Q9(R1) Quality Risk 
Management 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
May 2023 
ICH-Quality 
 
  Q9(R1) Quality Risk 
Management 
Guidance for Industry 
 
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https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics-guidances 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
May 2023 
ICH-Quality 
 
  Contains Nonbinding Recommendations 
FOREWORD 
 
The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use (ICH) has the mission of achieving greater regulatory harmonization worldwide to 
ensure that safe, effective, and high-quality medicines are developed, registered, and maintained 
in the most resource-efficient manner.  By harmonizing the regulatory expectations in regions 
around the world, ICH guidelines have substantially reduced duplicative clinical studies, 
prevented unnecessary animal studies, standardized safety reporting and marketing application 
submissions, and contributed to many other improvements in the quality of global drug 
development and manufacturing and the products available to patients.  
 
ICH is a consensus-driven process that involves technical experts from regulatory authorities and 
industry parties in detailed technical and science-based harmonization work that results in the 
development of ICH guidelines.  The commitment to consistent adoption of these consensus-
based guidelines by regulators around the globe is critical to realizing the benefits of safe, 
effective, and high-quality medicines for patients as well as for industry.  As a Founding 
Regulatory Member of ICH, the Food and Drug Administration (FDA) plays a major role in the 
development of each of the ICH guidelines, which FDA then adopts and issues as guidance to 
industry. 
 
  Contains Nonbinding Recommendations 
TABLE OF CONTENTS 
 
I.  INTRODUCTION (1) ....................................................................................................... 1 
II.  SCOPE (2).......................................................................................................................... 3 
III.  PRINCIPLES OF QUALITY RISK MANAGEMENT (3) .......................................... 3 
IV.  GENERAL QUALITY RISK MANAGEMENT PROCESS (4) .................................. 3 
A.  Responsibilities (4.1) ...................................................................................................................... 4 
B.  Initiating a Quality Risk Management Process (4.2) .................................................................. 5 
C.  Risk Assessment (4.3)..................................................................................................................... 5 
D.  Risk Control (4.4) ........................................................................................................................... 6 
E.  Risk Communication (4.5) ............................................................................................................. 7 
F.  Risk Review (4.6) ............................................................................................................................ 7 
V.  RISK MANAGEMENT METHODOLOGY (5) ............................................................ 7 
A.  Formality in Quality Risk Management (5.1) ............................................................................. 8 
B.  Risk-Based Decision-Making (5.2) ............................................................................................. 10 
C.  Managing and Minimizing Subjectivity (5.3) ............................................................................ 11 
VI.  INTEGRATION OF QUALITY RISK MANAGEMENT INTO INDUSTRY AND 
REGULATORY OPERATIONS (6) ......................................................................................... 11 
A.  The Role of Quality Risk Management in Addressing Product Availability Risks Arising 
From Quality/Manufacturing Issues (6.1) .......................................................................................... 12 
VII.  DEFINITIONS (7) .......................................................................................................... 15 
VIII.  REFERENCES (8) .......................................................................................................... 17 
ANNEX I: QUALITY RISK MANAGEMENT METHODS AND TOOLS ......................... 19 
A.  Basic Risk Management Facilitation Methods (I.1) .................................................................. 19 
B.  Failure Mode Effects Analysis (FMEA) (I.2) ............................................................................. 19 
C.  Failure Mode, Effects, and Criticality Analysis (FMECA) (I.3) .............................................. 19 
D.  Fault Tree Analysis (FTA) (I.4) .................................................................................................. 20 
E.  Hazard Analysis and Critical Control Points (HACCP) (I.5) .................................................. 20 
F.  Hazard Operability Analysis (HAZOP) (I.6) ............................................................................ 21 
G.  Preliminary Hazard Analysis (PHA) (I.7) ................................................................................. 21 
H.  Risk Ranking and Filtering (I.8) ................................................................................................. 22 
I.  Supporting Statistical Tools (I.9) ................................................................................................ 22 
ANNEX II: POTENTIAL APPLICATIONS FOR QUALITY RISK MANAGEMENT .... 23 
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A.  Quality Risk Management as Part of Integrated Quality Management Documentation (II.1)
  23 
B.  Quality Risk Management as Part of Regulatory Operations Inspection and Assessment 
Activities (II.2) ...................................................................................................................................... 24 
C.  Quality Risk Management as Part of Development (II.3) ........................................................ 25 
D.  Quality Risk Management for Facilities, Equipment, and Utilities Design of 
Facility/Equipment (II.4) ..................................................................................................................... 25 
E.  Quality Risk Management as Part of Materials Management Assessment and Evaluation of 
Suppliers and Contract Manufacturers (II.5) .................................................................................... 27 
F.  Quality Risk Management as Part of Production Validation (II.6) ........................................ 27 
G.  Quality Risk Management as Part of Laboratory Control and Stability Studies Out of 
Specification Results (II.7) ................................................................................................................... 28 
H.  Quality Risk Management as Part of Packaging and Labeling Design of Packages (II.8) .... 28 
I.  Quality Risk Management as Part of Supply Chain Control (II.9) ......................................... 28 
 
 
ii  Contains Nonbinding Recommendations 
Q9(R1) Quality Risk Management 
Guidance for Industry1 
 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You 
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the 
title page.   
 
 
 
I.  INTRODUCTION (1)2 
 
Risk management principles are effectively utilized in many areas of business and government 
including finance, insurance, occupational safety, public health, pharmacovigilance, and by 
agencies regulating these industries.  In the pharmaceutical sector, the principles and framework 
of ICH Q9, coupled with the official ICH training material that supports this guideline, are 
instrumental in enhancing the application of effective quality risk management by industry and 
regulators.  The importance of quality systems has been recognized in the pharmaceutical 
industry and it is evident that quality risk management is a valuable component of an effective 
quality system. 
 
It is commonly understood that risk is defined as the combination of the probability of 
occurrence of harm and the severity of that harm.  However, achieving a shared understanding of 
the application of risk management among diverse stakeholders is difficult because each 
stakeholder might perceive different potential harms, place a different probability on each harm 
occurring and attribute different severities to each harm.  In addition, subjectivity can directly 
impact the effectiveness of risk management activities and the decisions made.  Therefore, it is 
important that subjectivity is managed and minimized.  In relation to pharmaceuticals, although 
there are a variety of stakeholders, including patients and medical practitioners as well as 
government and industry, the protection of the patient is of prime importance when managing the 
risk to product quality and availability, when availability risks arise from quality/manufacturing 
issues. 
 
The manufacturing and use of a drug (medicinal) product, including its components, necessarily 
entail some degree of risk.  The risk to its quality is just one component of the overall risk.  It is 
important to understand that product quality is assured based on appropriate risk- based decision-
 
1 This guidance was developed within the Expert Working Group (Quality) of the International Council for 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and has been 
subject to consultation by the regulatory parties, in accordance with the ICH process.  This document has been 
endorsed by the ICH Assembly at Step 4 of the ICH process, January 2023.  At Step 4 of the process, the final draft 
is recommended for adoption to the regulatory bodies of the ICH regions.  
2 The numbers in parentheses reflect the organizational breakdown of the document endorsed by the ICH Assembly 
at Step 4 of the ICH process, January 2023. 
1  Contains Nonbinding Recommendations 
making throughout the product lifecycle, such that the attributes that are important to the quality 
of the drug (medicinal) product are maintained and the product remains safe and effective. 
 
