Ispe Vol7 Risk Mapp 2010

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Disclaimer: This Guide is meant to assist pharmaceutical manufacturers in the design and construction of new and renovated

facilities that are required to comply with the requirements of the US Food and Drug Administration (FDA). The International Society for Pharmaceutical Engineering (ISPE) cannot ensure, and does not warrant, that a facility built in accordance with this Guide will be acceptable to the FDA.

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All trademarks used are acknowledged.

ISBN 1-931879-97-4

Volume 7

Risk-BasedManufacture of

Pharmaceutical ProductsFirst Edition / September 2010

A Guide to Managing Risks Associated with Cross-Contamination

For individual use only. Copyright ISPE 2010. All rights reserved.




Page 2 ISPE Baseline Guide: Risk-Based Manufacture of Pharmaceutical Products

Foreword Theglobalpharmaceuticalindustryandregulatorsarerespondingtothechallengeofsignificantlyimprovingtheway

drug development and manufacturing is managed. New concepts are being developed and applied including science based risk management approaches, a focus on product and process understanding, and modern Quality Systems.

Uncertainty about the requirements for regulatory compliance may discourage innovation and technological advancement, and can drive up costs. ISPE Guidance Documents aim to describe current good practices that can helpacompanytodevelopanapproachthatiseffective,cost-efficient,andincompliancewithexistingregulationsand related guidance.

ISPE seeks close involvement of international regulators, including the US FDA, in the development of these ISPE Guidance Documents, which cover many important aspects of pharmaceutical development and manufacturing. TheseGuidanceDocumentsareexcellentexamplesofhowISPE,regulators,andindustrycanworkco-operativelyforpublicbenefit.WethanktheFDAfortheirreviewandcommentstothisGuide.

These Guidance Documents are solely created and owned by ISPE. They are not regulations, standards, or regulatory guideline documents, and facilities built in conformance with the Guidance Documents may or may not meet FDA or other regulatory requirements.

A continued working relationship between ISPE and international regulators will be fruitful for regulators, industry, and most importantly for public health.





ISPE Baseline Guide: Page 3Risk-Based Manufacture of Pharmaceutical Products

Acknowledgments This Guide advocates a holistic approach to maintaining the risk of cross contamination below acceptable limits.

Soitisonlyfittingthatitwasdevelopedinthisspiritbyamulti-disciplinary,multi-culturalteamofindustryexperts,whichincludedprofessionalswithexpertiseinqualitysystems,toxicology,manufacturing,processandcontainmentengineering, industrial hygiene, and compliance. This Guide was a true team effort, each of the team members provided a special talent or aspect to make this project a success and they are acknowledged.

Authors

MarcW.Abromovitz,CIH,Director,IndustrialHygiene,JohnsonandJohnson/GPSG,USA Tom Brennan, Co-Founder and Technical Director, EirGen Pharma Ltd., Ireland LesleyA.Burgess,DirectorofGlobalIndustrialHygiene,AstraZeneca,USA JeffCampie,formerlySeniorDirector/GlobalQualityAssurance,GileadSciencesInc.,USA LisaA.Cardo,CIH,Manager,OperationalSustainabilityManager,GlaxoSmithKline,Italy NigelHamilton,QualityDirector,Sanofi-Aventis,UnitedKingdom MalcolmHolmes,formerlyDirector,QualityAssurance,GlaxoSmithKline,UnitedKingdom PeterJ.Marshall,SeniorPharmaceuticalEngineer,AstraZenecaPharmaceuticals,UnitedKingdom *BruceD.Naumann,PhD,DABT,Director,OccupationalandEnvironmentalToxicology,Merck,USA MorihikoTakeda,President,PharmaSolutionsCo.,Ltd.,Japan AndrewWalsh,MS,IndustryProfessor,StevensInstituteofTechnology/President,Clean6Sigma,LLC,USA JulianWilkins,VicePresident,PharmaConsultUS,USA *StephanieWilkins,PE,President,PharmaConsultUS,USA PaulWreglesworth,formerlyAstraZeneca,UnitedKingdom

*Indicates Co-Chairs of the Document Development Task Team.

Other Contributors

PamDavison,formerlyTechnicalDirectorBlendingandPowderHandling,GlaxoSmithKline,UnitedKingdom GoIritani,SeniorMechanicalEngineer,JGCCorporation,Japan DeniseProulx,SeniorDirector,HSEUSR&DSites,Sanofi-Aventis,USA EdwardV.SargentMPH,PhD,DABT,ManagingDirector,EVSargentLLC,USA PatriciaA.Weideman,PhD,Director,GlobalOccupationalandEnvironmentalToxicology,Merck,USA LawrenceG.Wylie,PhD,CIH,CSPDirectorEnvironmentalHealthandSafety,TheScrippsResearchInstitute,USA

Regulators

EdwinMelendez,ConsumerSafetyOfficer,CDER/OC/DMPQ/FDA,USA DianeRaccasi,Microbiologist,CDER/OC/DMPQ/FDA,USA CatherineLefebvre,Regulator,Afssaps/EMADedicatedFacilitiesWorkingGroup,France VincentGazin,ChefdUnitToxicologieClinique,Afssaps,France Dr.UrsKopp,SwissMedic,Switzerland






Special Thanks to:

JessicaHunt,Manager,ClinicalManufacturing,Merck,USA MarcosPereira,QualityandComplianceDirector,JanssenCilagFarmaceuticaLtda,Brazil AstraZenecafortheoriginalLogicDiagramconcept

The Risk-MaPP Task Team would like to thank ISPE for technical writing and editing support by Gail Evans (ISPE TechnicalDocumentsWriter/Editor)andSionWyn(ISPETechnicalConsultant).

Coverphotos:TopandmiddlephotoscourtesyofSKAN,www.skan.ch.BottomphotocourtesyofSartorius,www.sartorius.com.

ISPE Headquarters3109W.Dr.MartinLutherKingJr.Blvd.,Suite250,Tampa,Florida33607USA

Tel:+1-813-960-2105,Fax:+1-813-264-2816

ISPE Asia Pacific Office73BukitTimahRoad,#04-01RexHouse,Singapore229832

Tel:+65-6496-5502,Fax:+65-6336-6449

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ISPE European OfficeAvenuedeTervueren,300,B-1150Brussels,Belgium

Tel:+32-2-743-4422,Fax:+32-2-743-1550

www.ISPE.org





ISPE Baseline Guide: Page 5Risk-Based Manufacture of Pharmaceutical Products

Table of Contents 1 Introduction ......................................................................................................................... 7 1.1 ApproachtoIdentifyHighlyHazardousDrugs ............................................................................................. 8

1.2 RiskManagement/AssessmentModeltoAddresstheControlstoComplywith21CFR211.42(c) ............ 8 1.3 HowtheApproachFitsIntoCleaningValidation .......................................................................................... 9 1.4 Background .................................................................................................................................................. 9 1.5 ScopeofthisGuide.................................................................................................................................... 10 1.6 CurrentSituation ........................................................................................................................................ 10 1.7 HowtoUsethisGuide ............................................................................................................................... 11

2 Concepts and Regulatory Philosophy ............................................................................ 13 2.1 OverviewoftheRiskManagementApproach ............................................................................................ 14 2.2 Acceptable Risk .........................................................................................................................................15 2.3 TheGMPandIndustrialHygieneBalance .................................................................................................16

