Guidance for Industry 

Q9 Quality Risk Management 

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) 

June 2006 

ICH 
Guidance for Industry 

Q9 Quality Risk Management 

Additional copies are available from: 

Office of Training and Communication 

Division of Drug Information, HFD-240 

Center for Drug Evaluation and Research 

Food and Drug Administration 

5600 Fishers Lane 

Rockville, MD 20857 

(Tel) 301-827-4573 

 http://www.fda.gov/cder/guidance/index.htm 

Office of Communication, Training and 

Manufacturers Assistance, HFM-40 

Center for Biologics Evaluation and Research 

 Food and Drug Administration 

1401 Rockville Pike, Rockville, MD 20852-1448 

 http://www.fda.gov/cber/guidelines.htm. 

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) 

June 2006 

ICH 
TABLE OF CONTENTS 

I. INTRODUCTION (1)....................................................................................................... 1

II. SCOPE (2).......................................................................................................................... 2

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) ..................................................................4

C. Risk Assessment (4.3).....................................................................................................................4

D. Risk Control (4.4)...........................................................................................................................5

E. Risk Communication (4.5).............................................................................................................6

F. Risk Review (4.6)............................................................................................................................6

V. RISK MANAGEMENT METHODOLOGY (5)............................................................ 7

VI. INTEGRATION OF QUALITY RISK MANAGEMENT INTO INDUSTRY AND 

 REGULATORY OPERATIONS (6)............................................................................... 7

VII. DEFINITIONS (7) ............................................................................................................ 9

VIII. REFERENCES (8).......................................................................................................... 11

ANNEX I: RISK MANAGEMENT METHODS AND TOOLS ......................................... 12

I.1 Basic Risk Management Facilitation Methods..........................................................................12

I.2 Failure Mode Effects Analysis (FMEA).....................................................................................12

I.3 Failure Mode, Effects and Criticality Analysis (FMECA).......................................................12

I.4 Fault Tree Analysis (FTA) ..........................................................................................................13

I.5 Hazard Analysis and Critical Control Points (HACCP)..........................................................13

I.6 Hazard Operability Analysis (HAZOP).....................................................................................14

I.7 Preliminary Hazard Analysis (PHA)..........................................................................................14

I.8 Risk Ranking and Filtering.........................................................................................................14

I.9 Supporting Statistical Tools........................................................................................................15

ANNEX II: POTENTIAL APPLICATIONS FOR QUALITY RISK MANAGEMENT. 16

II.1 Quality Risk Management as Part of Integrated Quality Management.................................16

II.2 Quality Risk Management as Part of Regulatory Operations.................................................17

II.3 Quality Risk Management as Part of Development..................................................................18

II.4 Quality Risk Management for Facilities, Equipment and Utilities .........................................18

II.5 Quality Risk Management as Part of Materials Management ................................................19
II.6 Quality Risk Management as Part of Production .....................................................................20

II.7 Quality Risk Management as Part of Laboratory Control and Stability Studies..................20

II.8 Quality Risk Management as Part of Packaging and Labelling..............................................21
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Guidance for Industry1

Q9 Quality Risk Management 

This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It 

does not create or confer any rights for or on any person and does not operate to bind FDA or the public. 

You can use an alternative approach if the approach satisfies the requirements of the applicable statutes 

and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for 

implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate 

number listed on the title page of this guidance. 

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. Although there are some examples of the use of quality risk 

management in the pharmaceutical industry today, they are limited and do not represent the full 

contributions that risk management has to offer. In addition, the importance of quality systems

has been recognized in the pharmaceutical industry, and it is becoming 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 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 by managing the risk to quality should be 

considered of prime importance. 

 

1

 This guidance was developed within the Expert Working Group (Quality) of the International Conference on 

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 Steering Committee at Step 4 of the ICH process, November 2005. At Step 4 of the process, 

the final draft is recommended for adoption to the regulatory bodies of the European Union, Japan, and the United 

States. 

2 Arabic numbers reflect the organizational breakdown in the document endorsed by the ICH Steering Committee at 

Step 4 of the ICH process, November 2005. 
Contains Nonbinding Recommendations

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The manufacturing and use of a drug 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 should be maintained throughout the product lifecycle such that 

the attributes that are important to the quality of the drug product remain consistent with those 

used in the clinical studies. An effective quality risk management approach can further ensure 

the high quality of the drug product to the patient by providing a proactive means to identify and 

control potential quality issues during development and manufacturing. In addition, use of 

quality risk management can improve the decision making if a quality problem arises. Effective 

quality risk management can facilitate better and more informed decisions, can provide 

regulators with greater assurance of a company’s ability to deal with potential risks, and can 

beneficially affect the extent and level of direct regulatory oversight. 