An effective quality risk management approach can further ensure the quality of the drug 
(medicinal) product to the patient by providing a proactive means to identify and control 
potential quality issues during development, manufacturing, and distribution.  This includes an 
appropriate application of root cause analysis that can identify and address the root cause(s) and 
other causal factors (e.g., human-related) of such issues.  A proactive approach to quality risk 
management is beneficial, as it facilitates robust product design and continual improvement, and 
it is of strategic importance in achieving an effective pharmaceutical quality system (see the 
International Council for Harmonisation (ICH) guidance for industry Q10 Pharmaceutical 
Quality System (ICH Q10) (April 2009)3 for guidance in relation to an effective pharmaceutical 
quality system).  Additionally, use of quality risk management can improve the decision-making 
if a quality problem arises. 
 
In the development phase and as part of validation, quality risk management is part of building 
knowledge and understanding risk scenarios, so that appropriate risk control can be decided upon 
for use during the commercial manufacturing phase.  In this context, knowledge is used to make 
informed risk-based decisions, trigger re-evaluations and stimulate continual improvements.  
Effective and proactive quality risk management can enable better, more informed, and timely 
decisions throughout the lifecycle.  This can provide regulators with greater assurance of a 
companys ability to deal with potential risks and avert problems and can beneficially affect the 
extent and level of direct regulatory oversight. 
 
The application of digitalization and emerging technologies in the manufacture and control of 
drug (medicinal) products can lead to risk reduction when such technologies are fit for their 
intended use.  However, they can also introduce other risks that may need to be controlled.  The 
application of quality risk management to the design, validation and technology transfer of 
advanced production processes and analytical methods, advanced data analysis methods and 
computerized systems is important. 
 
The purpose of this document is to offer a systematic approach to quality risk management that 
leads to better, more informed, and timely decisions.  It serves as a foundation or resource 
document that is independent of, yet supports, other ICH Quality documents and complements 
existing quality practices, requirements, standards, and guidelines within the pharmaceutical 
industry and regulatory environment.  It specifically provides guidance on the principles and 
some of the tools of quality risk management that can enable more effective and consistent risk-
based decisions, both by regulators and industry, regarding the quality of drug substances and 
drug (medicinal) products across the product lifecycle.  It is not intended to create any new 
expectations beyond the current regulatory requirements. 
 
An understanding of formality in quality risk management 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 
 
3 We update guidances periodically.  To make sure you have the most recent version of a guidance, check the FDA 
guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents.  
2  Contains Nonbinding Recommendations 
increased levels of rigor and effort.  An understanding of formality can also 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. 
 
Appropriate use of quality risk management can facilitate but does not obviate industrys 
obligation to comply with regulatory requirements and does not replace appropriate 
communications between industry and regulators.  Quality risk management should not be used 
in a manner where decisions are made that justify a practice that would otherwise, in accordance 
with regulations and/or guidance, be deemed unacceptable. 
 
In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
the word should in Agency guidances means that something is suggested or recommended, but 
not required.   
 
 
II.  SCOPE (2) 
 
This guideline provides principles and examples of tools for quality risk management that can be 
applied to different aspects of pharmaceutical quality.  These aspects include development, 
manufacturing, distribution, and the inspection and submission/review processes throughout the 
lifecycle of drug substances, drug (medicinal) products, biological and biotechnological products 
(including the use of raw materials, solvents, excipients, packaging and labeling materials in 
drug (medicinal) products, biological and biotechnological products). 
 
 
III.  PRINCIPLES OF QUALITY RISK MANAGEMENT (3) 
 
Two primary principles of quality risk management are: 
The evaluation of the risk to quality should be based on scientific knowledge and ultimately link 
to the protection of the patient.  (Note: Risk to quality includes situations where product 
availability may be impacted, leading to potential patient harm.) 
The level of effort, formality and documentation of the quality risk management process should 
be commensurate with the level of risk. 
 
 
IV.  GENERAL QUALITY RISK MANAGEMENT PROCESS (4) 
 
Quality risk management is a systematic process for the assessment, control, communication, 
and review of risks to the quality of the drug (medicinal) product across the product lifecycle.  A 
model for quality risk management is outlined in the diagram (Figure 1).  Other models could be 
used.  The emphasis on each component of the framework might differ from case to case but a 
robust process will incorporate consideration of all the elements at a level of detail that is 
commensurate with the specific risk. 
3  Contains Nonbinding Recommendations 
 
Figure 1:  Overview of a typical quality risk management process. 
 
  Initiate 
  Quality Risk Management Process 
 
 
Risk Assessment 
 
Hazard Identification 
 
 
Risk Analysis 
 
 
Risk Evaluation 
 
  unacceptable 
R
  n  Risk Control  is
o k
  cati  Ma
ni Risk Reduction  n
  mu ag
e
m m
  o e
  Risk C Risk Acceptance  nt too
  ls 
 
Output / Result of the 
  Quality Risk Management Process 
 
 
Risk Review 
 
Review Events 
 
 
 
Decision nodes are not shown in the diagram above because decisions can occur at any point in 
the process.  These decisions might be to return to the previous step and seek further information, 
to adjust the risk models or even to terminate the risk management process based upon 
information that supports such a decision.  Note: unacceptable in the flowchart does not only 
refer to statutory, legislative, or regulatory requirements, but also to the need to revisit the risk 
assessment process. 
 
A.  Responsibilities (4.1) 
 
Quality risk management activities are usually, but not always, undertaken by interdisciplinary 
teams.  When teams are formed, they should include experts from the appropriate areas (e.g., 
quality unit, product development, business development, engineering, regulatory affairs, 
production operations, sales and marketing, supply chain, legal, statistics and clinical) in addition 
to individuals who are knowledgeable about the quality risk management process. 
 
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  Decision makers should: 
 
  Take responsibility for coordinating quality risk management across various functions 
and departments of their organization; 
 
  Assure that a quality risk management process is defined, deployed, and reviewed and 
that adequate resources and knowledge are available; and 
 
  Assure that subjectivity in quality risk management activities is managed and minimized, 
to facilitate scientifically robust risk-based decision-making 
 
B.  Initiating a Quality Risk Management Process (4.2) 
 
Quality risk management should include systematic processes designed to coordinate, facilitate 
and improve science-based decision-making with respect to risk.  Possible steps used to initiate 
and plan a quality risk management process might include the following: 
 
  Define the problem and/or risk question, including pertinent assumptions identifying the 
potential for risk 
 
  Assemble background information and/ or data on the potential hazard, harm, or human 
health impact relevant to the risk assessment 
 
  Identify a leader and necessary resources 
 
  Specify a timeline, deliverables, and appropriate level of decision-making for the risk 
management process 
 
C.  Risk Assessment (4.3) 
 
Risk assessment consists of the identification of hazards and the analysis and evaluation of risks 
associated with exposure to those hazards (as defined below).  Quality risk assessments begin 
with a well-defined problem description or risk question.  When the risk in question is well 
defined, an appropriate risk management tool (see examples in section V (5)) and the types of 
information needed to address the risk question will be more readily identifiable.  As an aid to 
clearly defining the risk(s) for risk assessment purposes, three fundamental questions are often 
helpful: 
 
(1) What might go wrong? 
(2) What is the likelihood (probability) it will go wrong? 
(3) What are the consequences (severity)? 
 
