PQLI Definition of Criticality
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This paper describes progress made by the Criticality Task Team within the ISPE PQLI initiative. It aims to provide a concise, coherent, and universal approach for determining criticality for parameters, material attributes, conditions, and quality attributes. The work also clarifies the risk based distinctions governing the assignment of criticality to provide consistency and facilitate the adoption and implementation of Quality by Design (QbD) principles in the development of pharmaceutical manufacturing processes. The application of the concept of criticality presented in this paper aligns with the principles of ICH Q8, Q9 and Q10 guidelines.
KeywordsPQLI Design space Criticality Control strategy Critical quality attribute Critical process parameter Knowledge space Target product profile Product and process knowledge Quality by design Quality risk management
The word “critical” is an adjective and its use to describe pharmaceutical quality or manufacturing process variables requires context.1 The use of the word “critical” to define a process variable, step or attribute can be subjective, relying on individual assessment of relative risk, based on empirical knowledge, direct experience or data. Therefore, its meaning is neither universal nor definitive. In fact, industry concerns regarding the regulatory implications of labeling a process variable, attribute or step as “critical” have produced a variety of cautiously crafted and detailed definitions for its use. This position paper was developed and written to provide a concise, coherent and universal approach for delineating criticality for process variables, e.g., parameters, material attributes, conditions, etc., and quality attributes. The purpose of this position paper is to clarify the risk based distinctions governing the assignment of criticality to provide some measure of consistency and facilitate the adoption and implementation of Quality by Design (QbD) principles in the development of pharmaceutical manufacturing processes.
The assessment of criticality as it relates to pharmaceutical quality is generally determined as a function of risk. However a legitimate risk assessment is neither effective nor confident when made in the absence of product knowledge or process understanding and experience. The pharmaceutical industry has traditionally assessed risk, particularly during development, based predominantly on empirical knowledge, understanding derived from manufacturing experience. The advent of Quality by Design has shifted the paradigm from a retrospective to a prospective, systematic and risk-based approach to develop process understanding. The need to prioritize and focus experiments on meaningful variable interactions, to characterize relevant design space boundaries and establish appropriate control strategies warrants a robust definition of criticality.
Criticality can describe any feature or material attribute, property or characteristic of a drug substance, component, excipient, drug product or device and/or any process attribute, parameter, condition or factor in the manufacture of a drug product.
Criticality Analysis distinguishes non-critical variables from both known and potentially critical variables while delineating levels or degrees of risk (e.g. high or low) by which known and potentially critical sources of variability which may impact the quality of the product are assessed.
Critical impact may be attributed to multiple variables operating in sequence or in concert.
As a result of a Criticality Analysis, designation of non-critical and critical categories for process variables and/or product attributes provides a relative and qualitative classification of their impact to quality, and by extension to safety and efficacy3 of the drug product for the patient.
A control can reduce the level of criticality but it does not change the potential for severity of harm/impact even though it may reduce the probability and/or increase detectability.
A control that reduces the level of criticality for a process variable, by definition, becomes a critical control point /parameter/ (HACCP).
A few drug product CQAs, such as sterility, will always be critical. These CQAs may be dosage form specific.
Criticality Analysis is relevant in development of design space and design space boundaries and establishing effective control strategies.
The Criticality Analysis Decision Tree differentiates business decisions, categorizes non-critical variables in accordance with risk and, at the discretion of the sponsor, provides flexibility to designate levels of criticality governed by relative levels of risk.
As attribute or parameter boundaries approach edges of failure the level of criticality increases with an increase in the level of risk.
Process parameters or variables controlled to evaluate business attributes are not necessarily critical unless demonstrated to directly or indirectly impact quality of the drug product.
Risk Identification — finding what risks exist and/or might exist — problems and potential problems
Risk Evaluation — severity, probability and detectability
- Risk Control — detectability, i.e., risk management versus risk measurement and monitoring
➢Risk Reduction—well grounded science and justifiable decision making to the extent necessary to provide appropriate assurance and high degree of probability of safety, efficacy and quality
➢Risk Mitigation—development of design space, controls and/or measurements to demonstrate reduction in the severity of risk.
- ➢Risk Acceptance—
✓ Some level of risk may remain
✓ Some level of risk may be appropriate considering the benefit accrued
✓ Some level of risk may be practicably achievable
✓Acceptance of residual risk in accordance with benefit for patient
- Risk Communication —
➢‘Customers’ need to know what risks have been considered, how they have been managed and/or controlled and what residual risk has been accepted.