3 Quality System Requirements ......................................................................................... 19 3.1 GxPQualityPolicies .................................................................................................................................. 19 3.2 GxPQualityStandards .............................................................................................................................. 20 3.3 Gap Analysis .............................................................................................................................................. 20 3.4 Auditing of Quality Systems ....................................................................................................................... 20 3.5 ApplicationtoCross-Contamination........................................................................................................... 20 3.6 TheLogicDiagram..................................................................................................................................... 21

4 Risk Assessment .............................................................................................................. 31

5 Risk Identification ............................................................................................................. 33 5.1 DefinitionofHazard ................................................................................................................................... 33 5.2 HazardContinuumandPrioritizationforRiskAssessment........................................................................ 34 5.3 EstablishingHealth-BasedExposureLimits ..............................................................................................35

5.4 SettingHealth-BasedSafetyThresholds/AcceptanceLimits ..................................................................... 42 5.5 SettingOccupationalExposureLimits(OELs) ...........................................................................................46

6 Risk Analysis ..................................................................................................................... 47 6.1 HolisticApproachtoRiskAnalysis ............................................................................................................. 48 6.2 Tools ........................................................................................................................................................... 48 6.3 RoutesforCross-Contamination................................................................................................................50 6.4 ProbabilityofOccurrence...........................................................................................................................55 6.5 ProductExposureRiskinNon-ProductContactAreas ..............................................................................60 6.6 Detection ....................................................................................................................................................61

7 Risk Evaluation ................................................................................................................. 63 7.1 Cleaning Process Performance Capability ................................................................................................64 7.2 Cleaning Evaluation for New Products ......................................................................................................64 7.3 Residue on Non-Product Contact Surfaces ...............................................................................................64

8 Risk Control....................................................................................................................... 67 8.1 HolisticallyBalancedApproach ..................................................................................................................68






9 Risk Reduction .................................................................................................................. 71 9.1 HierarchyofRiskReduction ...................................................................................................................... 72 9.2 RiskReduction:RoutesofExposure ......................................................................................................... 73 9.3 The Role of Pharmaceutical Research and Development in Risk Reduction ............................................76 9.4 Process and Related Technologies ............................................................................................................ 77 9.5 TheRoleofFacilityEngineeringinRiskReduction ................................................................................... 79 9.6 HVAC ......................................................................................................................................................... 84 9.7 Containment Related Technologies ...........................................................................................................85 9.8 Personal Protective Equipment (PPE) and Gowning .................................................................................86

10 Risk Acceptance ............................................................................................................... 87

11 Risk Management Tools ................................................................................................... 89 11.1 RiskRankingorRiskMatrix ....................................................................................................................... 90 11.2 Failure Mode and Effects Analysis (FMEA) ............................................................................................... 91

12 Risk Review ....................................................................................................................... 95

13 Risk Communication ........................................................................................................ 97 13.1 Summary Document Template ................................................................................................................... 98

14 Appendix 1 Risk-MaPP Application Examples .......................................................... 101 14.1 Introduction .............................................................................................................................................. 101 14.2 Scenario1(ObviouslyAcceptable) .......................................................................................................... 102 14.3 Scenario2(ObviouslyUnacceptable)......................................................................................................105 14.4 Scenario 3 (Apparently Acceptable (but was not)) ................................................................................... 107 14.5 Scenario4(ApparentlyUnacceptable(butwas)) .................................................................................... 117 14.6 LogicDiagram .......................................................................................................................................... 128

15 Appendix 2 Bibliography............................................................................................. 129 15.1 References ............................................................................................................................................... 129 15.2 ReadingList ............................................................................................................................................. 133

16 Appendix 3 Glossary ................................................................................................... 137 16.1 AbbreviationsandAcronyms ................................................................................................................... 137 16.2 Definitions ................................................................................................................................................ 141





1 Introduction





ISPE Baseline Guide: Page 7Risk-Based Manufacture of Pharmaceutical Products Introduction

1 Introduction The ISPE Baseline Guide: Risk-Based Manufacture of Pharmaceutical Products (Risk-MaPP) provides a scientific

risk-based approach based on ICH Q9 (Reference 28, Section 15.1) to manage the risk of cross-contamination to maintain an appropriate balance between product quality and operator safety. This allows the selection of the appropriate risk control strategies to be implemented on a case-by-case basis to maintain patient safety and assure product quality.

The science of toxicology recognizes the principle of a continuum of hazard associated with all compounds, even within individual classes of compounds. Zero risk is considered scientifically unachievable and not necessary. These compounds, or classes of compounds, have historically included hormones, cytotoxic compounds, genotoxic compounds, live vaccines, and veterinary products. Sensitizers such as Beta-Lactam antibiotics have received particular scrutiny due to severity of risk.

The International Conference on Harmonisation (ICH) in their Q9 Quality Risk Management document (Reference 28, Section 15.1) state The manufacturing and use of a drug product, including its components, necessarily entail some degree of risk.

The FDA also has acknowledged this fact in the Report to the FDA Commissioner from the Task Force on Risk Management, May 1999, Although medicinal products are required to be safe, safety does not mean zero risk. A safe product is one that has reasonable risks, given the magnitude of the benefits expected and the alternative available.

In addition, the EMEA acknowledged this fact in their Action Plan to Further Progress the European Risk Management Strategy, 4 May 2005 (Reference 10, Section 15.1), However, in view of the increasing and justified demands from patients and the general public for an adequate protection of public health, resulting in the availability of safe and effective medicines, it is important to re-emphasise that the concept of zero risk does not apply to medicinal products. The licensing of medicinal products needs to be assessed in the context of the benefit/risk balance concept, whereby demonstrated benefits must outweigh known risks, leading to a favourable benefit/risk ratio and the resulting marketing authorisation.

When considering multi-product facilities, to satisfy regulatory requirements risk management processes are necessary to determine and document reasonable and acceptable risk. This Guide provides a process that allows manufacturers to assess risk and determine where control strategies are necessary to meet acceptable limits for cross-contamination. The control strategies to manage risk can vary from administrative to full dedication or segregation. Typically, some combination of control strategies may be necessary.

During the planning meetings for this Baseline Guide, the FDA specifically requested that this Guide:

provide an approach to identify highly hazardous drugs

provide a risk management/assessment model that gives a clear view on how to address the controls to comply with 21 CFR 211.42(c) (Reference 15, Section 15.1)

discuss how the approach fits into cleaning validation

Other regulatory bodies such as the EMA, MHLW, JPMDA, WHO, Health Canada, Swissmedic, ANVISA, and PIC/S were provided the opportunity to review and comment during the development of this Guide. Comments received were addressed.





Page 8 ISPE Baseline Guide:Introduction Risk-Based Manufacture of Pharmaceutical Products

1.1 Approach to Identify Highly Hazardous Drugs

The original intention of this Guide was to provide a method to identify highly hazardous compounds. However, during development, it became apparent that an approach to identify acceptable risk in the manufacture of pharmaceutical products was more appropriate.

In order to identify acceptable risk, it is necessary to first assess and categorize a compound. Using information such as toxicological data, about a hazard or specific population risks, will help mitigate emotive, hazard-based decision making. Terms such as potent, cytotoxic, cytostatic, and steroid are not precise when categorizing specific API hazard potential, and conclusions based on a reactive response, rather than specific scientific data, should be avoided.

