1、Designation: E2476 16Standard Guide forRisk Assessment and Risk Control as it Impacts the Design,Development, and Operation of PAT Processes forPharmaceutical Manufacture1This standard is issued under the fixed designation E2476; the number immediately following the designation indicates the year of
2、original adoption or, in the case of revision, the year of last revision. A number in parentheses indicates the year of last reapproval. Asuperscript epsilon () indicates an editorial change since the last revision or reapproval.INTRODUCTIONThis document provides guidance on the implementation of ri
3、sk assessment and risk control forProcess Analytical Technology (PAT) processes within the pharmaceutical industry. Whereverpossible, other appropriate standards on risk assessment/management have been referenced andacknowledged. Where practical, further details of methods and additional references
4、have beenprovided for information within the appendixes.The application of risk assessment and risk control is pivotal to the creation of PAT systems, whichare described as “science-based” and “risk-based.” Such application starts at an early stage in thedevelopment of the process and continues thro
5、ughout development and production. In the productionphase, it is a crucial component of applying continuous improvement to the process.RELATIONSHIP TO ICH Q9The ICH Q9 Guideline for Quality Risk Management is intended for general application within thepharmaceutical industry. ICH Q9 describes the re
6、quirements for pharmaceutical quality riskmanagement and considers the risk as “risk to the patient.”This document provides specific guidance on the risk assessment and risk control phases identifiedin ICH Q9 in a limited set of conditions. It is applicable where the manufacturing method is complian
7、twith Process Analytical Technology (PAT) principles, and where the primary considerations areproduct quality and reduction of process and product variability. The only component of risk to patientconsidered here is risk to product quality. Other components fall outside the scope of the document.In
8、addition, other areas identified in ICH Q9, such as general risk management and riskcommunication, are not considered here.This document provides guidance which applies to the design, development, and operation of PATsystems. It should be considered as a specific extension, supporting the ICH Q9 gui
9、dance for theseprocesses.1. Scope1.1 This document provides guidance on the assessment ofrisks to product quality within and related to PAT processes inthe pharmaceutical industry. It addresses those risks to productquality arising from, associated with, identified by, or modifiedby the implementati
10、on of PAT in pharmaceutical developmentand manufacturing for primary, secondary, and biotech sectorsof the industry. It does not replace those assessments of riskcurrently undertaken by pharmaceutical companies, but is,rather, an additional component focused specifically upon theevaluation and desig
11、n of PAT processes. See Practice E2474,Guide E2500, and ICH Q8.1This guide is under the jurisdiction of ASTM Committee E55 on Manufactureof Pharmaceutical and Biopharmaceutical Products and is the direct responsibility ofSubcommittee E55.01 on Process Understanding and PAT System Management,Implemen
12、tation and Practice.Current edition approved Nov. 1, 2016. Published November 2016. Originallyapproved in 2009. Last previous edition approved in 2009 as E2476 09. DOI:10.1520/E2476-16.Copyright ASTM International, 100 Barr Harbor Drive, PO Box C700, West Conshohocken, PA 19428-2959. United States11
13、.2 This standard does not purport to address all of thesafety concerns, if any, associated with its use. It is theresponsibility of the user of this standard to establish appro-priate safety and health practices and determine the applica-bility of regulatory limitations prior to use. Note that safet
14、y inthis context refers to operational and operator safety, not topatient safety.2. Referenced Documents2.1 ASTM Standards:2E2474 Practice for Pharmaceutical Process Design UtilizingProcess Analytical TechnologyE2500 Guide for Specification, Design, and Verification ofPharmaceutical and Biopharmaceu
15、tical ManufacturingSystems and EquipmentE2363 Terminology Relating to Process Analytical Technol-ogy in the Pharmaceutical Industry2.2 Other Standards:FDA Guidance for Industry PATA Framework for Inno-vative Pharmaceutical Development, Manufacturing, andQuality Assurance3ICH Q8 (R2) Pharmaceutical D
16、evelopment4ICH Q9 Quality Risk Management4ICH Q10 Pharmaceutical Quality System4IEC 60812 Analysis Techniques for System ReliabilityProcedure for Failure Mode and Effects Analysis(FMEA)5IEC 61025 Fault Tree Analysis (FTA)5IEC 61882 Hazard and Operability Studies (HAZOPStudies)Application Guide5ISO 2
17、2000 Food Safety Management SystemsRequirements for any Organization in the Food Chain6WHO Technical Report 908 WHO Expert Committee onSpecifications for Pharmaceutical Preparations3. Terminology3.1 The terminology specific to this guide will be incorpo-rated into Terminology E2363.4. Significance a