➢Risk communication can also be a strategic part of a risk management program
The criticality decision tree is divided into two decision classifications to facilitate Criticality Analysis. The top classification is labeled Foundational and serves as the basis for subsequent decisions delineating critical from non-critical variables. In the absence of a modern risk-based quality system, a traditional specification may serve as the basis for determining critical and non-critical variables and is typically demonstrated by empirical, process experience. The decision to develop a control strategy based on traditional specification limits without benefit of multivariate analysis is driven by business needs at the discretion of the sponsor.
Similarly, a decision to proceed with a risk-based, systematic and prospective approach to pharmaceutical development relies on evaluating risk relative to impact on safety, efficacy and quality. This categorization differentiates non-critical from potentially critical variables, parameters and attributes based primarily on the severity or magnitude of the risk. Subsequently, a variable, parameter or attribute is assessed to delineate levels of criticality based on whether the probability and the ability to detect the risk is low or high. Provisions in this process suggest the use of a Risk Filter to discriminate levels of risk once a variable is categorized as potentially critical. The Risk Filter identifies several examples (by no means exhaustive) to provide the basis to evaluate relative risk.
The level of criticality labeled “X” allows for classification of variables, parameters and attributes for which risk (probability and detectability) has not been definitively ascertained or is secondary or ancillary to other factors. Variables, parameters and attributes labeled “X” may require re-evaluation when making changes to multi-variate design space. In addition, more than two levels of criticality may be used to describe the level of risk for variables labeled “X”.
The Criticality Analysis Decision Tree is applicable to API, drug product, biological and device processes and products. The integrity of the risk assessment is predicated on a robust quality system in alignment with principles articulated in ICH Q9 and Q10  and dependent on well developed knowledge space for the manufacturing process. As process understanding and knowledge increase during the lifecycle of a product the delineation of criticality serves as an iterative process to reassess the risk of process variables and quality attributes.
Detailed Explanation of Criticality Analysis Decision Tree
Product quality and performance are ensured through the design of effective and capable, i.e., robust manufacturing processes
Product and process specifications are based on a mechanistic understanding of how formulation and process factors affect product quality and performance.5
Continuous product and process improvement
Relevant regulatory policies and procedures are tailored to reflect current level of scientific knowledge and associated risk
- Risk-based regulatory approaches recognize:
➢ the level of scientific understanding of how formulation and manufacturing process factors affect product quality and performance
➢ the capability of process control strategies to prevent or mitigate the risk of producing a poor quality product
Prior knowledge is an appropriate basis for risk assessment decisions for new and legacy products that proceed through the “QbD” approach.
The bottom layer of the criticality decision tree process introduces the risk assessment strategy employed by a QbD approach to product and process development. This decision tree can be used to assess the criticality of variables in a product or process, i.e., attributes and parameters. The blue decision diamond requesting a response to the question, “What is the potential for variables to impact quality?” distinguishes the first “category of criticality” by segregating variables that do not have an impact on quality and designating them non-critical.
Those variables that may have an impact on quality fall into the second “category of criticality” which can be subsequently evaluated through appropriate risk assessment, as denoted by the “Risk Filter” into “levels of criticality” designated as either critical or some intermediate level “X” defined by the magnitude and attenuation of severity, probability and detectability of risk.
Attributes6 fall within two major categories, those that are the measurable properties of a material and those that are the measurable characteristics of the process used to manufacture a material. Quality Attributes have an impact on patient safety, efficacy or quality. An attribute should be defined as a Quality Attribute where precedented pharmaceutical knowledge suggests a link may exist even if a direct, scientifically demonstrable link has not been made between the attribute and patient safety, efficacy and/or quality.
Variables or parameters that may have important implications for business purposes, i.e., reducing costs, optimizing yield, improving process efficiency, environmental and/or worker safety, etc., or variables associated with a delivery device and/or packaging of the drug product. may be assessed for their level of criticality relative to business criteria. However these variables are not, by definition, necessarily critical with regards to safety and/or efficacy and should not be defined as critical from a regulatory perspective.
