ASTM E2476-09
(Guide)Standard Guide for Risk Assessment and Risk Control as it Impacts the Design, Development, and Operation of PAT Processes for Pharmaceutical Manufacture
Standard Guide for Risk Assessment and Risk Control as it Impacts the Design, Development, and Operation of PAT Processes for Pharmaceutical Manufacture
SIGNIFICANCE AND USE
This guide is intended to provide guidance regarding the use of risk analysis in the development, day-to-day running, and continuous improvement of pharmaceutical processes incorporating Process Analytical Technology (PAT). Since PAT is defined as being “risk-based” (see FDA Guidance for Industry), it is important that a consistent approach to the use of risk methodologies is adopted, to ensure rapid transfer of process understanding within the development and manufacturing teams, and to the regulators where that is appropriate.
4.2 This guidance only covers those aspects of risk assessment related to “risk to product quality.” Other aspects (such as “risk to patient”) should be covered in the conventional manner.
SCOPE
1.1 This document provides guidance on the assessment of risks to product quality within and related to PAT processes in the pharmaceutical industry. It addresses those risks to product quality arising from, associated with, identified by, or modified by the implementation of PAT in pharmaceutical development and manufacturing for primary, secondary, and biotech sectors of the industry. It does not replace those assessments of risk currently undertaken by pharmaceutical companies, but is, rather, an additional component focused specifically upon the evaluation and design of PAT processes. See Practice E 2474, Guide E 2500, and ICH Q8.
1.2 This standard does not purport to address all of the safety concerns, if any, associated with its use. It is the responsibility of the user of this standard to establish appropriate safety and health practices and determine the applicability of regulatory limitations prior to use. Note that safety in this context refers to operational and operator safety, not to patient safety.
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Designation: E2476 − 09
StandardGuide for
Risk Assessment and Risk Control as it Impacts the Design,
Development, and Operation of PAT Processes for
Pharmaceutical Manufacture
This standard is issued under the fixed designation E2476; the number immediately following the designation indicates the year of
original adoption or, in the case of revision, the year of last revision. A number in parentheses indicates the year of last reapproval. A
superscript epsilon (´) indicates an editorial change since the last revision or reapproval.
INTRODUCTION
This document provides guidance on the implementation of risk assessment and risk control for
Process Analytical Technology (PAT) processes within the pharmaceutical industry. Wherever
possible, other appropriate standards on risk assessment/management have been referenced and
acknowledged. Where practical, further details of methods and additional references have been
provided for information within the appendixes.
The application of risk assessment and risk control is pivotal to the creation of PAT systems, which
are described as “science-based” and “risk-based.” Such application starts at an early stage in the
development of the process and continues throughout development and production. In the production
phase, it is a crucial component of applying continuous improvement to the process.
RELATIONSHIP TO ICH Q9
The ICH Q9 Guideline for Quality Risk Management is intended for general application within the
pharmaceutical industry. ICH Q9 describes the requirements for pharmaceutical quality risk
management and considers the risk as “risk to the patient.”
This document provides specific guidance on the risk assessment and risk control phases identified
in ICH Q9 in a limited set of conditions. It is applicable where the manufacturing method is compliant
with Process Analytical Technology (PAT) principles, and where the primary considerations are
productqualityandreductionofprocessandproductvariability.Theonlycomponentofrisktopatient
considered here is risk to product quality. Other components fall outside the scope of the document.
In addition, other areas identified in ICH Q9, such as general risk management and risk
communication, are not considered here.
This document provides guidance which applies to the design, development, and operation of PAT
systems. It should be considered as a specific extension, supporting the ICH Q9 guidance for these
processes.
1. Scope the pharmaceutical industry. It addresses those risks to product
quality arising from, associated with, identified by, or modified
1.1 This document provides guidance on the assessment of
by the implementation of PAT in pharmaceutical development
risks to product quality within and related to PAT processes in
and manufacturing for primary, secondary, and biotech sectors
1 of the industry. It does not replace those assessments of risk
This guide is under the jurisdiction of ASTM Committee E55 on Manufacture
ofPharmaceuticalandBiopharmaceuticalProductsandisthedirectresponsibilityof currently undertaken by pharmaceutical companies, but is,
Subcommittee E55.01 on Process Understanding and PAT System Management,
rather, an additional component focused specifically upon the
Implementation and Practice.
evaluation and design of PAT processes. See Practice E2474,
Current edition approved May 15, 2009. Published July 2009. DOI: 10.1520/
E2476-09. Guide E2500, and ICH Q8.
Copyright © ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959. United States
E2476 − 09
1.2 This standard does not purport to address all of the process understanding within the development and manufac-
safety concerns, if any, associated with its use. It is the turing teams, and to the regulators where that is appropriate.
responsibility of the user of this standard to establish appro-
4.2 This guidance only covers those aspects of risk assess-
priate safety and health practices and determine the applica-
mentrelatedto“risktoproductquality.”Otheraspects(suchas
bility of regulatory limitations prior to use. Note that safety in
“risk to patient”) should be covered in the conventional
this context refers to operational and operator safety, not to
manner.
patient safety.