18、nd Use4.1 This guide is intended to provide guidance regarding theuse of risk management in the development, day-to-dayrunning, and continuous improvement of pharmaceutical pro-cesses incorporating Process Analytical Technology (PAT).Since PAT is defined as being “risk-based” (see FDA Guidancefor In
19、dustry), it is important that a consistent approach to theuse of risk methodologies is adopted, to ensure rapid transfer ofprocess understanding within the development and manufac-turing teams, and to the regulators where that is appropriate.4.2 This guidance only covers those aspects of risk assess
20、-ment related to “risk to product quality.” Other aspects (such as“risk to patient”) should be covered in the conventionalmanner.5. Principles of Risk Assessment and Risk Control5.1 BackgroundRisk management has been widely usedin manufacturing and service industries for many years. Insome industrie
21、s, risk management has become formalized intoa highly structured approach which has become the subject ofstandardization. This standardization has a number of benefitsincluding:5.1.1 Widespread acceptance based on consensus among allinterested parties, which makes regulatory approval easier,5.1.2 Ea
22、sy comparison of equivalent processes betweensites, companies, and continents,5.1.3 Ready transferability of skilled labor, and5.1.4 Standardized training.5.2 High-Level Characteristics of Risk AssessmentA riskassessment for a PAT process has, in addition to the principlesoutlined in ICH Q9, a numbe
23、r of key characteristics:5.2.1 It is systematic and structured.5.2.2 It is primarily evidence-based. Evidence may includedirect experience, historical knowledge, professionaljudgment, etc.5.2.3 It specifically focuses upon uncertainty or variability,or both, in product quality and the causes of such
24、 uncertainty/variability.5.2.4 It is an integral component of the decision-makingprocess.5.2.5 It guides risk control and mitigation; that is, it recog-nizes that the primary consideration is product quality andidentifies those areas where risks must be reduced and providesa mechanism for assessing
25、when the risk has been sufficientlyreduced.5.2.6 It is multi-layered. It can be applied at many levels,that is, lower-level, more detailed assessments feeding intohigher-level, broader scope assessments. (For example, ahigher-level risk assessment for the finished product will havelower-level risk a
26、ssessments for each of the process stageswhich feed into it.) Breaking risk assessment into layers makescomplex evaluations simpler to perform, simpler to understand,and simplifies the generation of a detailed response. It alsoassists in the process of identifying specific targets for reducingthe ri
27、sk.5.2.6.1 In general, an initial high-level risk assessment willidentify most of the high-risk areas. Subsequent lower-levelrisk assessments, and resulting mitigation actions, will focusinitially upon these identified areas of high risk, moving tothose areas of intermediate and lower risk at a late
28、r stage in theprocess. This later amelioration of the risk may be part of acontinuous improvement process.5.2.7 It is dynamic and iterative. It will remain active for thelifecycle of a product, responding to changing commercial,2For referenced ASTM standards, visit the ASTM website, www.astm.org, or
29、contact ASTM Customer Service at serviceastm.org. For Annual Book of ASTMStandards volume information, refer to the standards Document Summary page onthe ASTM website.3Available from Food and Drug Administration (FDA), 5600 Fishers Ln.,Rockville, MD 20857, http:/www.fda.gov.4Available from Internati
30、onal Council for Harmonisation of Technical Require-ments for Pharmaceuticals for Human Use (ICH), ICH Secretariat, P.O. Box 195,1211 Geneva 20, Switzerland, http:/www.ich.org.5Available from International Electrotechnical Commission (IEC), 3 rue deVaremb, Case postale 131, CH-1211, Geneva 20, Switz
31、erland, http:/www.iec.ch.6Available from American National Standards Institute (ANSI), 25 W. 43rd St.,4th Floor, New York, NY 10036, http:/www.ansi.org.E2476 162manufacturing, and scientific conditions and the availability ofadditional information or process understanding, or both.5.3 High-Level Cha
32、racteristics of Risk Control:5.3.1 Once risks have been clearly identified and prioritized,and the need for risk mitigation agreed, the process of riskcontrol takes effect. Risk control has a number of key charac-teristics:5.3.1.1 Risks which are identified during the assessmentshould receive a prop
33、ortionate response. The response shouldbe related to the probability of the event occurring, the severityof the results, and the detectability of the event.5.3.1.2 Risk control actions for a new process occur in aspecific order:(1) Perform design changes to reduce the risk. (That is,enacting modific