Elements necessary to perform a Criticality Analysis, (i.e., risk assessment tools, functional relationships to critical quality attributes, and the criteria by which a variable is designated as critical, in combination with other variables or independently), may be determined from (1) prior knowledge, (2) results from concerted and prospective designed (e.g., multi-variate) experimentation and (3) demonstrated process experience. The quality of a product as defined in accordance with ICH Q 6A8 is a minimum standard and is a reflection of the Target Product Profile. The Target Product Profile describes the quality attributes of the product for its intended use and administration. While an assessment of risk is predicated on the established foundation of a robust quality system as defined in accordance with ICH Q (10), the primary assessment and designation of criticality should be made relative to impact to safety and efficacy of the drug product to the patient which are dependent on measures of quality as reflected by its Quality Attributes. Development and establishment of product Quality Attributes to meet the Target Product Profile introduces a standard level of quality, the measured assessment of which will establish critical quality attribute (CQA) boundaries A well justified risk assessment identifies criteria to establish the appropriate and relevant elements of a control strategy. The quality of a product is measured by the demonstrated application of that control strategy.
sources of variability are explained
“Quality Attributes” can be predicted based on key inputs, e.g., process parameters, material attributes, etc.
process capability of “Quality Attributes” meets acceptance levels
The application of principles of Quality by Design in the development of process understanding is predicated on risk assessment. Risk assessments provide an evaluation of process variables relative to their level of expected impact on quality.
Probability — the likelihood of an occurrence.
Severity — the magnitude of the impact of a consequence.
Detectability — the level or ability at which an occurrence can be measured.
Sensitivity (optional) — the attenuation of interactions between multivariate dimensions.
There are differences in designation of criticality and level of risk between API and drug product parameters.
Critical outcomes may be attributed to multiple variables operating in concert.
Control strategy based solely on testing does not make a CQA or CPP non-critical; it just makes it controlled. The severity of the risk does not change with an assurance of control, only the probability of risk is reduced with an assurance of control.
Use of descriptive adjectives to define criticality should include context.
Several levels of criticality may be used to describe multiple levels of risk.
As attribute or parameter boundaries approach edges of failure the level of criticality increases with the level of risk.
Criticality is intended to be revisited and assessed during product lifecycle.
that may have an indirect impact on safety and/or efficacy by themselves or in combination with other variables,
where risk is mitigated
where demonstration of knowledge transfer for non-critical variables requires additional evaluation.
A material or process attribute or parameter that is categorized as critical has either been demonstrated or based on prior knowledge known to have a direct or indirect impact on patient safety, therapeutic efficacy, in vivo pharmacokinetic/pharmacodynamic performance and patient compliance for which failure to control within demonstrable acceptance criteria produces an unrecoverable result. A Critical Process Parameter CPP is a process input that, when varied beyond a limited range, has a direct and significant influence on a CQA. A Critical Quality Attribute is a quantifiable property of an intermediate or final product that is considered critical for establishing the intended purity, efficacy, and safety of the product. That is, the property must be within a predetermined range to ensure final product quality. Risk is controlled for a CQA by establishing a product specification for the affected attribute. See ICH Q8 Pharmaceutical Development 
Lifecycle Management — Increased Product/Process Understanding
During the lifecycle of a product there is a presumption that an increase in process understanding and product knowledge derived from continuous improvement and optimization activities as well as increased manufacturing experience may require re-assessment of attributes, parameters and other variables. In accordance with ICH Q9 definition of risk management the Criticality Analysis Decision Tree should be used for periodic reassessment. Variables, parameters and attributes implicated in changes to manufacturing processes or product criteria should be evaluated relative to relevant quality attributes. Changes to material or process attributes or parameters controlled to evaluate business criteria are not necessarily treated as critical unless there is a demonstrated link to safety, efficacy and quality of the drug product. Changes in designation from one level or category of criticality to another must be demonstrated by data or increased knowledge, i.e., modeling and improved interpretation of already existing data etc., and may require appropriate notification to regulatory authorities.
Throughout the lifecycle of a product, control strategy should differentiate levels of criticality depending on the impact to the quality of the drug product as defined by the relationship of process variables and parameters and material attributes to quality attributes.
1. Attribute - A characteristic or inherent property of feature. (ASTM E2363-06a)
2. Change Management - A systematic approach to proposing, evaluating, approving, implementing and reviewing changes. (ICH Q10 EWG)
3. Continuous Verification - An approach to process validation in which manufacturing process performance is continuously monitored and evaluated. (ICH Q9)
4. Control Strategy - A planned (like word ‘planned’) set of controls, derived from current product and process understanding, that assures process performance and product quality. The controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control. (ICH Q10 EWG)
5. Critical (For Small Molecules Only) - Critical describes a feature or aspect of a raw material, intermediate, process or product that is generally identified through an assessment of the extent to which its variation can have impact on the quality of the drug product, and which therefore requires control to ensure that the product is of acceptable quality. (ICH Q8R)
v5a. Critical (For Biologics Only) - An input parameter that must be controlled within a meaningful, narrow range to ensure that drug substance product Critical Quality Attributes meet specifications.