To identify acceptable risk, health-based limits should be developed by toxicologists from:

toxicological and pharmacological data

data that are submitted, as required, with Marketing Applications (i.e., New Drug Applications (NDAs), Biological License Applications (BLAs), or Marketing Authorization Applications (MAAs)) normally in Common Technical Document (CTD) format

data from clinical trials

This Guide refers to this as the Acceptable Daily Exposure (ADE). The ADE represents a dose that is unlikely to cause an adverse effect if an individual is exposed, by any route (e.g., intrathecal, inhaled), at or below this dose every day for a lifetime. By definition, a robust ADE limit should be established with pertinent toxicological data and it should be protective of all populations by all routes of administration. When appropriate, the ADE may be adjusted to accommodate specific sub-populations or routes that may allow a higher ADE value. The acceptable limits for cross-contamination, cleaning validation, and worker safety are derived from these data, but the application of uncertainty factors to these data might be different for quality versus workplace health and hygiene, primarily due to differences in the subpopulations at risk and potential route(s) of exposure. See Section 5 of this Guide for further information on how these limits are derived.

Hazard is the inherent property of a compound to produce harm. If a hazard is present, then a risk exists.

Risk is the combination of the probability of occurrence of harm and the severity of that harm.

Since the hazard (including its severity) cannot be changed, the primary way to control health risks to the worker, risk to the patient via cross-contamination of the product, or contamination of the environment is to control the level of exposure to the hazard. Therefore, the probability of harm occurring (or risk) is a function of the level of exposure.

1.2 Risk Management/Assessment Model to Address the Controls to Comply with 21 CFR 211.42(c)

21 CFR 211.42(c) (Reference 15, Section 15.1) states that Operations shall be performed within specifically defined areas of adequate size. There shall be separate or defined areas or such other control systems for the firms operations as are necessary to prevent contamination or mixups during the course of the following procedures:

It should be noted that other regulatory bodies such as the EMA, the WHO, and the MHLW have similar requirements. In addition, the US FDA Center for Biologics Evaluation and Research (CBER) has recently updated 21 CFR 600.11 (Reference 16, Section 15.1) to allow the manufacture of live vaccines in multi-product facilities, provided adequate controls are established to prevent cross-contamination. This Guide can assist vaccine manufacturers in determining and documenting that adequate control is provided to maintain the risk of cross-contamination below acceptable levels.






To determine the control systems that meet the intent of the US FDA CFR, risk assessments should be undertaken, starting with the development of the health-based acceptance criteria (e.g., ADE, cleaning validation limits). These provide the basis for a risk analysis, which includes exposure assessments to provide a risk profile. Each manufacturer should determine if the risk is acceptable without establishing further control strategies to manage the risk. If the risk is above acceptable levels, then further risk reduction strategies should be employed. See Section 10 of this Guide for further information on risk reduction.

The risk management approach should be continued throughout the life cycle of the product. This type of risk-based approach provides and documents an understanding of the products being processed, the processes being used, and the way the equipment and facility will be cleaned to support both patient and worker safety. Risk management measures should include safe handling of materials, to minimize the potential for cross-contamination and to protect workers from unacceptable exposures. When this is accomplished, manufacturers should be able to make products with a degree of flexibility in the manufacturing process, while maintaining both patient and worker safety.

1.3 How the Approach Fits Into Cleaning Validation

Residues from a compound which remain after cleaning on equipment or other product contact surfaces may pose a risk to patient safety. A scientifically based risk assessment of such compounds should be performed, in order to understand the impact of this risk.

Cleaning procedures should be developed to minimize the risk from residues. To reduce risk, cleaning procedures should be capable of reducing residues to, or below, a predetermined safe level based on the risk assessment for a compound.

An appropriate cleaning agent should be identified for each compound. A scientifically based risk assessment should be performed on the cleaning agent, which should pose the least risk to patient safety.

A risk analysis of the cleaning procedure should be performed, using the information obtained from the initial risk assessment of a compound, to determine the acceptability of the cleaning procedure.

A comparison of cleaning residue data and the ADE for a compound provides a scientific means of analyzing the risk posed to patient safety by residues of that compound.

1.4 Background

Where production of a single product needs the entire capacity of a facility, issues of cross-contamination are of less concern. Where two or more products are to be manufactured in one facility, one room within a facility, or by using common equipment (linked or separate), the potential for cross-contamination becomes a significant issue for consideration.

The principles of risk management are integral to all aspects of the pharmaceutical business, from finance to product quality, patient safety, and occupational health. However, it has been recognized that risk management and quality system approaches have not been consistently utilized by companies or in some aspects of pharmaceutical manufacturing. Regulators also may adopt risk averse strategies, particularly during inspections.

Consistent with the principles embodied in ICH Q9 (Reference 28, Section 15.1), a systematic approach is needed to provide guidance in the identification of risks requiring control strategies to manage them effectively. This should be applied at all stages in the manufacture of pharmaceutical products. Such an approach includes risk assessments that are formally conducted to assist with the identification, implementation, and verification of appropriate risk control strategies as part of the overall risk management process.






Control strategies in alignment with quality systems should be holistically developed and maintained for the life cycle of the product. Multi-dimensional controls and cross-contamination safeguards (structural, procedural, etc.) should be employed to minimize the likelihood of product mix-ups and cross-contamination potential, while providing workers adequate protection from occupational exposure risks. For APIs, toxicologists incorporate information available from pre-clinical and clinical regulatory submissions to calculate ADE values. These values can be used to assess risk for product quality. The same data can be used to assess risk for worker protection.

Throughout this Guide, API refers to primary (active pharmaceutical ingredient) and pharmaceutical products refers to secondary (formulated product), packaged or any intermediate bulk material or by-product generated in the course of pharmaceutical production. This Guide also uses the term exposure which refers to patient, product, operator, and environmental exposures, unless specifically clarified within the text. The term controls as used throughout this Guide encompasses all types of controls including:

process controls

operational controls

the full range of engineering controls

procedural controls

administrative controls

1.5 Scope of this Guide

This Guide provides the framework for a risk-based approach to manage the risk of cross-contamination in the manufacture of all classes of pharmaceutical products. Although the primary focus of this Guide is on the GxP issue of cross-contamination, where appropriate, industrial hygiene issues are mentioned to highlight the similarities and differences of the two areas of concern.

The risk management approach should be commensurate with the different levels or degrees of risk, to ensure that cross-contamination will be maintained at or below acceptable limits. This Guide addresses methods for determining the acceptable limits, as well as suggestions for documentation of the risk management process.

This Guide is intended to provide professionals in the pharmaceutical industry with a consistent approach on setting acceptable limits to assess the potential of cross-contamination causing an undue risk to patient safety. This approach is intended to allow manufacturers to contain manufacturing cost while facilitating safe and affordable drug product. This Guide should be used in conjunction with local and/or applicable (multi-national manufacturing platforms) regulatory requirements and other guidance documents already available to the pharmaceutical manufacturing industry.

The principles described in this Guide can be applied equally to large and small molecular weight APIs, pre-clinical and clinical materials, and commercially marketed products.

1.6 Current Situation

For some time, the pharmaceutical industry has developed effective control strategies for protecting workers and for preventing cross-contamination of pharmaceutical products. In recent years, regulators worldwide have scrutinized in greater detail practices put in place to avoid cross-contamination. When GxP expectations were distilled and incorporated by the industry, the compliant method to control cross-contamination was to dedicate or segregate facilities and equipment. However, regulatory agency observations have repeatedly been generated against the inappropriate flow between such dedicated facilities of people, paper, and movable equipment. In addition, in the






past decade, technological advances such as increased sensitivity in detection, quality control methods, and more reliable containment systems are providing technical solutions that can reduce the potential of cross-contamination below critical, health-based levels.