5. Principles of Risk Assessment and Risk Control
2. Referenced Documents
5.1 Background—Risk management has been widely used
2.1 ASTM Standards:
in manufacturing and service industries for many years. In
E2474 Practice for Pharmaceutical Process Design Utilizing
some industries, risk management has become formalized into
Process Analytical Technology
a highly structured approach which has become the subject of
E2500 Guide for Specification, Design, and Verification of
standardization. This standardization has a number of benefits
Pharmaceutical and Biopharmaceutical Manufacturing
including:
Systems and Equipment
5.1.1 Widespread acceptance based on consensus among all
E2363 Terminology Relating to ProcessAnalytical Technol-
interested parties, which makes regulatory approval easier,
ogy in the Pharmaceutical Industry
5.1.2 Easy comparison of equivalent processes between
2.2 Other Standards:
sites, companies, and continents,
FDA Guidance for Industry PAT—A Framework for Inno-
5.1.3 Ready transferability of skilled labor, and
vative Pharmaceutical Development, Manufacturing, and
5.1.4 Standardized training.
Quality Assurance
5.2 High-Level Characteristics of Risk Assessment—A risk
ICH Q8 Pharmaceutical Development
assessment for a PAT process has, in addition to the principles
ICH Q9 Quality Risk Management
outlined in ICH Q9, a number of key characteristics:
IEC 60812 Analysis Techniques for System Reliability—
5.2.1 It is systematic and structured.
Procedure for Failure Mode and Effects Analysis
5.2.2 It is primarily evidence-based. Evidence may include
(FMEA)
direct experience, historical knowledge, professional
IEC 61025 Fault Tree Analysis (FTA)
judgment, etc.
IEC 61882 Hazard and Operability Studies (HAZOP
5.2.3 It specifically focuses upon uncertainty and/or vari-
Studies)—Application Guide
ability in product quality and the causes of such uncertainty/
ISO 22000 Food Safety Management Systems—
variability.
Requirements for any Organization in the Food Chain
5.2.4 It is an integral component of the decision-making
WHO Technical Report 908 WHO Expert Committee on
process.
Specifications for Pharmaceutical Preparations
5.2.5 It guides risk control and mitigation; that is, it recog-
3. Terminology
nizes that the primary consideration is product quality and
identifiesthoseareaswhererisksmustbereducedandprovides
3.1 The terminology specific to this guide will be incorpo-
a mechanism for assessing when the risk has been sufficiently
rated into Terminology E2363.
reduced.
4. Significance and Use 5.2.6 It is multi-layered. It can be applied at many levels,
that is, lower-level, more detailed assessments feeding into
4.1 Thisguideisintendedtoprovideguidanceregardingthe
higher-level, broader scope assessments. (For example, a
use of risk analysis in the development, day-to-day running,
higher-level risk assessment for the finished product will have
and continuous improvement of pharmaceutical processes
lower-level risk assessments for each of the process stages
incorporating ProcessAnalyticalTechnology (PAT). Since PAT
which feed into it.) Breaking risk assessment into layers makes
is defined as being “risk-based” (see FDA Guidance for
complexevaluationssimplertoperform,simplertounderstand,
Industry), it is important that a consistent approach to the use
and simplifies the generation of a detailed response. It also
of risk methodologies is adopted, to ensure rapid transfer of
assistsintheprocessofidentifyingspecifictargetsforreducing
the risk.
For referenced ASTM standards, visit the ASTM website, www.astm.org, or
5.2.6.1 In general, an initial high-level risk assessment will
contact ASTM Customer Service at service@astm.org. For Annual Book of ASTM
identify most of the high-risk areas. Subsequent lower-level
Standards volume information, refer to the standard’s Document Summary page on
risk assessments, and resulting mitigation actions, will focus
the ASTM website.
Available from Food and Drug Administration (FDA), 5600 Fishers Ln.,
initially upon these identified areas of high risk, moving to
Rockville, MD 20857, http://www.fda.gov.
those areas of intermediate and lower risk at a later stage in the
Available from International Conference on Harmonisation of Technical
process. This later amelioration of the risk may be part of a
Requirements for Registration of Pharmaceuticals for Human Use (ICH), ICH
continuous improvement process.
Secretariat, c/o IFPMA, 15 ch. Louis-Dunant, P.O. Box 195, 1211 Geneva 20,
Switzerland, http://www.ich.org.
5.2.7 Itisdynamicanditerative.Itwillremainactiveforthe
Available from International Electrotechnical Commission (IEC), 3 rue de
lifecycle of a product, responding to changing commercial,
Varembé, Case postale 131, CH-1211, Geneva 20, Switzerland, http://www.iec.ch.
manufacturing, and scientific conditions and the availability of
Available fromAmerican National Standards Institute (ANSI), 25 W. 43rd St.,
4th Floor, New York, NY 10036, http://www.ansi.org. additional information and/or process understanding.