Hazard identification is a systematic use of information to identify hazards referring to the risk 
question or problem description.  Information can include historical data, theoretical analysis, 
informed opinions, and the concerns of stakeholders.  Hazard identification addresses the What 
5  Contains Nonbinding Recommendations 
might go wrong? question, including identifying the possible consequences.  This provides the 
basis for further steps in the quality risk management process. 
 
Risk analysis is the estimation of the risk associated with the identified hazards.  It is the 
qualitative or quantitative process of linking the likelihood of occurrence and severity of harms.  
In some risk management tools, the ability to detect the harm (detectability) also factors in the 
estimation of risk. 
 
Risk evaluation compares the identified and analyzed risk against given risk criteria.  Risk 
evaluations consider the strength of evidence for all three of the fundamental questions. 
In doing an effective risk assessment, the robustness of the data set is important because it 
determines the quality of the output.  Revealing assumptions and reasonable sources of 
uncertainty will enhance confidence in this output and/or help identify its limitations. 
 
Uncertainty is due to a combination of incomplete knowledge about a process and its expected or 
unexpected variability.  Typical sources of uncertainty include gaps in knowledge, gaps in 
pharmaceutical science and process understanding, sources of harm (e.g., failure modes of a 
process, sources of variability), and probability of detection of problems. 
 
The output of a risk assessment is either a quantitative estimate of risk or a qualitative 
description of a range of risk.  When risk is expressed quantitatively, a numerical probability is 
used.  Alternatively, risk can be expressed using qualitative descriptors, such as high, 
medium, or low, which should be defined in as much detail as possible.  Sometimes a risk 
score is used to further define descriptors in risk ranking.  In quantitative risk assessments, a 
risk estimate provides the likelihood of a specific consequence, given a set of risk-generating 
circumstances.  Thus, quantitative risk estimation is useful for one particular consequence at a 
time.  Alternatively, some risk management tools use a relative risk measure to combine multiple 
levels of severity and probability into an overall estimate of relative risk.  The intermediate steps 
within a scoring process can sometimes employ quantitative risk estimation. 
 
D.  Risk Control (4.4) 
 
Risk control includes decision-making to reduce and/or accept risks.  The purpose of risk control 
is to reduce the risk to an acceptable level.  The amount of effort used for risk control should be 
proportional to the significance of the risk.  Decision makers might use different processes, 
including benefit-cost analysis, for understanding the optimal level of risk control. 
 
Risk control might focus on the following questions: 
 
(1) Is the risk above an acceptable level? 
(2) What can be done to reduce or eliminate risks? 
(3) What is the appropriate balance among benefits, risks, and resources? 
(4) Are new risks introduced as a result of the identified risks being controlled? 
 
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Risk reduction focuses on processes for mitigation or avoidance of quality risk when it exceeds a 
specified (acceptable) level (see Fig. 1).  Risk reduction might include actions taken to mitigate 
the severity and probability of harm.  Processes that improve the detectability of hazards and 
quality risks might also be used as part of a risk control strategy.  The implementation of risk 
reduction measures can introduce new risks into the system or increase the significance of other 
existing risks.  Hence, it might be appropriate to revisit the risk assessment to identify and 
evaluate any possible change in risk after implementing a risk reduction process. 
 
Risk acceptance is a decision to accept risk.  For some types of harms, even the best quality risk 
management practices might not entirely eliminate risk.  In these circumstances, it might be 
agreed that an appropriate quality risk management strategy has been applied and that quality 
risk is reduced to a specified (acceptable) level.  This (specified) acceptable level will depend on 
many parameters and should be decided on a case-by-case basis. 
 
E.  Risk Communication (4.5) 
 
Risk communication is the sharing of information about risk and risk management between the 
decision makers and others.  Parties can communicate at any stage of the risk management 
process (see Fig. 1: dashed arrows).  The output/result of the quality risk management process 
should be appropriately communicated and documented (see Fig. 1: solid arrows).  
Communications might include those among interested parties; e.g., regulators and industry, 
industry, and the patient, within a company, industry, or regulatory authority, etc.  The included 
information might relate to the existence, nature, form, probability, severity, acceptability, 
control, treatment, detectability, or other aspects of risks to quality.  Communication need not be 
carried out for each and every risk acceptance.  Between the industry and regulatory authorities, 
communication concerning quality risk management decisions might be conducted through 
existing channels as specified in regulations and guidances. 
 
F.  Risk Review (4.6) 
 
Risk management should be an ongoing part of the quality management process.  A mechanism 
to review or monitor events should be implemented. 
 
The output/results of the risk management process should be reviewed to take into account new 
knowledge and experience.  Once a quality risk management process has been initiated, that 
process should continue to be utilized for events that might impact the original quality risk 
management decision, whether these events are planned (e.g., results of product review, 
inspections, audits, change control) or unplanned (e.g., root cause from failure investigations, 
recall).  The frequency of any review should be based upon the level of risk.  Risk review might 
include reconsideration of risk acceptance decisions (section IV.D (4.4)). 
 
 
V.  RISK MANAGEMENT METHODOLOGY (5) 
 
Quality risk management supports a scientific and practical approach to decision-making.  It 
provides documented, transparent, and reproducible methods to accomplish steps of the quality 
7  Contains Nonbinding Recommendations 
risk management process based on current knowledge about assessing the probability, severity 
and sometimes detectability of the hazards, and their associated risks.  While detectability may 
not be a discrete factor in some quality risk management methods, detection controls are 
important as they can reduce the probability of occurrence of harm. 
 
Traditionally, risks to quality have been assessed and managed in a variety of ways (empirical 
and/or internal procedures) based on, for example, compilation of observations, trends, and other 
information.  Such approaches continue to provide useful information that might support topics 
such as handling of complaints, quality defects, deviations, and allocation of resources. 
 
Additionally, the pharmaceutical industry and regulators can assess and manage risk using 
recognized risk management tools and/ or internal procedures (e.g., standard operating 
procedures).  Below is a non-exhaustive list of some of these tools (further details in Annex 1 
and section VIII (8)): 
 
  Basic risk management facilitation methods (flowcharts, check sheets etc.) 
  Failure Mode Effects Analysis (FMEA) 
  Failure Mode, Effects and Criticality Analysis (FMECA) 
  Fault Tree Analysis (FTA) 
  Hazard Analysis and Critical Control Points (HACCP) 
  Hazard Operability Analysis (HAZOP) 
  Preliminary Hazard Analysis (PHA) 
  Risk ranking and filtering 
  Supporting statistical tools 
 
It might be appropriate to adapt these tools for use in specific areas pertaining to drug substance 
and drug (medicinal) product quality.  Quality risk management methods and the supporting 
statistical tools can be used in combination (e.g., Probabilistic Risk Assessment).  Combined use 
provides flexibility that can facilitate the application of quality risk management principles. 
 
The degree of rigor and formality of quality risk management should reflect available knowledge 
and be commensurate with the level of uncertainty, importance, and complexity of the issue to be 
addressed. 
 
A.  Formality in Quality Risk Management (5.1) 
 
Formality in quality risk management is not a binary concept (i.e., formal/informal); varying 
degrees of formality may be applied during quality risk management activities, including when 
making risk-based decisions.  In this way, formality can be considered a continuum (or 
spectrum), ranging from low to high. 
 