Worldwide, regulators are not currently in agreement as to the acceptable level of controls required for the compliant manufacture of highly hazardous compounds (i.e., those compounds that can cause serious adverse effects at low doses) within multi-product facilities. Several major regulatory agencies allow for the production of highly hazardous compounds by campaign, provided adequate separation and suitably validated cleaning procedures are present, while other major regulatory bodies do not allow certain highly hazardous compounds in multi-product facilities at all.

The FDA regulation that often is cited when there are concerns with cross contamination is 21 CFR 211.42 (Reference 15, Section 15.1) that states There shall be separate or defined areas or such other control systems for the firms separation as are necessary to prevent contamination... for all classes of compounds.

The EU Guide to Good Manufacturing Practice (section 5.19) (Reference 14, Section 15.1) states Cross- contamination should be avoided by appropriate technical or organizational measures. The appropriate measures should be determined following a quality risk assessment as described in paragraph 3.6.

ICH Q7, (Reference 26, Section 15.1), section IV.D (4.4) on containment states Dedicated production areas..should be employed in the production of highly sensitizing materials, such as penicillins or cephalosporins. The use of dedicated production areas should also be considered when material of an infectious nature or high pharmacological activity or toxicity is involved unless validated inactivation and/or cleaning procedures are established and maintained.

Risk assessments as outlined in this Guide provide a method to document that cross-contamination can be maintained below acceptable levels when processing multiple products in one facility.

The current situation finds that there is some variation between regulatory authorities in the interpretation of commensurate control strategies associated with pharmaceutical manufacturing.

Obviously, in select cases, it may be necessary to manufacture pharmaceutical products in segregated or dedicated facilities. These decisions should be made on a case-by-case basis and depend both on the inherent hazards associated with the pharmaceutical product and on the ability or inability of the manufacturer to demonstrate there is no significant cross-contamination or carry-over to another product. Alternatively, the decision to provide segregated or dedicated facilities may be based on business or operational reasons. Whatever the basis for these decisions, they should be holistically developed and captured in a documented risk management plan.

1.7 How to Use this Guide

The approach as outlined in this Guide is applicable to multi-product facilities, dedicated equipment, dedicated areas within facilities, as well as dedicated facilities, and is intended to offer a consistent approach, while still allowing flexibility and innovation in selecting and applying the controls necessary to manage the risk of cross-contamination to acceptable levels.

The layout of this Guide mirrors the Quality Risk Management Process as defined in ICH Q9 (Reference 28, Section 15.1), specifically:

Chapter 2 Concepts and Regulatory Philosophy provides a general overview of regulatory expectations and identifies key concepts presented in the Guide.

Chapter 3 discusses the fundamentals of a Quality System (see ICH Q10 (Reference 29, Section 15.1) for more information) and provides a methodology to logically go through the process and balance the needs of GxP and IH.






Chapter 4 addresses Risk Assessment, which includes the risk identification, risk analysis, and risk evaluation steps of the risk management process.

Chapter 5 provides background on Risk Identification for cross contamination including setting health-based limits.

Chapter 6 discusses Risk Analysis and the factors that affect exposure.

Chapter 7 focuses on Risk Evaluation where a comparison is made between the risk criteria and the identified level of risk.

Chapter 8 explains Risk Control strategies which include the risk reduction and risk acceptance steps of the risk management process.

Chapter 9 describes the Risk Acceptance step of the risk management process.

Chapter 10, Risk Reduction, provides some areas to address when risk needs to be further reduced.

Chapter 11 describes some of the risk assessment tools available.

Chapter 12 and 13 discuss Risk Review and Risk Communication respectively as ongoing processes to make sure the risk is maintained below acceptable levels. Chapter 13 also includes a Summary Document Template for the Quality Risk Management Plan.

The Appendices provide references, a glossary of terms, and examples of the risk assessment process described within the body of the document.

The information provided in this Guide is intended to help the user understand the relationship of hazard, exposure, and risk so that a formal documented risk management approach for selecting control strategies to minimize risks can be prepared. If done properly, the stakeholders should be able to demonstrate a full understanding of the processes being evaluated. Consistent documentation across the hazard continuum is integral in this approach so that the regulators can be confident that a well thought out plan to reduce risk to an acceptable level has been established.





2 Concepts and Regulatory Philosophy





ISPE Baseline Guide: Page 13Risk-Based Manufacture of Pharmaceutical Products Concepts and Regulatory Philosophy

2 Concepts and Regulatory Philosophy The pharmaceutical industry is experiencing a transformation. In the 1990s, the ICH was formed to promote joint

international harmonization of regulatory requirements between industry and regulators for the manufacture and development of pharmaceutical products. In the early 2000s, regulatory agencies began encouraging manufacturers to improve their processes to increase both safety and efficiency.

From 2005 through 2008, ICH working groups produced several significant documents; ICH Q8, Q9, and Q10 (References 27, 28, and 29, Section 15.1). These documents are being adopted by the ICH parties (US, Japan, and EU).

ICH Q8 (Reference 27, Section 15.1) introduced Quality by Design which is based on the concept that quality should be built into a product with a thorough understanding of the product and process by which it is developed and manufactured along with a knowledge of the risks involved in manufacturing the product and how best to mitigate those risks.

ICH Q10 (Reference 29, Section 15.1) discusses the importance of an effective pharmaceutical quality system throughout the product lifecycle, and responsibility of senior managers to create quality policy that assure compliance with applicable regulatory requirements and facilitates continual improvement.

In 2002, the Head of Medicines Agencies (HMA) agreed upon on the outline of a European Risk Management Strategy (ERMS). In 2005, the EMEA issued an Action Plan to Further Progress the European Risk Management Strategy. Also in 2005, EMEA issued a Concept Paper Dealing with the Need for Updated GMP Guidance Concerning Dedicated Facilities in the Manufacture of Certain Medicinal Products (Reference 11, Section 15.1).

In 2002, the FDA announced its Pharmaceutical cGMPS for the 21st Century A Risk-Based Approach (Reference 18, Section 15.1) initiative which was intended to modernize FDAs regulation of pharmaceutical quality for veterinary and human drugs and select human biological products such as vaccines. In 2007, the FDA changed the name of the initiative to Pharmaceutical Quality for the 21st Century A Risk-Based Approach to capture the larger issue of product quality, with cGMPs being an important tool towards improving overall product quality.

The goals outlined in the FDAs Pharmaceutical Quality for the 21st Century A Risk-Based Approach support:

new technological advances by the pharmaceutical industry

modern quality management techniques, including implementation of quality systems approaches, to all aspects of pharmaceutical production and quality assurance

risk-based approaches that focus both industry and Agency attention on critical areas

regulatory review, compliance, and inspection policies are based on state-of-the-art pharmaceutical science

In 2005, Dr. Janet Woodcock, chair, Council on Pharmaceutical Quality, FDA provided a view on the desired state of the pharmaceutical industry as A maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high-quality drug products without extensive regulatory oversight.

In early 2008, Center for Biologics Evaluation and Research (CBER) revised 21 CFR 600.11(e)(4) (Reference 16, Section 15.1) The revisions provide that live vaccine processing steps may be performed in multiproduct manufacturing buildings and areas when appropriate controls exist to prevent cross contamination of other products and areas. We recognize that advances in facility, utility, system, and equipment design, as well as in sterilization, decontamination, and disinfection technologies have increased the ability of manufacturers to control the manufacture of biological products and the equipment used in their manufacture. The use of appropriate controls, procedures, and processes provides an adequate degree of confidence that a product meets the expected levels of safety, purity,





Page 14 ISPE Baseline Guide:Concepts and Regulatory Philosophy Risk-Based Manufacture of Pharmaceutical Products

and potency. Areas of special concern, such as containment, decontamination, sterilization, and disinfection can be addressed using currently available controls, procedures, and processes.