34、ations to the basic process that deliver higherquality or more consistent product. This is a key reason foradopting PAT.)(2) Add control features to reduce the process risk. (That is,putting extra features on the process the primary function ofwhich is to reduce some facet of the risk, which is a ke
35、ycomponent of PAT.)(3) Apply methods improving detectability (such as, stan-dard operating procedures, guidelines, company practices, stafftraining, staff selection, etc.) to reduce risk.5.3.1.3 For an existing process, the sequence may be differ-ent.5.3.1.4 These actions should ideally be applied i
36、n the orderlisted. When a risk is identified, the design team should firstseek to remove the risk by changing the fundamental processdesign. If this is not possible, they should then seek to modifyequipment design or process conditions to reduce the risk.Only if neither of these are practical should
37、 they use the thirdapproach of imposing specific working practices. Some modi-fication in this order may be necessary when an existingprocess is being considered and the costs associated withfundamental design change are prohibitive.5.3.1.5 Once this process is complete, the remaining risksare known
38、 as residual risks. Residual risks are:(1) Risks which remain higher than the acceptable risklevel, but which cannot practicably be further reduced byredesign, risk control, or standard procedures/training/etc.When such risks occur, it will then be necessary to implementa post-process risk mitigatio
39、n measures such as off-line testing.5.3.1.6 Residual risks must be fully documented and shouldbe subject to a formal acceptance procedure at least oncebefore final process approval.5.3.1.7 It is recognized that, in the application of riskcontrol:(1) Changes must be viable in technical, regulatory, a
40、ndcommercial contexts. Where changes do not meet thesecriteria, it must be explicitly so stated in the risk report.(2) Reducing the risk on a process may still mean that theprocess carries high risk after a particular stage. Subsequentrisk mitigation will be necessary.(3) Changing a process to reduc
41、e one risk may aggravateanother risk. The objective is to minimize the overall risk. Thismay result in a high risk remaining unaddressed at a particularstage, which then needs to be addressed by subsequent riskcontrol actions.(4) Changing a process to reduce one risk may introduceanother risk. This
42、risk, in turn, must be assessed and priori-tized.6. Preparation for Risk Assessment and Risk Control6.1 Adequate preparation is a key component of an effectiverisk assessment and risk control strategy.6.2 Objectives of the Risk AssessmentTo achieve timely,effective results from a risk assessment and
43、 risk controlprocess, the scope and objectives of the work shall be clearlydefined at the earliest possible stage.6.3 Selection of the Risk Assessment/Control Group:6.3.1 The group assessing these risks shall include experi-enced practitioners with all of the relevant key skills to identifyand evalu
44、ate the key factors in the process under consideration.The group should therefore include, or have direct access to,subject matter experts with expertise or extensive experience inappropriate areas such as:6.3.1.1 Drug(s), intermediates, and excipients in the formappropriate to the industry sector,6
45、.3.1.2 Design and function of the drug product,6.3.1.3 Scientific or technical issues, or both, of processdesign,6.3.1.4 Design and function of the process equipment,6.3.1.5 Measurement systems,6.3.1.6 Development of process and control models,6.3.1.7 Design and function of process controls,6.3.1.8
46、Existing production,6.3.1.9 Current operating practices (including agreed workrules and practices),6.3.1.10 Known problems with the product, either in manu-facturing or subsequent use,6.3.1.11 Company quality records and procedures,6.3.1.12 Company laboratory capabilities and practices,6.3.1.13 Recr
47、uitment and training policies in so far as theyimpact the process,6.3.1.14 Company maintenance records and procedures,and6.3.1.15 Company validation practices and procedures orcontinuous quality verification.6.3.2 Individuals may fulfill one or more of these roles. It isnot necessary for everyone to
48、 be present throughout theassessment, but a core group that is involved throughout shouldbe clearly identified.6.3.3 At least one member of the group should be fullytrained to perform risk assessments.6.4 Collection and Preparation of InformationAs far as ispossible, all relevant information necessa
49、ry for the risk assess-ment should be collected or prepared before the start of theprocess. This helps to ensure that the assessment process doesnot become fragmented.E2476 1636.5 Consistency of Approach:6.5.1 The estimation of risk will usually be quasi-quantitative, and, therefore, on an arbitrary scale. However it isimportant that measures are put in place to ensure that:6.5.1.1 The estimation of risk is consistent from one projectto another,6.5.1.2 The estimation of risk is consistent from one assess-ment team to another, and6.5.1.3 The estimation of risk is suffi