When determining how much formality to apply to a given quality risk management activity, 
certain factors may be considered.  These may include, for example, the following: 
 
  Uncertainty: The term uncertainty in quality risk management means lack of knowledge 
about hazards, harms and, consequently, their associated risks.  The level of uncertainty 
8  Contains Nonbinding Recommendations 
that is associated with the area being risk assessed informs how much formality may be 
required to manage potential risks.  Systematic approaches for acquiring, analyzing, 
storing, and disseminating scientific information are essential for generating knowledge, 
which in turn informs all quality risk management activities.  Uncertainty may be reduced 
via effective knowledge management, which enables accumulated and new information 
(both internal and external) to be used to support risk-based decisions throughout the 
product lifecycle. 
 
  Importance: The more important a risk-based decision may be in relation to product 
quality, the higher the level of formality that should be applied, and the greater the need 
to reduce the level of uncertainty associated with it. 
 
  Complexity: The more complex a process or subject area is to a quality risk management 
activity, the higher the level of formality that should be applied to assure product quality. 
 
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. 
 
The overall approach for determining how much formality to apply during quality risk 
management activities should be described within the quality system.  Resource constraints 
should not be used to justify the use of lower levels of formality in the quality risk management 
process.  Risk scores, ratings and assessments should be based on an appropriate use of evidence, 
science, and knowledge.  Regardless of how much formality is applied, the robust management 
of risk is the goal of the process. 
 
The following may be characteristics of higher levels of formality: 
 
  All parts of the quality risk management process (risk assessment, risk control, risk 
review and risk communication) are explicitly performed, and stand-alone quality risk 
management reports or related documents which address all aspects of the process may 
be generated and are documented (e.g., within the quality system). 
 
  Quality risk management tools, including those shown in Annex 1, are used in some or 
all parts of the process. 
 
  A cross-functional team is assembled for the quality risk management activity. 
 
  Use of a facilitator, with experience and knowledge of the quality risk management 
process, may be integral to a higher formality process. 
 
The following may be characteristics of lower levels of formality: 
 
  One or more parts of the quality risk management process are not performed as stand- 
alone activities but are addressed within other elements of the quality system which may 
have risk assessment and risk control activities embedded within them. 
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  Quality risk management tools might not be used in some or all parts of the process. 
 
  A cross-functional team might not be necessary. 
 
  Standalone quality risk management reports might not be generated.  The outcome of the 
quality risk management process is usually documented in the relevant parts of the 
quality system. 
 
Note: As indicated above, degrees of formality between the above higher and lower levels also 
exist and may be used. 
 
B.  Risk-Based Decision-Making (5.2) 
 
Risk-based decision-making is inherent in all quality risk management activities; it provides an 
essential foundation for decision makers in an organization.  Effective risk-based decision- 
making begins with determining the level of effort, formality and documentation that should be 
applied during the quality risk management process.  The decisions made from quality risk 
management activities include those in relation to what hazards exist, the risks associated with 
those hazards, the risk controls required, the acceptability of the residual risk after risk controls, 
and the communication and review of quality risk management activities and outputs. 
 
As all decision-making relies on the use of knowledge, see ICH Q10 for guidance in relation to 
knowledge management.  It is important also to ensure the integrity of the data that are used for 
risk-based decision-making. 
 
Approaches to risk-based decision-making: 
 
There are different processes that may be used to make risk-based decisions; these are directly 
related to the level of formality that is applied during the quality risk management process.  (See 
section V.A (5.1) above for guidance on what constitutes formality in quality risk management.) 
 
Higher levels of formality in quality risk management may require higher levels of structure in 
relation to risk-based decision-making.  There can be varying degrees of structure with regard to 
approaches for risk-based decision-making.  These degrees of structure can be considered to be 
on a continuum (or spectrum).  Below are descriptions of highly structured vs. less structured 
processes, and for rule-based processes when making risk-based decisions: 
 
  Some risk-based decision-making processes are highly structured and can involve a 
formal analysis of the available options that exist before making a decision.  They 
involve an in- depth consideration of relevant factors associated with the available 
options.  Such processes might be used when there is a high degree of importance 
associated with the decision, and when the level of uncertainty and/or complexity is high. 
 
  Other risk-based decision-making processes are less structured; here, simpler approaches 
are used to arrive at decisions, and they primarily make use of existing knowledge to 
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support an assessment of hazards, risks, and any required risk controls.  Such processes 
might still be used when there is a high degree of importance associated with the 
decision, but the degree of uncertainty and/or complexity is lower. 
 
  Decisions might also be made using rule-based (or standardized) approaches, which do 
not require a new risk assessment to make such decisions.  This is where there are SOPs, 
policies or well understood requirements in place which determine what decisions must 
be made.  Here, rules (or limits) may be in place which govern such decisions; these may 
be based on a previously obtained understanding of the relevant risks and they usually 
lead to predetermined actions and/or expected outcomes. 
 
The above approaches to risk-based decision-making are beneficial because they address 
uncertainty through knowledge, facilitating informed decisions by regulators, and the 
pharmaceutical industry in a multitude of areas.  They also help recognize where uncertainty 
remains, so that appropriate risk controls (including improved detection) may be identified to 
enhance understanding of those variables and further reduce the level of uncertainty. 
 
C.  Managing and Minimizing Subjectivity (5.3) 
 
Subjectivity can impact every stage of a quality risk management process, especially the 
identification of hazards and the estimation of probability of occurrence and severity of harm.  It 
can also impact the estimation of risk reduction and the effectiveness of decisions made from 
quality risk management activities. 
 
Subjectivity can be introduced in quality risk management through differences in how risks are 
assessed and in how hazards, harms and risks are perceived by different stakeholders, (e.g., bias).  
Subjectivity can also be introduced when risk questions are inadequately defined, and when tools 
have poorly designed risk scoring scales. 
 
While subjectivity cannot be completely eliminated from quality risk management activities, it 
may be controlled by addressing bias and assumptions, the proper use of quality risk 
management tools and maximizing the use of relevant data and sources of knowledge (see ICH 
Q10, section II.E.1 (1.6.1)). 
 
All participants involved with quality risk management activities should acknowledge, 
anticipate, and address the potential for subjectivity. 
 
 
VI.  INTEGRATION OF QUALITY RISK MANAGEMENT INTO INDUSTRY AND 
REGULATORY OPERATIONS (6) 
 
Quality risk management is a process that supports science-based and practical decisions when 
integrated into quality systems (see Annex II).  As outlined in the introduction, appropriate use 
of quality risk management does not obviate industrys obligation to comply with regulatory 
requirements.  However, effective quality risk management can facilitate better and more 
informed decisions, can provide regulators with greater assurance of a companys ability to deal 
11  Contains Nonbinding Recommendations 
with potential risks, and might affect the extent and level of direct regulatory oversight.  In 
addition, quality risk management can facilitate better use of resources by all parties. 
 
Training of both industry and regulatory personnel in quality risk management processes 
provides for greater understanding of decision-making processes and builds confidence in quality 
risk management outcomes. 
 
Quality risk management should be integrated into existing operations and documented 
appropriately.  Annex II provides examples of situations in which the use of the quality risk 
management process might provide information that could then be used in a variety of 
pharmaceutical operations.  These examples are provided for illustrative purposes only and 
should not be considered a definitive or exhaustive list.  These examples are not intended to 
create any new expectations beyond the requirements laid out in the current regulations. 
 