These concepts apply to many aspects of pharmaceutical manufacturing. Applying these concepts to manage the risk of cross-contamination, introduces the following key concepts:

1. Risk is a function of hazard and exposure. Any compound should be considered a hazard. The severity of this hazard will depend on the type of effect that can be caused and on the dose at which this effect will appear. Exposure is the level of contact with the compound. Risk is the likelihood that a compound will produce harm under specified conditions of exposure. To minimize risk, manufacturing conditions and procedures should be established to control exposure, thus minimizing the probability that a compound will produce adverse effects.

2. There is a continuum of hazard: there are no distinct lines at which to distinguish certain compounds as low hazard from others that are high hazard.

3. Pharmacological and toxicological descriptions (dose-response, No-Observed-Adverse-Effect Level (NOAEL), and ADE) should be used to assess the hazards of compounds. Terms such as potent, cytotoxic, cytostatic, and other product class definitions tend to induce an emotional response that may imply that without exception these compounds are always difficult to handle and require the highest level of control.

4. A consistent, robust, and science risk-based approach in decision making should be made across the hazard continuum.

5. Zero risk is not achievable. As such, an organization should ensure a well-supported estimation of risk, a strong scientific rationale for risk acceptance, and a robust design approach.

6. Health-based values, such as ADEs, should be used to set limits for the determination of acceptable risk.

7. Exposure, and subsequently risk, can be reduced to acceptable levels by a variety of methods (this includes strictly excluding the presence of certain compounds by design).

8. GxP is the primary focus; however, industrial hygiene (worker safety) and other health and safety concerns also should be addressed. Solutions can vary and are sometimes conflicting. Effective risk management requires a shared understanding and a holistic application of assessment and control, to acceptable levels to achieve the appropriate balance between these different needs (this includes strictly excluding the presence of certain compounds by design).

9. Plausible pathways for exposure, whether for patient, product, or worker should be addressed, and misconceptions on exposure pathways need to be correctly understood.

2.1 Overview of the Risk Management Approach

A risk management approach should be applied to the handling of pharmaceutical products. This should be a holistically-defined process to formally identify hazards and understand risks to assist decision making for implementation of appropriate approaches for risk control. Although this process should be a formal part of an organizations quality system, the level of effort and detail for the risk management process can, and should, vary based on the perceived risks.

The risk assessment process should be used to derive criteria that can assist in decision making and control strategies to manage the risks to both patient and workers. The risk assessment should be a transparent evaluation of all data relevant to hazard identification, assessment of potency (dose-response) and severity, exposure assessment, and characterization of risk. The risk assessment should be documented and should include a discussion of all assumptions and limitations inherent to the risk assessment performed. Risk control strategies that






are implemented should be commensurate with the level of risk. The ultimate decision on the appropriate control strategy implemented may rely on both qualitative and quantitative data.

ICH Q9 (Reference 28, Section 15.1) outlines a quality risk management process that is iterative and consists of the identification of the hazards and the analysis and evaluation of risks associated with exposure to those hazards, as well as control strategies to manage the risks. This Guide follows the steps outlined in ICH Q9 and customizes them to address cross-contamination risks.

Figure 2.1: ICH Q9 Quality Risk Management Process

2.2 Acceptable Risk

An API represents a hazard, as it is capable of producing biological effects (e.g., pharmacological or toxicological). The likelihood that these effects will occur depends on:

the dose-response relationship

the level of exposure

the amount absorbed

The main premise of this Guide is that if exposure to an API is kept below a pre-specified level that is determined safe, this would indicate low risk for adverse health effects in exposed individuals. At this level of exposure, the risk of experiencing any effects is extremely low and is considered acceptable.





Page 16 ISPE Baseline Guide:Concepts and Regulatory Philosophy Risk-Based Manufacture of Pharmaceutical Products

Regulatory agencies and expert committees use a similar hazard assessment process to establish safe levels of exposure to substances that include chemicals in the workplace and the environment, food additives, and impurities in pharmaceutical products. A number of different terms have been used to describe the health-based limits developed for different purposes. For example, for many years ADI values have been established for indirect food additives. Tolerable Intake (TI) values have been developed for similar purposes. The ICH has recommended Permitted Daily Exposure (PDE) values for residual solvents in pharmaceutical products. More recently, the European Medicines Agency Committee on Human Medicinal Products (CHMP) has published a guideline on setting limits for genotoxic impurities in pharmaceutical products. The US EPA establishes Reference Doses (RfDs) and Reference Concentrations (RfCs) to regulate air and water emissions. Examples of Occupational Exposure Limits (OELs) include:

OSHA Permissible Exposure Levels (PELs)

ACGIH Threshold Limit Values (TLVs)

AIHA Workplace Environmental Exposure Levels (WEELs)

UK HSE Workplace Exposure Limits (WELs)

German AGW and MAK values

EC SCOEL Indicative Occupational Exposure Limit Values (IOELVs)

The health endpoint of concern will influence what level of risk is acceptable. For example, the ACGIH TLV Committee recommends that exposures to irritants be maintained just below a level that can cause irritation. Exposures are allowed to approach this level, as this effect is a mild and reversible one. For target organ effects and other non-cancer endpoints, safety factors (also called uncertainty factors, assessment factors, and chemical-specific adjustment factors) are used by limit-setting groups worldwide. These are applied to the No-Observed-Adverse-Effect Level (NOAEL) for the critical endpoint (the first significant effect observed at the low end of the dose-response curve) to derive a safe level of exposure. The critical effect for patients may be different than that for operators due to differences in the route(s) of exposure. This often represents the first clinically significant pharmacological effect. The actual risk cannot be easily quantified, but no unwanted effects are expected at or below this dose, i.e., there is a margin of safety reflected by the ADE. The lower the exposure is below the limit the larger the margin of safety.

A different approach has been used for carcinogens that are based on risk. OSHA has promulgated PELs for carcinogenic substances to maintain cancer risks in the range of 1 in 1,000, a level of risk that corresponds to the overall risk of dying on the job. The US EPA and California EPA (Proposition 65) regulate carcinogens to 1 in 100,000 excess cancer risk in the general population while the EMEA CHMP guideline (Reference 12, Section 15.1) uses 1 in 100,000 excess cancer risk for genotoxic impurities.

In order to determine the level of acceptable risk, a number of factors need to be balanced by the benefits associated with a product. These benefits are different for patients and workers.

2.3 The GMP and Industrial Hygiene Balance

A clear strategy is necessary to assess risk in either the Industrial Hygiene (IH) or cGMP setting and to define scientifically based criteria in order to make decisions for managing risk. Although criteria for both are derived from the same toxicological or clinical data, the way in which these data are used to derive acceptable limits and adequate control strategies will differ. It is important to understand these differences and the possible consequences of confusing the two.

The key differences relate to the application and interpretation of target population, routes of exposure, and acceptability criteria. These are summarized in the Table 2.1.






Table 2.1: Summary of Differences for IH and cGMP Considerations

Balancing the needs of both IH and GMP interests is very important in ensuring that all risks, to product or worker, are adequately managed. Only through recognizing the differing needs and identifying a strategy that can address both is it possible to achieve effective and economic operation of a manufacturing facility.