6. Critical Process Parameter - A process input that, when varied beyond a limited range, has a direct and significant influence on a CQA. (PQRI Robustness Paper)
7. Critical Quality Attribute - A quantifiable property of an intermediate or final product that is considered critical for establishing the intended purity, efficacy, and safety of the product. (ICH Q8R)
8. Design Space - The multidimensional combinations and interaction of input variables (e.g. material attributes) and process parameters that have been demonstrated to provide assurance of quality. Working within the design space is not considered as a change. Movement out of the design space is considered to be a change and would normally initiate a regulatory post-approval change process. Design space is proposed by the applicant and is subject to regulatory assessment and approval. (ICH Q8)
9. Design of Experiments (DoE) - The arrangement in which an experimental program is to be conducted, and the selection of the levels (versions) of one or more factors or factor combinations to be included in the experiment.
9a. Formal Experimental Design - A structured, organized method for determining the relationship between factors affecting a process and the output of that process. Also known as “Design of Experiments”. (ICH Q8)
10. Detectability - The ability to discover or determine the existence, presence, or fact of a hazard. (ICH Q9)
11. Edge of Failure - the boundary to a variable or parameter, beyond which the relevant quality attributes or specification cannot be met. (ICH Q8R)
12. Innovation - The introduction of new technologies or methodologies to pharmaceutical development and manufacturing. (ICH Q10 EWG)
13. Harm - Damage to health, including the damage that can occur from loss of product quality or availability.
14. “X” Key - There is managed risk relative to impacting the safety or efficacy of a product; well controlled.
15. Key Process Parameter (KPP) (For Small Molecules Only) - Process parameters that may impact a critical quality attribute. In contrast to a critical process parameter, a key process parameter has a reduced risk of impacting the safety or efficacy of the product, even though there is a relationship to a critical quality attribute. The risk of failure is mitigated by applying a robust proactive control strategy through internal quality management system to reduce the natural variability of the parameter in question. Operating ranges for key process parameters may be filed as regulatory commitments.
15a. Key Process Parameter (KPP) (For Biologics Only) - An adjustable parameter (variable) of the process that, when maintained within a narrow range, ensures optimum process performance. A key process parameter does not affect critical product quality attributes.
16. Knowledge Management - Systematic approach to collecting, analyzing, storing, and disseminating information related to products, processes and components. (ICH Q10 EWG)
17. Lifecycle - All phases in the life of a product from the initial development through marketing until the product’s discontinuation. Synonymous with Product Lifecycle. (ICH Q8)
18. Non-Critical - There is a negligible risk of impacting the safety or efficacy of a product. Syn: Regulatory Insignificant.
19. Non-Critical Process Parameter (For Small Molecules Only) - A process parameter that has a negligible risk of impacting the safety or efficacy of a product. It impacts Non-Critical Quality Attributes which are not related to the safety or efficacy of a product. Non-Critical Process Parameters are managed only by internal quality and change control systems.
19a. Non-Critical Process Parameter (For Biologics Only) - All input parameters that fall outside of the definition for critical process parameters are non-critical. Non-critical process parameters may be further subdivided into Key and Non-Key process parameters, in cases where process performance impact is demonstrated.
20. Non-Critical Quality Attribute - A quality attribute that has a low risk of impacting the safety or efficacy of a product. Non-Critical Quality Attributes are managed only by internal quality and change control systems.
21. Non-Key Process Parameter (non-KPP) (For Biologics Only) - An input parameter that has been demonstrated to be easily controlled or has a wide acceptable limit.