Examples for industry and regulatory operations (see Annex II): 
 
  Quality management 
 
Examples for industry operations and activities (see Annex II): 
 
  Development 
  Facility, equipment, and utilities 
  Materials management 
  Production 
  Laboratory control and stability testing 
  Packaging and labeling 
  Supply chain control 
 
Examples for regulatory operations (see Annex II): 
 
  Inspection and assessment activities 
 
While regulatory decisions will continue to be taken on a regional basis, a common 
understanding and application of quality risk management principles could facilitate mutual 
confidence and promote more consistent decisions among regulators on the basis of the same 
information.  This collaboration could be important in the development of policies and guidelines 
that integrate and support quality risk management practices. 
 
A.  The Role of Quality Risk Management in Addressing Product Availability 
Risks Arising From Quality/Manufacturing Issues (6.1) 
 
Quality/manufacturing issues, including non-compliance with Good Manufacturing Practice 
(GMP), are a significant cause of product availability issues (e.g., product shortages).  The 
interests of patients are served by risk-based drug shortage prevention and mitigation activities 
that help to proactively manage supply chain complexities and ensure availability of needed drug 
(medicinal) products. 
12  Contains Nonbinding Recommendations 
 
While manufacturing and supply chain diversity can be enablers of product availability, 
increasingly complex supply chains lead to interdependencies that can introduce systemic 
quality/manufacturing risks impacting supply chain robustness.  The application of quality risk 
management enables the proactive identification and implementation of preventive measures that 
support product availability. 
 
An effective pharmaceutical quality system drives both supply chain robustness and sustainable 
GMP compliance.  The pharmaceutical quality system, including management responsibilities, 
also uses quality risk management and knowledge management to provide an early warning 
system that supports effective oversight and response to evolving quality/manufacturing risks 
from the pharmaceutical company or its external partners.  When risk-based drug shortage 
prevention and mitigation activities are performed, the level of formality that is applied to those 
activities may vary (see section V.A (5.1)) and should be commensurate with the level of risk 
associated with a loss of availability of the product(s). 
 
Quality/manufacturing factors that can affect supply reliability, and hence product availability, 
include, but are not limited to, the following: 
 
(a) Manufacturing Process Variability and State of Control: 
 
Processes that exhibit excessive variability (e.g., process drift, non-uniformity) have capability 
gaps that can result in unpredictable outputs (e.g., quality, timeliness, and yield) and 
consequently can adversely impact product availability.  Quality risk management can help 
design monitoring systems that are capable of detecting departures from a state of control and 
deficiencies in manufacturing processes, so they can be investigated to address root causes. 
 
(b) Manufacturing Facilities and Equipment: 
 
A robust facility infrastructure can facilitate reliable supply; it includes suitable equipment and 
well-designed facilities for manufacturing (including packaging and testing).  Robustness can be 
affected by multiple factors, such as an aging facility, insufficient maintenance or an operational 
design that is vulnerable to human error.  Risks to supply can be reduced by addressing these 
factors, as well as through the use of modern technology, such as digitalization, automation, 
isolation technology, amongst others. 
 
(c) Oversight of Outsourced Activities and Suppliers: 
 
Quality system governance includes assuring the acceptability of supply chain partners over the 
product lifecycle.  Approval and oversight of outsourced activities and material suppliers is 
informed by risk assessments, effective knowledge management, and an effective monitoring 
strategy for supply chain partner performance.  A successful manufacturing partnership is 
strengthened by appropriate communication and collaboration mechanisms (See section II.G 
(2.7) of ICH Q10).  When substantial variability is identified in the quality and safety of supplied 
materials or in the services provided, enhanced review and monitoring activities are justified.  In 
some cases, it may be necessary to identify a new supply chain entity (e.g., a pre-qualified 
alternative option) to perform a function. 
13  Contains Nonbinding Recommendations 
 
Note that the guidance in Annex II.B, in relation to the application of quality risk management as 
part of Regulatory Operations, can be useful to consider in the context of product availability 
risks. 
 
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VII.  DEFINITIONS (7) 
 
Decision Maker(s): Person(s) with the competence and authority to make appropriate and timely 
quality risk management decisions. 
 
Detectability: The ability to discover or determine the existence, presence, or fact of a hazard. 
 
Harm: Damage to health, including the damage that can occur from loss of product quality or 
availability. 
 
Hazard: The potential source of harm (ISO/IEC Guide 51:2014). 
 
Hazard Identification: The systematic use of information to identify potential sources of harm 
(hazards) referring to the risk question or problem description. 
 
Product Lifecycle: All phases in the life of the product from the initial development through 
marketing until the products discontinuation. 
 
Quality: The degree to which a set of inherent properties of a product, system or process fulfills 
requirements (see ICH Q6A definition specifically for quality of drug substance and drug 
(medicinal) products.) 
 
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. 
 
Quality System: The sum of all aspects of a system that implements quality policy and ensures 
that quality objectives are met. 
 
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. 
 
Risk: The combination of the probability of occurrence of harm and the severity of that harm 
(ISO/IEC Guide 51:2014). 
 
Risk Acceptance: An informed decision to take a particular risk (ISO Guide 73:2009). 
 
Risk Analysis: The estimation of the risk associated with the identified hazards. 
 
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. 
 
Risk-Based Decision-Making: An approach to, or a process of, making decisions that considers 
knowledge about risks relevant to the decision and whether risks are at an acceptable level. 
 
  15  Contains Nonbinding Recommendations 
Risk Communication: The sharing of information about risk and risk management between the 
decision maker and other stakeholders. 
 
Risk Control: Actions implementing risk management decisions (ISO Guide 73:2009). 
 
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. 
 
Risk Management: The systematic application of quality management policies, procedures, and 
practices to the tasks of assessing, controlling, communicating, and reviewing risk. 
 
Risk Reduction: Actions taken to lessen the probability of occurrence of harm and the severity 
of that harm. 
 
Risk Review: Review or monitoring of output/results of the risk management process 
considering (if appropriate) new knowledge and experience about the risk. 
 
Severity: A measure of the possible consequences of a hazard. 
 
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. 
 
Trend: A statistical term referring to the direction or rate of change of a variable(s). 
 
  16  Contains Nonbinding Recommendations 
VIII.  REFERENCES (8) 
 
Guidances for Industry1 
 
1.  International Council for Harmonisation (ICH) guidance for industry Q8 Pharmaceutical 
Development (May 2006). 
 
2.  ICH guidance for industry Q10 Pharmaceutical Quality System (April 2009). 
 
3.  ICH guidance for industry Q11 Development and Manufacture of Drug Substances 
(Chemical Entities and Biotechnological/Biological Entities) (November 2012). 
 
4.  ICH guidance for industry Q12 Technical and Regulatory Considerations for 
Pharmaceutical Product Lifecycle Management (May 2021). 
 
International Organization for Standardization (ISO)/International Electrotechnical Commission 
(IEC) Guides 
 
1.  ISO/IEC Guide 73:2009: Risk ManagementVocabulary. 
 
2.  ISO/IEC Guide 51:2014: Safety AspectsGuideline for their inclusion in standards. 
 
3.  IEC 61025: Fault Tree Analysis (FTA). 
 
4.  IEC 60812:2018: Failure modes and effects analysis (FMEA and FMECA). 
 
5.  IEC 61882:2016: Hazard and operability studies (HAZOP studies)Application guide. 
 
6.  ISO 14971:2019: Medical devicesApplication of risk management to medical devices. 
 
7.  ISO 7870-1:2019: Control Charts, General Guidelines. 
 
8.  ISO 7870-4:2021: Cumulative Sum Charts. 
 
9.  ISO 7870-3:2020: Acceptance Control Charts. 
 
10. ISO 7870-2:2013: Shewhart Control Charts. 
 
Literature 
 
1.  World Health Organization, 2003, Application of Hazard Analysis and Critical Control Point 
(HACCP) Methodology to Pharmaceuticals, Technical Report Series, No 908, Annex 7. 
 