Perspective Industrial Hygiene Quality (cGMP)

WHO/WHAT Exposed Worker ProductPopulation Variables (Age, Usually healthy Introducing risk to Patient via theImmunology, Fitness) product

Route of Entry Inhalation Product Cross-Contamination Dermal by settled powder or retained Transmucosal Membranes product X into/onto Product Y Ingestion Patient Ingestion, IV

Primary Exposure Mechanism(s) - Inhalation - Mix-Up or How exposure/cross- (Settled dust can be re-suspended wrong materialscontamination occurs to be breathed at another time) - Retention - Skin Absorption inadequate cleaning contact, via wounds - Mechanical Transfer - Mucous Membranes moving residue from one thing to Contaminated worker touches another mucous membranes - Airborne Transfer - Ingestion powder available in air and contacts product, equipment

Basis of Standards for Risk Occupational Exposure Limit Acceptable Daily Exposure (ADE)Assessment (OEL) expressed by an AIRBORNE expressed as mg/day concentration (mass per cubic meter Cleaning Limit of air) to address primary route of expressed as mg/swab or mg/l to entry for exposure: Inhalation address primary route of exposure: Ingestion, IV





3 Quality System Requirements





ISPE Baseline Guide: Page 19Risk-Based Manufacture of Pharmaceutical Products Quality System Requirements

3 Quality System Requirements Awelldefinedqualitysystemshouldconsistofgovernancedocumentswhicharecomplementedbyaconcisesetof

tacticalorproceduralrequirements.TheoverarchingdocumentationmatrixshouldprovidethebasisofconsistencyrequiredforthecreationofasustainablequalitysystemmodelwhichenablestheICHQ10(Reference29,Section15.1)lifecycleapproachacrosstheGxP-regulatedfunctionswithinanorganization.

Figure 3.1: Quality Management System

3.1 GxP Quality Policies

OrganizationsshouldestablishcorporateGxPqualitypolicieswhichaccuratelycapturetherelevantregulatoryexpectations.

Tofacilitatethedevelopmentofaninterdependentandintegratedqualitysystem,itisessentialfororganizationstosolicitrepresentationandinputsfromallGxPareasofthecompany,directlyorindirectlyexpectedtobeworkingwithinacommonframeworkofregulatoryexpectations.

OrganizationsshouldestablishandextendcorporateGxPqualitypolicieswhichaccuratelycapturetheregulatoryexpectations,acrossthoseareasoftheorganizationneedingtobeinalignmentwiththerequirements.TheseGxPpoliciesanddecisionsshouldbeunderpinnedbygoodscience.Oncedeveloped,thepoliciesshouldbeacornerstoneofthequalitysystemandactasanenablerinthecreationoftacticalbuildingblockssuchasstandards,procedures,andmetricreportingtools.

Qualitysystemsshouldbesustainable.





Page 20 ISPE Baseline Guide:Quality System Requirements Risk-Based Manufacture of Pharmaceutical Products

3.2 GxP Quality Standards

Thesecondtierofgovernancedocuments,oftencalledQualityorTechnicalStandards,shouldfocusondrivingtheconsistencyoftheapproach,terminology,andmeasurements(oftenreferredtoasDashboards),whichassistintheidentificationandcontrolofrisk.

Nomenclatureshouldbestandardizedthroughoutanorganization.

Predefinedmeasurements(ordashboards)shouldbeestablishedtohelpidentifyandcommunicateareaswhichpresentanelevatedrisktothebusiness,Managementresponsibilitiesandaccountabilitieswithinanorganizationshouldbeconsideredwhendetailsarecommunicated.

3.3 Gap Analysis

Oncetheoverarchinggovernancequalityexpectationshavebeendeveloped,agapassessmentshouldbeperformed.Therelevantdisciplinesshouldassesscurrentproceduralandstructuralcontrols,formallydocumentgapswhichexist,anddeveloparemediationplanforendorsementbyseniormanagement.

3.4 Auditing of Quality Systems

Auditstrategiesshouldbeestablished.AuditfunctionsshouldhaveappropriatetraininginboththeprinciplescontainedwithinICHQ9(Reference28,Section15.1)andothercurrentandemergingregulatoryexpectations.Theschedulingandfrequencyofqualitysystemauditsshouldbeconcomitantwithrisk.

Duringsystem-basedaudits,auditorsshouldidentifyareasofelevatedriskwhileconcurrentlycapturingthequalitysystem(s)impactedbytherespectiveline-itemfinding(s).Singlelineitemobservationsshouldbeevaluatedforpotentialincorporationintoamultiple-pointqualitysystembasedobservationwithasingularclassificationand/orrating(e.g.,Critical/Major/Minor)inordertoassistCorrectiveAndPreventativeAction(CAPA).

Toreinforcemanagementaccountabilityforremediationofauditfindings,personnelfromtheareaswheretheobservationsweregeneratedshouldattendtheauditcloseoutmeeting.Thelevelofmanagementattendanceattheauditcloseoutmeetingshouldcorrespondtothecriticalityofanyobservations.Distributionofanauditreportshouldreflecttheresultant(orapparent)risktotheorganization.ThereshouldbeformalexpectationsassociatedwiththetimeframesforauditresponseandproposedCAPAactivities.ItisveryimportantthattheauditfunctionremainsactivelyembeddedintheprocessuntilverifiableCAPAremediationeffortshavebeenconcluded.

Auditgroupsshouldanticipatearegulatorsidentificationofinsufficientmanufacturingcontrolsarisingfromnon-compliantriskmanagementandqualitysystemstrategies.

3.5 Application to Cross-Contamination

ThekeyconceptsdiscussedinthisGuideshouldbeusedasaframeworkfromwhichtodevelopstandards,tools,andapproachestomanagetheriskofcross-contamination.

Acase-by-caseassessmentshouldbeperformedoftheriskfactorsthatconcurrentmanufactureofseveralproductsmaycause.RiskassessmentsshouldbeperformedtoproperlyunderstandtheimplicationsforbothIHandGxP.Whileeachisnormallyconsideredseparately,topreventanysignificantimbalance,theimplicationsofdecisionstakenduringanassessmentforIHshouldbecheckedagainstthoseforGxP.






3.6 The Logic Diagram

Alogicdiagramisasimpletoolthatcanbeusedtoguideateamthroughaprocesstodeterminetheneedfordedicatedfacilities.(Section3.6.1shouldbereadinconjunctionwiththeflowdiagraminChapter14ofthisGuide.)Determiningtheneedfordedicatedfacilitiesshouldbeperformedbyamulti-disciplinaryteam,sothatallrequiredareasareaddressedappropriately.

Thelogicdiagramisdividedintotwo,addressingbothGMP/RegulatorylogicandIHlogic.Bothareequallyimportantastheydealwithaspectsofriskassociatedwiththedifferentpopulationsthatmaybeexposedtothehazardunderreview(rightsideproduct,leftsideworker).

Wherededicatedfacilitiesareimplementedforbusinessreasons,theriskassessmentshouldclearlystatethatthisisabusinessdecisionandnotacross-contaminationissue.

3.6.1 Considering the GMP/Regulatory Factors

SeeFigure3.2.Foralargerversionofthediagram,refertoChapter14ofthisGuide.

Figure 3.2: GMP/Regulatory Factors






3.6.1.1 Gathering Hazard Information (e.g., Health-Based Criteria)

BoththeIHandGMPcriteriaaredrawnfromcommontoxicologicalorclinicaldatasources.Eachshouldhaveascience-basedapproachtoriskmanagementandclearstrategiesforassessmentofpotentialexposure,(e.g.,monitoring).TheADEisnormallythehealth-basedcriterionusedinassessingGMPconcernsrelatedtocross-contamination.TheOELisnormallythehealth-basedcriterionusedinassessingairborneproductintheworkplace.