22. Normal Operating Range (NOR) - A defined range, within the Proven Acceptable Range, specified in the manufacturing instructions as the target and range at which a process parameter is controlled, while producing unit operation material or final product meeting release criteria and Critical Quality Attributes. (PQRI Robustness Paper)
23. Parameter - A measurable or quantifiable characteristic of a system or process. (ASTM E2363-06a)
24. Pharmaceutical Quality System - Management system to direct and control a pharmaceutical company with regard to quality. (ICH Q10 EWG based upon ISO 9000-2005)
25. Process Analytical Technologies (PAT) - A system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes with the goal of assuring final product quality. (ICH Q8, FDA PAT Guidance; ASTM E2363-06a, PQRI Robustness Paper, and EU definition)
26. Process Parameter - A process variable (e.g., temperature, compression force) that can be assigned values to be used as control levels or operating limits. (Pfizer Quality Standard definition)
27. Proven Acceptable Range - A characterized range at which a process parameter may be operated within, while producing unit operation material or final product meeting release criteria and Critical Quality Attributes. (PQRI Robustness Paper)
28. Process Robustness - Ability of a process to tolerate variability of materials and changes of the process and equipment without negative impact on quality. (ICH Q8)
29. Quality - The suitability of either a drug substance or drug product for its intended use. This term includes such attributes as the identity, strength, and purity (ICH Q8)
30. Quality Attribute - A physical, chemical, or micro-biological property or characteristic that directly or indirectly relates to pre-defined product quality (safety, identity, strength, purity, and marketability of the product). (GPB Critical Process Parameters: Glossary of Associated Terms, DRAFT 05Jan’05, GAA)
31. Quality by Design - A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding based on sound science and quality risk management. (ICH Q8R)
32. Quality Risk Management - A systematic process for the assessment, control, communication and review of risks to the quality of the drug (medicinal) product across the product lifecycle. (ICH Q9)
33. Quality System - The sum of all aspects of a system that implements quality policy and ensures that quality objectives are met. (ICH Q9)
34. Real Time Release - Real time release is an outcome of a control strategy in which product quality is assured for batch release through a combination of process information and input or in-process material attribute measurements during manufacturing in lieu of traditional off-line, end-product testing. (ICH Q8R)
35. Redefinition of Design Space - A redefinition of design space occurs when a manufacturing process fundamentally changes. For example, a change from wet granulation to dry granulation would require a redefinition of design space since the original process, on which the design space was based, no longer exists. A redefinition of the design space does not include an increase of knowledge around an existing process. For example, a reclassification of a parameter from CPP to KPP as a result of increased process knowledge is not a redefinition of design space since the subject process has not changed.
36. Requirements - The explicit or implicit needs or expectations of the patients or their surrogates (e.g., health care professionals, regulators and legislators). In this document, “requirements” refers not only to statutory, legislative, or regulatory requirements, but also to such needs and expectations. (ICH Q9)
37. Risk - The combination of the probability of occurrence of harm and the severity of that harm. (ICH Q9)
38. Risk Acceptance - The decision to accept risk. (ICH Q9)
39. Risk Analysis - The estimation of the risk associated with the identified hazards. (ICH Q9)
40. Risk Assessment - A systematic process of organizing information to support a risk decision to be made within a risk management process. It consists of the identification of hazards and the analysis and evaluation of risks associated with exposure to those hazards. (ICH Q9)
41. Risk Communication - The sharing of information about risk and risk management between the decision maker and other stakeholders. (ICH Q9)
42. Risk Control - Actions implementing risk management decisions. (ICH Q9)
43. Risk Evaluation - The comparison of the estimated risk to given risk criteria using a quantitative or qualitative scale to determine the significance of the risk. (ICH Q9)
44. Risk Identification - The systematic use of information to identify potential sources of harm (hazards) referring to the risk question or problem description. (ICH Q9)
45. Risk Management - The systematic application of quality management policies, procedures, and practices to the tasks of assessing, controlling, communicating and reviewing risk. (ICH Q9)
46. Risk Reduction - Actions taken to lessen the probability of occurrence of harm and the severity of that harm. (ICH Q9)
47. Risk Review - Review or monitoring of output/results of the risk management process considering (if appropriate) new knowledge and experience about the risk. (ICH Q9)
48. Robustness - The ability of a product/process to demonstrate acceptable quality and performance while tolerating variability in inputs. (PQRI Robustness Paper)
49. Stakeholder - Any individual, group or organization that can affect, be affected by, or perceive itself to be affected by a risk. Decision makers might also be stakeholders. For the purposes of this guideline, the primary stakeholders are the patient, healthcare professional, regulatory authority, and industry. (ICH Q9)
50. Trend - Tabulation or graphical plot of actual data used to determine a tendency or drift in conditions or performance.
Crit·i·cal adj: of essential importance. Several definitions for the word “critical” exist, each reflective of the word it modifies. The application of criticality presented in this abstract aligns with principles articulated in ICH Q8, Q9 and Q10 guidelines.
“A more systematic approach to development (also defined as quality by design) can include, for example, incorporation of prior knowledge, results of studies using design of experiments, use of quality risk management, and use of knowledge management (see ICH Q10) throughout the lifecycle of the product. Such a systematic approach can enhance the process to achieve quality and help the regulators to better understand a company’s strategy. Product and process understanding can be updated with the knowledge gained over the product lifecycle.”
A specification is not synonymous to control strategy. A specification is only one element of a control strategy.
At·tri·bute n: A quality or characteristic inherent in or ascribed to someone or something.
Pa·ram·e·ter n. One of a set of measurable factors, such as temperature and pressure, that define a system and determine its behavior and are varied in an experiment.
“The definition of quality is the suitability of either a drug substance or drug product for its intended use.”
ICH Q (9) Quality Risk Management
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