 
1 We update guidances periodically.  To make sure you have the most recent version of a guidance, check the FDA 
guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents.  
  17  Contains Nonbinding Recommendations 
2.  Kaoru Ishikawa (Translated by David J. Liu), 1985, What is Total Quality Control?: The 
Japanese Way, Prentice Hall Direct Publishers, Des Moines, IA, www.phdirect.com, ISBN 
0139524339. 
 
3.  Failure Mode and Effect Analysis, FMEA from Theory to Execution, 2nd Edition 2003, D. 
 
4.  Stamatis, ISBN 0873895983. 
 
5.  Process Mapping by the American Productivity & Quality Center, 2002, ISBN 1928593739. 
 
6.  Parenteral Drug Association, 2012, Implementation of Quality Risk Management for 
Pharmaceutical and Biotechnology Manufacturing Operations, Technical Report No. 54 
 
7.  Parenteral Drug Association, 2017, Points To Consider for Aging Facilities.   
 
8.  Parenteral Drug Association, 2014, Risk-Based Approach for Prevention and Management of 
Drug Shortages, Technical Report No. 68. 
 
9.  International Society for Pharmaceutical Engineering, 2013, Report on the ISPE Drug 
Shortages Survey. 
 
10. International Society for Pharmaceutical Engineering, 2014, Drug Shortages Prevention Plan.   
 
11. Tabersky, D, Woelfle, M, Ruess, J, Brem, S, and S. Brombacher, 2018, Recent Regulatory 
Trends in Pharmaceutical Manufacturing and Their Impact on the Industry, Chimia (Aarau), 
72(3):146-150. 
 
12. ODonnell, K, Tobin, D, Butler, S, Haddad, G, Kelleher, D, 2020, Understanding the 
Concept of Formality in Quality Risk Management, J Valid Technol, 26(3). 
 
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ANNEX I: QUALITY RISK MANAGEMENT METHODS AND TOOLS 
 
The purpose of this annex is to provide a general overview of and references for some of the 
primary tools that might be used in quality risk management by industry and regulators.  The 
references are included as an aid to gain more knowledge and detail about the particular tool.  
This is not an exhaustive list.  It is important to note that no one tool or set of tools is applicable 
to every situation in which a quality risk management procedure is used. 
 
It is neither always appropriate nor always necessary to use highly formal quality risk 
management methods and tools.  The use of less formal quality risk management methods and 
tools can also be considered acceptable.  See section V.A (5.1) in the main body of this guidance 
for guidance on what constitutes formality in quality risk management. 
 
A.  Basic Risk Management Facilitation Methods (I.1) 
 
Some of the simple techniques that are commonly used to structure risk management by 
organizing data and facilitating decision-making are: 
 
  Flowcharts 
  Check Sheets 
  Process Mapping 
  Cause and Effect Diagrams (also called an Ishikawa diagram or fish bone diagram) 
 
B.  Failure Mode Effects Analysis (FMEA) (I.2) 
 
FMEA (see IEC 60812) provides for an evaluation of potential failure modes for processes and 
their likely effect on outcomes and/or product performance. Once failure modes are established, 
risk reduction can be used to eliminate, contain, reduce, or control the potential failures.  FMEA 
relies on product and process understanding.  FMEA methodically breaks down the analysis of 
complex processes into manageable steps.  It is a powerful tool for summarizing the important 
modes of failure, factors causing these failures and the likely effects of these failures. 
 
Potential Areas of Use(s) 
 
FMEA can be used to prioritize risks and monitor the effectiveness of risk control activities.  
FMEA can be applied to equipment and facilities and might be used to analyze a manufacturing 
operation and its effect on product or process.  It identifies elements/operations within the system 
that render it vulnerable.  The output/ results of FMEA can be used as a basis for design or 
further analysis or to guide resource deployment.   
 
C.  Failure Mode, Effects, and Criticality Analysis (FMECA) (I.3) 
 
FMEA might be extended to incorporate an investigation of the degree of severity of the 
consequences, their respective probabilities of occurrence, and their detectability, thereby 
becoming a Failure Mode Effect and Criticality Analysis (FMECA; see IEC 60812).  For such an 
  19  Contains Nonbinding Recommendations 
analysis to be performed, the product or process specifications should be established.  FMECA 
can identify places where additional preventive actions might be appropriate to minimize risks. 
 
Potential Areas of Use(s) 
 
FMECA application in the pharmaceutical industry should mostly be utilized for failures and 
risks associated with manufacturing processes; however, it is not limited to this application.  The 
output of an FMECA is a relative risk score for each failure mode, which is used to rank the 
modes on a relative risk basis. 
 
D.  Fault Tree Analysis (FTA) (I.4) 
 
The FTA tool (see IEC 61025) is an approach that assumes failure of the functionality of a 
product or process.  This tool evaluates system (or subsystem) failures one at a time but can 
combine multiple causes of failure by identifying causal chains.  The results are represented 
pictorially in the form of a tree of fault modes.  At each level in the tree, combinations of fault 
modes are described with logical operators (AND, OR, etc.).  FTA relies on the experts process 
understanding to identify causal factors. 
 
Potential Areas of Use(s) 
 
FTA can be used to establish the pathway to the root cause of the failure.  FTA can be used to 
investigate complaints or deviations in order to fully understand their root cause and to ensure 
that intended improvements will fully resolve the issue and not lead to other issues (i.e., solve 
one problem yet cause a different problem).  Fault Tree Analysis is an effective tool for 
evaluating how multiple factors affect a given issue.  The output of an FTA includes a visual 
representation of failure modes.  It is useful both for risk assessment and in developing 
monitoring programs. 
 
E.  Hazard Analysis and Critical Control Points (HACCP) (I.5) 
 
HACCP is a systematic, proactive, and preventive tool for assuring product quality, reliability, 
and safety (see WHO Technical Report Series No 908, 2003 Annex 7).  It is a structured 
approach that applies technical and scientific principles to analyze, evaluate, prevent, and control 
the risk or adverse consequence(s) of hazard(s) due to the design, development, production, and 
use of products. 
 
HACCP consists of the following seven steps: 
 
1.  Conduct a hazard analysis and identify preventive measures for each step of the process 
 
2.  Determine the critical control points 
 
3.  Establish critical limits 
 
4.  Establish a system to monitor the critical control points 
  20  Contains Nonbinding Recommendations 
 
5.  Establish the corrective action to be taken when monitoring indicates that the critical 
control points are not in a state of control 
 
6.  Establish system to verify that the HACCP system is working effectively 
 
7.  Establish a record-keeping system 
 
Potential Areas of Use(s) 
 
HACCP might be used to identify and manage risks associated with physical, chemical, and 
biological hazards (including microbiological contamination).  HACCP is most useful when 
product and process understanding is sufficiently comprehensive to support identification of 
critical control points.  The output of a HACCP analysis is risk management information that 
facilitates monitoring of critical points not only in the manufacturing process but also in other 
life cycle phases. 
 