3.6.1.2 SpecificRequirementsforHandlingProductinaDedicatedFacility

Isthereawrittenregulationthatwouldprecludetheco-manufactureofthisproductwithothernon-relatedmaterials?

Thisisthefirstquestionofthelogicprocess.

TheusualexamplequotedisthatofthepenicillinclassofantibioticswheresomecurrentGMPs(EU:EudralexVol.4section5.19(a)(Reference14,Section15.1)andUS:21CFR211.42(c)(d))(Reference15,Section15.1)requireseparatefacilitiesfortheirmanufacture,processing,andpacking.AlthoughorganizationsmaychoosetochallengethelogicthatunderpinsthesespecificGMPs,inmostcases,organizationshavechosentoaccepttherestrictionaswritten.

Therearenumerousreasonstodedicateasingleproducttoasinglefacility,including:

asaconsequenceofaproductspecificagencyinspection

internalQArecommendation

manufacturingtechnologymaybeuniquetotheproduct

salesdemandmaybesufficientlyhightofullyutilizeavailablecapacity

Operationalreasonsfordedicatedfacilitiesshouldnotbeusedtosetaprecedentforsimilarmaterialsindifferentsettings;thisshouldbedeterminedonacase-by-casebasis.

Itmaynotbepossibletoreducethedegreeofrisktoanacceptablelevelwithoutincurringtimeorcostpenalties.Inthiscase,thepragmaticapproachmaybetodedicateafacility.Thesituationshouldbere-visitedifkeyfactorschange(manufacturingorcontainmenttechnologyimproves,demandchanges,etc.).

3.6.1.3 ObtainAppropriateCriteriatoSupportCleaning

Properutilizationofequipmentandfacilitiesrequiresknowledgeofthepotentialforretentionorcarryoverfromoneproducttoanother.Thisisacharacteristicbasedonthechemicalandphysicalnatureofthecompoundandthedesignandmaterialsofconstructionoftheequipment.Theacceptablelevelofretentionorcarryovershouldbedetermined,onacase-by-casebasis,takingintoaccountthehazard(s)presentedbytheproductandthenatureandrouteofadministrationoftheproductthatwillnextbeprocessedintheequipment,unit,orfacility.Anappropriatesafetymarginshouldbeincorporatedwhenestablishingacceptablelevels.SeeChapter5ofthisGuideforfurtherinformation.

3.6.1.4 Cleaning(Retention)Aspects

Cancleaningbecarriedouttomeettherequiredcriteria?

Factorstobeconsideredwhenassessingwhetherthecleaningcriteriacanbemetordetected,include:






Feasibilityifaverylowlevelofacceptablecarryoverisdefined,arethereanalyticalmethodsthatwillachievethelevelofdetectionrequired?Ifanaggressivecleaningagent(e.g.,causticsoracids)willbeused,whateffectswillthiscleaningagenthaveontheequipmentormaterialsofconstruction?Willtherebepittingorcorrosionofsurfaceswithlongtermuse?Willequipmentpartsbecomecorrodedordamagedovertime(e.g.,gasketmaterials)?Theriskassessmentshouldconsidersuchpossibilities.

Practicabilitywouldtheeffortrequiredtoperformcleaningtothedefinedlevelbepractical?Wouldthefacilityneedtobeshutdownforanextendedperiod?Wouldextrapersonnelberequiredtoundertakethecleaning?Wouldhighvolumesofsolventorotherchemicalsberequiredpresentingadifferentriskscenario(e.g.,exposureofworkerstothecleaningmaterials,containmentandcostofdisposalofsolvents)?

Costarethedirectandindirectcostsassociatedwithanextendedcleandownacceptable?Ifthisisaonceayearscenario,theanswermaybeyes,butifthisisanexercisethatmayneedtobeconductedweekly,itmaynotbeaneconomicoption.

Patienttheaboveconsiderationsdonotsupersedetheneedsofthepatientwhoultimatelywillbeadministeredorconsumethedrugproduct.Allriskassessmentsshouldincorporatepotentialrisktopatientasafactor.

Ifthesefactorscanallbeaddressedsatisfactorily,thentheuseofamulti-productfacilitymaybeaviableoptionfortheprocessingormanufactureofthematerialorproductunderconsideration.Iftheanswerisno,ornoteasilytoanyoftheabovequestions,thensomeelementofdedicationshouldbeconsidered.

Anumberofadditionalquestionsshouldbeaddressedbeforeconfirmingthefeasibilityofamulti-productfacility.Thelogicdiagramposesfurtherquestions,whichshouldbeansweredonacase-by-casebasistodeterminethedegreeofdedicationthatmayberequired.

3.6.1.5 Mix-Up Aspects

Areprocedures,controls,andfacilitiesdesignedsuchthatmix-upisavoided?

Factorstobeconsideredwhenassessingwhethermix-upcanbeavoidedinclude:

Procedures/SOPsidentifyareaswheretheexistingproceduresmayfailortheconsequencesiftheproceduresarenotfollowed.Areadditionalproceduresneeded?Aretheexistingprocedurestoocomplicatedtofollow?Aretheproceduresverifiedbysuitablemeans?

Controlsidentifyareaswheretheexistingcontrolsmayfail.Areadditionalcontrolsneeded?

FacilityDesignisthefacilitylayoutsuchthattherearenosharedprocessflowsorareasofprocessoverlap?Orifnot,cantheproceduresandcontrolseffectivelypreventmix-up?

Ifthesefactorscanallbeaddressedsatisfactorily,thentheuseofamulti-productfacilitymaybeaviableoptionfortheprocessingormanufactureofthematerialorproductunderconsideration.Iftheanswerisnoornoteasilytoanyoftheabovequestions,thensomeelementofdedicationshouldbeconsidered.SeeChapter6ofthisGuideforfurtherinformation.

3.6.1.6 Mix-upResolution

Canprocedures/controlsordesignelementsbeintroducedormodifiedtoavoidmix-up?

Itmaybenecessarytoconductanumberofspecific,low-level,assessmentsinordertobeconfidentthatanyrisksassociatedwiththeaccommodationandprocessingofthematerialunderconsiderationcanbemanagedorreducedtoanacceptablelevel.Inthissituation,itshouldbepossibletouseamulti-productfacility.






3.6.1.7 PartialMix-upResolution

Canprocedures/controlsordesignelementsbeintroducedormodifiedtoavoidmix-upforsomeofthestages?

Ifthesefactorscannotbeaddressedeasily,dedicationmayneedtobeconsidered.Totaldedicationofanentirefacilitymaybeunnecessary;however,evenifachievablewithoutincurringasignificantextracost.Instead,amorelimitedapproachtosegregationordedicationmaybeacosteffectiveoption.

3.6.1.8 Mechanical Transfer

Isthepotentialformechanicaltransfercontrolledtosafepre-determinedlevels?

Factorstobeconsideredwhenassessingwhetherthemechanicaltransfercriteriacanbemetinclude:

ProcessIstheprocessclosed?Canmaterialescapetheprocessandbetransportedaroundthefacilityviaequipment,product,intermediates,supplies,andpersonnelmovingthroughthefacility?

ProceduresAreproceduresand/orcontrolsinplacetominimizemechanicaltransfersuchasgownchangespriortoleavingprocessingrooms?Areproceduresand/orcontrolsinplacethatstatesequipmentistobewipeddownpriortoleavingtheprocessingrooms?Aretheremeanstopreventtransferfromfeetorwheels?