E2476 − 09
5.3 High-Level Characteristics of Risk Control: (4) Changing a process to reduce one risk may introduce
another risk. This risk, in turn, must be assessed and priori-
5.3.1 Onceriskshavebeenclearlyidentifiedandprioritized,
tized.
and the need for risk mitigation agreed, the process of risk
control takes effect. Risk control has a number of key charac-
6. Preparation for Risk Assessment and Risk Control
teristics:
5.3.1.1 Riskswhichareidentifiedduringtheanalysisshould
6.1 Adequatepreparationisakeycomponentofaneffective
receive a proportionate response. The response should be risk assessment and risk control strategy.
related to the probability of the event occurring, the severity of
6.2 Objectives of the Risk Assessment—To achieve timely,
the results, and the detectability of the event.
effective results from a risk assessment and risk control
5.3.1.2 Risk control actions for a new process occur in a
process, the scope and objectives of the work shall be clearly
specific order:
defined at the earliest possible stage.
(1) Perform design changes to reduce the risk. (That is,
6.3 Selection of the Risk Assessment/Control Group:
enacting modifications to the basic process that deliver higher
6.3.1 The group assessing these risks shall include experi-
quality or more consistent product. This is a key reason for
encedpractitionerswithalloftherelevantkeyskillstoidentify
adopting PAT.)
andevaluatethekeyfactorsintheprocessunderconsideration.
(2) Addcontrolfeaturestoreducetheprocessrisk.(Thatis,
The group should therefore include, or have direct access to,
putting extra features on the process the primary function of
subjectmatterexpertswithexpertiseorextensiveexperiencein
which is to reduce some facet of the risk, which is a key
appropriate areas such as:
component of PAT.)
6.3.1.1 Drug(s), intermediates and excipients in the form
(3) Apply methods improving detectability (such as, stan-
appropriate to the industry sector,
dard operating procedures, guidelines, company practices, staff
6.3.1.2 Design and function of the drug product,
training and/or selection, etc.) to reduce risk.
6.3.1.3 Scientific and/or technical issues of process design,
5.3.1.3 For an existing process, the sequence may be differ-
6.3.1.4 Design and function of the process equipment,
ent.
6.3.1.5 Measurement systems,
5.3.1.4 These actions should ideally be applied in the order
6.3.1.6 Development of process and control models,
listed. When a risk is identified, the design team should first
6.3.1.7 Design and function of process controls,
seek to remove the risk by changing the fundamental process
6.3.1.8 Existing production,
design. If this is not possible, they should then seek to modify
6.3.1.9 Current operating practices (including agreed work
equipment design or process conditions to reduce the risk.
rules and practices),
Only if neither of these are practical should they use the third
6.3.1.10 Known problems with the product, either in manu-
approach of imposing specific working practices. Some modi-
facturing or subsequent use,
fication in this order may be necessary when an existing
6.3.1.11 Company quality records and procedures,
process is being considered and the costs associated with
6.3.1.12 Company laboratory capabilities and practices,
fundamental design change are prohibitive.
6.3.1.13 Recruitment and training policies in so far as they
5.3.1.5 Once this process is complete, the remaining risks
impact the process,
are known as residual risks. Residual risks are:
6.3.1.14 Company maintenance records and procedures,
(1) Risks which remain higher than the acceptable risk
and
level, but which cannot practicably be further reduced by
6.3.1.15 Company validation practices and procedures or
redesign, risk control, or standard procedures/training/etc.
continuous quality verification.
When such risks occur, it will then be necessary to implement
6.3.2 Individuals may fulfill one or more of these roles. It is
apost-processriskmitigationmeasuressuchasoff-linetesting.
not necessary for everyone to be present throughout the
5.3.1.6 Residual risks must be fully documented and should
assessment,butacoregroupthatisinvolvedthroughoutshould
be subject to a formal acceptance procedure at least once
be clearly identified.
before final process approval.
6.3.3 At least one member of the group should be fully
5.3.1.7 It is recognized that, in the application of risk
trained to perform risk assessments.
control:
6.4 Collection and Preparation of Information—As far as is
(1) Changes must be viable in technical, regulatory, and
possible, all relevant information necessary for the risk assess-
commercial contexts. Where changes do not meet these
ment should be collected or prepared before the start of the
criteria, it must be explicitly so stated in the risk report.
process. This helps to ensure that the assessment process does
(2) Reducing the risk on a process may still mean that the
not become fragmented.
process carries high risk after a particular stage. Subsequent
risk mitigation will be necessary. 6.5 Consistency of Approach:
(3) Changing a process to reduce one risk may aggravate 6.5.1 The estimation of risk will usually be quasi-
quantitative, and, therefore, on an arbitrary scale. However it is
another risk.The objective is to minimize the overall risk.This
may result in a high risk remaining unaddressed at a particular important that measures are put in place to ensure that:
...
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