.

Cliff Campbell is senior consultant, KPC.

When referring to this article, please cite it as O’Donnell, K and Campbell, C. Quality Quartets in Risk-Based Qualification: ICH Q9(R1) Considerations. 

Articles

Quality Quartets may be used to achieve knowledge-driven, risk-based approaches to commissioning and qualification that are consistent with ICH Q9(R1) principles. 

Quality Quartets in  Risk-Based Qualification: ICH Q9(R1) Considerations

The Quality Quartet is a proposed technical mechanism to eliminate inconsistencies and deficiencies within and between the commissioning and qualification (C&Q) and process validation (PV) lifecycles. Quality Quartets are four-component objects comprising two process and two system parts, but itemized and managed as singularities. Using a combination of International Council for Harmonisation (ICH) and International Society of Pharmaceutical Engineering (ISPE) terminology, the process parts are critical quality attribute (CQA) and critical process parameter (CPP), and the related system parts are critical aspect (CA) and critical design element (CDE). When implemented, Quality Quartets clearly demonstrate 100% connectivity between C&Q and PV datasets. They also facilitate unambiguous communication between product development and facility delivery silos, and between manufacturers and regulators. 

ISPE re-issued its C&Q Baseline Guide in 2019 to take account of the global regulatory expectation for patient-centric, risk-based design and delivery of manufacturing processes and systems. The guide now runs to more than 200 pages, including appendices (1). 

This paper explains the essential aspects of the guide. The guide is summarized by annotating its underlying principles and recommended workflow. Several practical recommendations are included targeted at optimizing implementation of the guide. Advantages of grouping CQAs, CPPs, CAs, and CDEs into Quality Quartets are discussed.

When referring to this article, please cite it as Campbell, C. Quality Quartets in Risk-Based Qualification. 

Quality Quartet Registers connect Quality Quartets to their process system or unit operation “parent.”

Quality Quartets in Risk-Based Qualification

Biopharma systems and processes are outlined in the introductory section of this monograph. A new knowledge management (KM) paradigm is then described, beginning with an analysis of United States and European Union regulatory requirements, and of prevailing commissioning and qualification (C&Q) and quality risk management (QRM) guidance from the International Society for Pharmaceutical Engineering (ISPE) and International Council for Harmonisation (ICH).

Points to Consider for Knowledge Management Acceleration

Quality and Regulatory Sourcebook March 2023

The KM paradigm is a response to the expectation that C&Q and QRM be integrated and accelerated, on urgent fast-track projects (the new normal) in particular. It is based on pattern recognition, and on the insight that process-related critical quality attributes (CQAs) and critical process parameters (CPPs), and plant-related critical aspects (CAs, or functions) and critical design elements (CDEs, or components), are best managed via a previously unrecognized fundamental object called quality quartet, comprising CQA:CPP:CA:CDE parts. Several well-established and universally accepted benchmarks are listed in support of the paradigm.

Pharmaceutical Technology’s Quality and Regulatory Sourcebook 

When referring to this article, please cite it as Campbell, C. Points to Consider for Knowledge Management Acceleration. 

Pharmaceutical Technology Quality and Regulatory Sourcebook

Quality quartets support an integrated and stable combination of
commissioning and qualification and quality risk management processes.