The purpose of this document is to offer a systematic approach to quality risk management. 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, by both regulators and industry, 

regarding the quality of drug substances and drug products across the product lifecycle. It is not 

intended to create any new expectations beyond the current regulatory requirements. 

It is neither always appropriate nor always necessary to use a formal risk management process 

(using recognized tools and/or internal procedures, e.g., standard operating procedures). The use 

of informal risk management processes (using empirical tools and/or internal procedures) can 

also be considered acceptable. Appropriate use of quality risk management can facilitate but does 

not obviate industry’s obligation to comply with regulatory requirements and does not replace 

appropriate communications between industry and regulators. 

FDA's guidance documents, including this guidance, do not establish legally enforceable 

responsibilities. Instead, guidances describe the Agency's 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 guidance 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, inspection, and submission/review processes throughout the 

lifecycle of drug substances, drug products, biological and biotechnological products (including 

the use of raw materials, solvents, excipients, packaging and labeling materials in drug products, 

biological and biotechnological products). 
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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; and 

• 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 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. 

Figure 1: Overview of a typical quality risk management process 

Risk Review

Risk Communication

Risk Assessment

Risk Evaluation

unacceptable

Risk Control

Risk Analysis

Risk Reduction

Risk Identification

Review Events

Risk Acceptance

Initiate

Quality Risk Management Process

Output / Result of the

Quality Risk Management Process

Risk Management tools

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 
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refer to statutory, legislative, or regulatory requirements, but also to indicate that the risk 

assessment process should be revisited. 

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, business development, engineering, regulatory affairs, production operations, sales 

and marketing, legal, statistics, and clinical) in addition to individuals who are knowledgeable 

about the quality risk management process. 

Decision makers should 

• take responsibility for coordinating quality risk management across various functions 

and departments of their organization and 

• ensure that a quality risk management process is defined, deployed, and reviewed and 

that adequate resources are available. 

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 critical 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 5) and the types of 

information that will 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)? 
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Risk 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. Risk identification addresses the “What 

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 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: 

• Is the risk above an acceptable level? 

• What can be done to reduce or eliminate risks? 

• What is the appropriate balance among benefits, risks and resources? 

• 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. Risk acceptance can be a formal decision to accept 

the residual risk or it can be a passive decision in which residual risks are not specified. 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). 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 effected 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). 
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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 

risk management process based on current knowledge about assessing the probability, severity, 

and, sometimes, detectability of the risk. 

Traditionally, risks to quality have been assessed and managed in a variety of informal 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. 

In addition, 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 nonexhaustive list of some of these tools (further details in Annex 1 and 

section VIII): 

• 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 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 complexity and/or criticality of the issue to be addressed. 

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 industry’s 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 company’s ability to deal 
Contains Nonbinding Recommendations

8

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 

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. 
Contains Nonbinding Recommendations

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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). 

Product lifecycle: All phases in the life of the product from the initial development through 

marketing until the product’s 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 

products). 

Quality risk management: A systematic process for the assessment, control, communication, 

and review of risks to the quality of the drug 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). 

Risk acceptance: The decision to accept risk (ISO Guide 73). 

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 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). 
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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 identification: The systematic use of information to identify potential sources of harm 

(hazards) referring to the risk question or problem description. 

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 guidance, 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). 
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VIII. REFERENCES (8) 

ICH Q8 Pharmaceutical Development. 

ISO/IEC Guide 73:2002 - Risk management - Vocabulary - Guidelines for use in standards. 

ISO/IEC Guide 51:1999 - Safety aspects - Guideline for their inclusion in standards. 

Process Mapping, American Productivity & Quality Center, 2002, ISBN 1928593739. 

IEC 61025 Fault tree analysis (FTA). 

IEC 60812 Analysis techniques for system reliability—Procedure for failure mode and effects 

analysis (FMEA). 

Failure Mode and Effect Analysis: FMEA from Theory to Execution, 2nd Edition 2003, D. H. 

Stamatis, ISBN 0873895983. 

Guidelines for Failure Modes and Effects Analysis (FMEA) for Medical Devices, 2003, Dyadem 

Press, ISBN 0849319102. 