F.  Hazard Operability Analysis (HAZOP) (I.6) 
 
HAZOP (see IEC 61882) is based on a theory that assumes that risk events are caused by 
deviations from the design or operating intentions.  It is a systematic brainstorming technique for 
identifying hazards using so-called guide-words.  Guide-words (e.g., No, More, Other Than, 
Part of, etc.) are applied to relevant parameters (e.g., contamination, temperature) to help identify 
potential deviations from normal use or design intentions.  It often uses a team of people with 
expertise covering the design of the process or product and its application. 
 
Potential Areas of Use(s) 
 
HAZOP can be applied to manufacturing processes, including outsourced production and 
formulation as well as the upstream suppliers, equipment and facilities for drug substances and 
drug (medicinal) products.  It has also been used primarily in the pharmaceutical industry for 
evaluating process safety hazards.  As is the case with HACCP, the output of a HAZOP analysis 
is a list of critical operations for risk management.  This facilitates regular monitoring of critical 
points in the manufacturing process. 
 
G.  Preliminary Hazard Analysis (PHA) (I.7) 
 
PHA is a tool of analysis based on applying prior experience or knowledge of a hazard or failure 
to identify future hazards, hazardous situations and events that might cause harm, as well as to 
estimate their probability of occurrence for a given activity, facility, product, or system.  The tool 
consists of: (1) the identification of the possibilities that the risk event happens; (2) the 
qualitative evaluation of the extent of possible injury or damage to health that could result; (3) a 
relative ranking of the hazard using a combination of severity and likelihood of occurrence; and 
(4) the identification of possible remedial measures. 
 
  21  Contains Nonbinding Recommendations 
Potential Areas of Use(s) 
 
PHA might be useful when analyzing existing systems or prioritizing hazards where 
circumstances prevent a more extensive technique from being used.  It can be used for product, 
process, and facility design as well as to evaluate the types of hazards for the general product 
type, then the product class, and finally the specific product.  PHA is most commonly used early 
in the development of a project when there is little information on design details or operating 
procedures; thus, it will often be a precursor to further studies.  Typically, hazards identified in 
the PHA are further assessed with other risk management tools such as those in this section. 
 
H.  Risk Ranking and Filtering (I.8) 
 
Risk ranking and filtering is a tool for comparing and ranking risks.  Risk ranking of complex 
systems typically requires evaluation of multiple diverse quantitative and qualitative factors for 
each risk.  The tool involves breaking down a basic risk question into as many components as 
needed to capture factors involved in the risk.  These factors are combined into a single relative 
risk score that can then be used for ranking risks.  Filters, in the form of weighting factors or 
cut-offs for risk scores, can be used to scale or fit the risk ranking to management or policy 
objectives. 
 
Potential Areas of Use(s) 
 
Risk ranking and filtering can be used to prioritize manufacturing sites for inspection/audit by 
regulators or industry.  Risk ranking methods are particularly helpful in situations in which the 
portfolio of risks and the underlying consequences to be managed are diverse and difficult to 
compare using a single tool.  Risk ranking is useful when management needs to evaluate both 
quantitatively assessed and qualitatively assessed risks within the same organizational 
framework. 
 
I.  Supporting Statistical Tools (I.9) 
 
Statistical tools can support and facilitate quality risk management.  They can enable effective 
data assessment, aid in determining the significance of the data set(s) and facilitate more reliable 
decision-making.  A listing of some of the principal statistical tools commonly used in the 
pharmaceutical industry is provided: 
 
Control Charts, for example: 
 
  Acceptance Control Charts (see ISO 7870-3:2020) 
  Cumulative Sum Charts (see ISO 7870-4:2021) 
  Shewhart Control Charts (see ISO 7870-2:2013) 
  Weighted Moving Average 
  Design of Experiments (DOE) 
  Histograms 
  Pareto Charts 
Process Capability Analysis 
  22  Contains Nonbinding Recommendations 
ANNEX II: POTENTIAL APPLICATIONS FOR QUALITY RISK MANAGEMENT 
 
This Annex is intended to identify potential uses of quality risk management principles and tools 
by industry and regulators.  However, the selection of particular risk management tools is 
completely dependent upon specific facts and circumstances. 
 
These examples are provided for illustrative purposes and only suggest potential uses of quality 
risk management.  This Annex is not intended to create any new expectations beyond the current 
regulatory requirements. 
 
A.  Quality Risk Management as Part of Integrated Quality Management 
Documentation (II.1) 
 
To review current interpretations and application of regulatory expectations; 
 
To determine the desirability of and/or develop the content for SOPs, guidelines, etc. 
 
Training and Education 
 
To determine the appropriateness of initial and/or ongoing training sessions based on education, 
experience and working habits of staff, as well as on a periodic assessment of previous training 
(e.g., its effectiveness); 
 
To identify the training, experience, qualifications, and physical abilities that allow personnel to 
perform an operation reliably and with no adverse impact on the quality of the product. 
 
Quality Defects 
 
To provide the basis for identifying, evaluating, and communicating the potential quality impact 
of a suspected quality defect, complaint, trend, deviation, investigation, out of specification 
result, etc. 
 
To facilitate risk communications and determine appropriate action to address significant product 
defects, in conjunction with regulatory authorities (e.g., recall). 
 
Auditing/Inspection 
 
To define the frequency and scope of audits, both internal and external, considering factors such 
as: 
 
  Existing legal requirements 
  Overall compliance status and history of the company or facility 
  Robustness of a companys quality risk management activities 
  Complexity of the site 
  Complexity of the manufacturing process 
  Complexity of the product and its therapeutic significance 
  23  Contains Nonbinding Recommendations 
  Number and significance of quality defects (e.g., recall) 
  Results of previous audits/inspections 
  Major changes of building, equipment, processes, key personnel 
  Experience with manufacturing of a product (e.g., frequency, volume, number of batches) 
  Test results of official control laboratories   
 
Periodic Review 
 
To select, evaluate and interpret trend results of data within the product quality review; 
 
To interpret monitoring data (e.g., to support an assessment of the appropriateness of revalidation 
or changes in sampling). 
 
Change Management/Change Control 
 
To manage changes based on knowledge and information accumulated in pharmaceutical 
development and during manufacturing; 
 
To evaluate the impact of the changes on the availability of the final product; 
 
To evaluate the impact on product quality of changes to the facility, equipment, material, 
manufacturing process or technical transfers; 
 
To determine appropriate actions preceding the implementation of a change, e.g., additional 
testing, (re)qualification, (re)validation or communication with regulators. 
 
Continual Improvement 
 
To facilitate continual improvement in processes throughout the product lifecycle. 
 
B.  Quality Risk Management as Part of Regulatory Operations Inspection and 
Assessment Activities (II.2) 
 
To assist with resource allocation including, for example, inspection planning and frequency, and 
inspection and assessment intensity (see Auditing section in Annex II.A (II.1)); 
 
To evaluate the significance of, for example, quality defects, potential recalls, and inspectional 
findings; 
 
To determine the appropriateness and type of post-inspection regulatory follow-up; 
 
To evaluate information submitted by industry including pharmaceutical development 
information; 
 
To evaluate impact of proposed variations or changes; 
 
  24  Contains Nonbinding Recommendations 
To identify risks which should be communicated between inspectors and assessors to facilitate 
better understanding of how risks can be or are controlled (e.g., parametric release, Process 
Analytical Technology (PAT)). 
 