The Basics of FMEA, Robin McDermott, Raymond J. Mikulak, Michael R. Beauregard, 1996, 

ISBN 0527763209. 

WHO Technical Report Series No. 908, 2003, Annex 7 Application of Hazard Analysis and 

Critical Control Point (HACCP) methodology to pharmaceuticals.

IEC 61882 - Hazard Operability Analysis (HAZOP). 

ISO 14971:2000 - Application of Risk Management to Medical Devices. 

ISO 7870:1993 - Control Charts. 

ISO 7871:1997 - Cumulative Sum Charts. 

ISO 7966:1993 - Acceptance Control Charts. 

ISO 8258:1991 - Shewhart Control Charts. 

What is Total Quality Control?: The Japanese Way, Kaoru Ishikawa (Translated by David J. 

Liu, 1985, ISBN 0139524339. 
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ANNEX I: 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. 

I.1 Basic Risk Management Facilitation Methods 

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) 

I.2 Failure Mode Effects Analysis (FMEA) 

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. 

I.3 Failure Mode, Effects, and Criticality Analysis (FMECA) 

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, Effects, and Criticality Analysis (FMECA; see IEC 60812). In order 

for such an 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. 
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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. 

I.4 Fault Tree Analysis (FTA) 

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. 

I.5 Hazard Analysis and Critical Control Points (HACCP) 

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 

(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 
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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 

lifecycle phases. 

I.6 Hazard Operability Analysis (HAZOP) 

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) are applied to relevant parameters (e.g., contamination, temperature) to help identify potential 

deviations from normal use or design intentions. HAZOP 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 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. 

I.7 Preliminary Hazard Analysis (PHA) 

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 

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. 

I.8 Risk Ranking and Filtering 

Risk ranking and filtering is a tool for comparing and ranking risks. Risk ranking of complex 

systems typically involves 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 
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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 for management to evaluate both 

quantitatively-assessed and qualitatively-assessed risks within the same organizational 

framework. 

I.9 Supporting Statistical Tools 

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: 

z Control charts, for example: 

— Acceptance control charts (see ISO 7966) 

— Control charts with arithmetic average and warning limits (see ISO 7873) 

— Cumulative sum charts (see ISO 7871) 

— Shewhart control charts (see ISO 8258) 

— Weighted moving average 

z Design of experiments (DOE) 

z Histograms 

z Pareto charts 

z Process capability analysis 
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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. 

II.1 Quality Risk Management as Part of Integrated Quality Management 

Documentation 

To review current interpretations and application of regulatory expectations 

To determine the desirability of and/or develop the content for SOPs, guidances, 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, taking into account 

factors such as: 

• Existing legal requirements 

• Overall compliance status and history of the company or facility 

• Robustness of a company’s quality risk management activities 

• Complexity of the site 

• Complexity of the manufacturing process 

• Complexity of the product and its therapeutic significance 

• Number and significance of quality defects (e.g., recall) 

• Results of previous audits/inspections 

• Major changes of building, equipment, processes, key personnel 
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• 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 

II.2 Quality Risk Management as Part of Regulatory Operations 

Inspection and assessment activities 

To assist with resource allocation including, for example, inspection planning and frequency, and 

inspection and assessment intensity (see Auditing section in Annex II.1) 

To evaluate the significance of, for example, quality defects, potential recalls, and inspectional 

findings 

To determine the appropriateness and type of postinspection regulatory follow-up 

To evaluate information submitted by industry, including pharmaceutical development 

information 

To evaluate impact of proposed variations or changes 

To identify risks that 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)). 
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II.3 Quality Risk Management as Part of Development 

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) 

II.4 Quality Risk Management for Facilities, Equipment and Utilities 

Design of facility/equipment 

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) 

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) 
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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 singlepurpose, 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 

II.5 Quality Risk Management as Part of Materials Management 

Assessment and evaluation of suppliers and contract manufacturers 

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) 
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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 guidances 

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). 

II.6 Quality Risk Management as Part of Production 

Validation 

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 noncritical process steps to facilitate design of a validation 

study 

In-process sampling & testing 

To evaluate the frequency and extent of in-process control testing (e.g., to justify reduced testing 

under conditions of proven control) 

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) 

II.7 Quality Risk Management as Part of Laboratory Control and Stability Studies 

Out of specification results 

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 
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II.8 Quality Risk Management as Part of Packaging and Labeling 

Design of packages 

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