C.  Quality Risk Management as Part of Development (II.3) 
 
To design a quality product and its manufacturing process to consistently deliver the intended 
performance of the product (see ICH Q8); 
 
To enhance knowledge of product performance over a wide range of material attributes (e.g., 
particle size distribution, moisture content, flow properties), processing options and process 
parameters; 
 
To assess the critical attributes of raw materials, solvents, Active Pharmaceutical Ingredient 
(API) starting materials, APIs, excipients, or packaging materials; 
 
To establish appropriate specifications, identify critical process parameters and establish 
manufacturing controls (e.g., using information from pharmaceutical development studies 
regarding the clinical significance of quality attributes and the ability to control them during 
processing); 
 
To decrease variability of quality attributes: 
 
  Reduce product and material defects; 
  Reduce manufacturing defects. 
 
To assess the need for additional studies (e.g., bioequivalence, stability) relating to scale up and 
technology transfer; 
 
To make use of the design space concept (see ICH Q8). 
 
D.  Quality Risk Management for Facilities, Equipment, and Utilities Design of 
Facility/Equipment (II.4) 
 
To determine appropriate zones when designing buildings and facilities, e.g., 
 
  Flow of material and personnel 
  Minimize contamination 
  Pest control measures 
  Prevention of mix-ups 
  Open versus closed equipment 
  Clean rooms versus isolator technologies 
  Dedicated or segregated facilities/equipment 
 
To determine appropriate product contact materials for equipment and containers (e.g., selection 
of stainless-steel grade, gaskets, lubricants); 
  25  Contains Nonbinding Recommendations 
 
To determine appropriate utilities (e.g., steam, gases, power source, compressed air, heating, 
ventilation, and air conditioning (HVAC), water); 
 
To determine appropriate preventive maintenance for associated equipment (e.g., inventory of 
necessary spare parts). 
 
Hygiene Aspects in Facilities 
 
To protect the product from environmental hazards, including chemical, microbiological, and 
physical hazards (e.g., determining appropriate clothing and gowning, hygiene concerns); 
 
To protect the environment (e.g., personnel, potential for cross-contamination) from hazards 
related to the product being manufactured. 
 
Qualification of Facility/Equipment/Utilities 
 
To determine the scope and extent of qualification of facilities, buildings, and production 
equipment and/or laboratory instruments (including proper calibration methods). 
 
Cleaning of equipment and environmental control 
 
To differentiate efforts and decisions based on the intended use (e.g., multi- versus single- 
purpose, batch versus continuous production); 
 
To determine acceptable (specified) cleaning validation limits. 
 
Calibration/Preventive Maintenance 
 
To set appropriate calibration and maintenance schedules. 
 
Computer Systems and Computer-Controlled Equipment 
 
To select the design of computer hardware and software (e.g., modular, structured, fault 
tolerance); 
 
To determine the extent of validation, e.g., 
 
  Identification of critical performance parameters 
  Selection of the requirements and design 
  Code review 
  The extent of testing and test methods 
  Reliability of electronic records and signatures 
 
  26  Contains Nonbinding Recommendations 
E.  Quality Risk Management as Part of Materials Management Assessment and 
Evaluation of Suppliers and Contract Manufacturers (II.5) 
 
To provide a comprehensive evaluation of suppliers and contract manufacturers (e.g., auditing, 
supplier quality agreements). 
 
Starting Material 
 
To assess differences and possible quality risks associated with variability in starting materials 
(e.g., age, route of synthesis). 
 
Use of Materials 
 
To determine whether it is appropriate to use material under quarantine (e.g., for further internal 
processing); 
 
To determine appropriateness of reprocessing, reworking, use of returned goods. 
 
Storage, Logistics and Distribution Conditions 
 
To assess the adequacy of arrangements to ensure maintenance of appropriate storage and 
transport conditions (e.g., temperature, humidity, container design); 
 
To determine the effect on product quality of discrepancies in storage or transport conditions 
(e.g., cold chain management) in conjunction with other ICH guidelines; 
 
To maintain infrastructure (e.g., capacity to ensure proper shipping conditions, interim storage, 
handling of hazardous materials and controlled substances, customs clearance); 
 
To provide information for ensuring the availability of pharmaceuticals (e.g., ranking risks to the 
supply chain). 
 
F.  Quality Risk Management as Part of Production Validation (II.6) 
 
To identify the scope and extent of verification, qualification, and validation activities (e.g., 
analytical methods, processes, equipment, and cleaning methods); 
 
To determine the extent for follow-up activities (e.g., sampling, monitoring and re-validation); 
 
To distinguish between critical and non-critical process steps to facilitate design of a validation 
study. 
 
In-Process Sampling and Testing 
 
To evaluate the frequency and extent of in-process control testing (e.g., to justify reduced testing 
under conditions of proven control); 
 
  27  Contains Nonbinding Recommendations 
To evaluate and justify the use of process analytical technologies (PAT) in conjunction with 
parametric and real time release. 
 
Production Planning 
 
To determine appropriate production planning (e.g., dedicated, campaign and concurrent 
production process sequences). 
 
G.  Quality Risk Management as Part of Laboratory Control and Stability 
Studies Out of Specification Results (II.7) 
 
To identify potential root causes and corrective actions during the investigation of out of 
specification results. 
 
Retest Period/Expiration Date 
 
To evaluate adequacy of storage and testing of intermediates, excipients and starting materials. 
 
H.  Quality Risk Management as Part of Packaging and Labeling Design of 
Packages (II.8) 
 
To design the secondary package for the protection of primary packaged product (e.g., to ensure 
product authenticity, label legibility). 
 
Selection of Container Closure System   
 
To determine the critical parameters of the container closure system. 
 
Label Controls 
 
To design label control procedures based on the potential for mix-ups involving different product 
labels, including different versions of the same label. 
 
I.  Quality Risk Management as Part of Supply Chain Control (II.9) 
 
Regarding product availability risks related to quality/manufacturing issues, product lifecycle 
oversight of the supply chain includes maintaining current knowledge of quality/manufacturing 
hazards and prioritizing efforts to manage such risks.  Understanding hazards to 
quality/manufacturing is critical to maintaining supply predictability.  When risks are well 
understood and controlled, a higher confidence in product availability can be attained. 
 
Manufacturing Process Variation and State of Control 
 
To decrease variability in the manufacturing process (e.g., process drift, non-uniformity) and 
associated capability gaps that can result in unpredictable outputs, adversely impact quality and 
consequently timeliness, yield and product availability; 
  28  Contains Nonbinding Recommendations 
 
To design monitoring systems that are capable of detecting departures from a state of control and 
deficiencies in manufacturing processes, so they can be appropriately investigated to determine 
root causes and any required risk mitigations. 
 
Manufacturing Facilities and Equipment 
 
To ensure that facility infrastructure and equipment are suitable and designed for robust 
manufacturing (this includes packaging and testing) (see Annex II.4); 
 
To establish facility and equipment maintenance programs that assure reliable facility and 
equipment performance; 
 
To ensure that the operational design of equipment is not vulnerable to human error; 
 
To obtain quality and efficiency gains through the utilization of digitalization, automation, 
isolation technology, and other innovations. 
 
Supplier Oversight and Relationships 
 
To enhance review and monitoring activities (see section III.G (2.7) of ICH Q10) when 
substantial variability is identified in the quality and safety of supplied materials or in the 
services provided. 
 
To manage external product availability risks relating to quality/manufacturing, (e.g., from raw 
material suppliers, contracted organizations, service providers, etc.). 
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