FacilityarethereotherGxPissuesthatmightintroducerisk?Forexample,wouldmovementofpersonnelormaterialswithinthefacilityorinadequatedifferentialpressuresbetweenmanufacturingzonesgivecauseforconcern?Amorespecificriskassessmenttoreviewtheseaspectsmaybewarranted.

OperationalStandardsIsthefacilitybeingoperatedtoastandardthatisadequatefortheprocessingofthematerialsunderconsideration?Isspecialistknowledgerequired?Doprocessandmaintenanceworkersneedspecialisttrainingpriortohandlingtheproduct?Iscontainmentmanagedthroughengineeringcontrolsaloneorareadditionalproceduralcontrolsused?Aretheseadequate?Ifthereisarelianceonengineeringcontrolsdoesthisintroduceissuesatchangeoverfromoneproducttoanother?SuchquestionsmaybeparticularlyrelevantifconsideringtheuseofathirdpartyCMO.

Ifthesefactorscanallbeaddressedsatisfactorily,thentheuseofamulti-productfacilitymaybeaviableoptionfortheprocessingormanufactureofthematerialorproductunderconsideration.Iftheanswerisnoornoteasilytoanyoftheabovequestions,thenappropriatededicationstrategiesshouldbeconsidered.SeeChapter6ofthisGuideforfurtherinformation.

3.6.1.9 MechanicalTransferResolution

Canmodificationsorproceduresbeputinplacetocontrolmechanicaltransfertosafepre-determinedlevels?


3.6.1.10 PartialMechanicalTransferResolution

Canmodificationsorproceduresbeputinplacetocontrolmechanicaltransfertosafepre-determinedlevelsforsomeofthestages?







3.6.1.11 Airborne Transfer

Isthepotentialforairbornetransfercontrolledtosafepre-determinedlevels?

Factorstobeconsideredwhenassessingwhethertheairbornetransfercriteriacanbemetinclude:

ProcessIstheproductexposedtotheroomenvironmentduringprocessing,transfer,orcleaning?Istheprocessclosed?Canmaterialescapetheprocess?

FacilityarethereotherGxPissuesthatmightintroducerisk?Forexample,wouldmovementofpersonnelormaterialswithinthefacilityorinadequatedifferentialpressuresbetweenmanufacturingzonesgivecauseforconcern?Arematerialandpersonnelairlocksprovided?Ifso,aretheyadequateatcontrollingairbornetransfer?Amorespecificriskassessmenttoreviewtheseaspectsmaybewarranted.

Ifthesefactorscanallbeaddressedsatisfactorily,thentheuseofamulti-productfacilitymaybeaviableoptionfortheprocessingormanufactureofthematerialorproductunderconsideration.Iftheanswerisnoornoteasilytoanyoftheabovequestions,thensomeelementofdedicationshouldbeconsidered.SeeChapter6ofthisGuideforfurtherinformation.

3.6.1.12 AirborneTransferResolution

Canmodificationsorproceduresbeputinplacetocontrolairbornetransfertosafepre-determinedlevels?


3.6.1.13 PartialAirborneTransferResolution

Canmodificationsorproceduresbeputinplacetocontrolairbornetransfertosafepre-determinedlevelsforsomeofthestages?


3.6.1.14 AccommodatingProductinaMulti-ProductFacility

Cantheproductbeaccommodatedinamulti-productfacility,butwithmorespecificdedication?

Whendealingwithhighlyhazardousmaterials,applicationofathoroughriskmanagementapproachtoaspecificaccommodationormanufacturingproposal,mayallowtheneedfortotaldedicationtobereasonablychallenged.However,theriskassessment(s)maynotprovidesufficientconfidencetoallowco-manufacturewithallotherproductscurrentlybeinghandledwithinthesamefacility.Insuchcases,itisworthconsideringsomelimiteddedicationorsegregationtoaddressthoseaspectsofthehandlingorprocessseenasstillposinganunacceptablelevelofrisk:

DedicatedUnit/Roominamulti-productfacilitydedicatingadefinedunit,room,orareamaybesufficienttoaddresslocalrisksassociatedwithcleaningand/orotherGxPconcernsuniquetothematerialsandprocessesunderconsideration.

DedicatedEquipmentdedicationofanindividualvesseloritemofprocessingequipment,orcontactparts(e.g.,feedchutes,compressiontooling,andfillingheads)maybeallthatisrequiredtoreducethespecificareaofriskunderreview.Considerationshouldbegiventothecleaning,storage,andsegregationofsuchitems.






DisposableEquipmentitmaybemoreeconomicaltodisposeofandreplacesmallitemsofequipment,e.g.,fillingtubing,filters,orglassware;anoptionwhichisbeingutilizedincreasinglyinthebiotechsector.Inthissituation,itisstillnecessarytoconsiderthecleaning/decontaminationrequirementsandtheconsequencesofdisposal.Howwilltheitemsbetransportedanddisposedof?Thisshouldbethesubjectofafurther,specific,riskassessment.

3.6.1.15 CleaningCriteriaforProcessStages

Canthecleaningcriteriabemetforsomestagesoftheprocess?

Wheretotaldedicationisnotapreferredoption,ariskassessmentshouldbeperformedataunit,room,orindividualprocessplantlevel.Itmaybepossibletoidentifypartsoftheprocesstrainorindividualitemsofequipmentthatwouldrequiretobededicatedbecausetheycannotreasonablybecleanedtotheacceptablelevels.Completededicationmaybepreferredwhereitisnotpossibletoidentifyasufficientportionoftheprocessthatcanmeetthechallengeofpracticability,feasibility,andcost.

3.6.1.16 IsolationofContaminatedEquipment

Canthecontaminatedequipmentbeisolatedtopreventcross-contaminationofotherpartsofthefacility?

Inascenariowhereoneitem(orareasonablylownumberofpieces)ofprocessequipmenthasbeenidentifiedasrequiringdedication,becausethecleaningcriteriacannotbeachieved,thenconsiderationshouldbegiventotheircleaningandstoragebetweenuse.

Cantheidentifiedequipmentbedecontaminatedandquarantined/storedsafely,suchthatitdoesnotposearisktoprocessormaintenanceoperatorsortotheworkingenvironment,andtherefore,providethepotentialforcross-contaminationwhilenotinuse?Woulditbestoredinthefacilityormovedelsewhere?Doeseitheroptiongenerateanewrisk?

3.6.2 Considering the Health and Hygiene Factors

SeeFigure3.3.AlargerversionofthediagramisprovidedinChapter14ofthisGuide.






Figure 3.3: Health and Hygiene Factors

3.6.2.1 Gather Hazard Information (e.g., Health-Based Criteria)

BoththeIHandGMPcriteriaaredrawnfromcommontoxicologicalorclinicaldatasources.Eachshouldhaveascience-basedapproachtoriskmanagementandclearstrategiesforassessmentofpotentialexposure,(e.g.,monitoring).TheOELisnormallythehealth-basedcriterionusedinassessingairborneproductintheworkplace.

3.6.2.2 AssessExposurePotential

Exposurepotentialmaydifferdependingonthewayamaterialisprocessedorthefacilitywhereprocessingoccurs.

Riskisafunctionofbothhazardandexposure.Evaluatingthelikelihoodofexposureisakeypartoftheriskmanagementprocess.Severalfactorsshouldbeconsidered:

Whoisatriskofexposure?Workersattheline,maintenancepersonnel,generalpersonnelinthearea,orQApersonnelwhensamplingproduct?

Whatfactorsmightinfluenceexposure?Isitadustypowder?Isitaliquid?Isitaclosedoropenprocess?Howwelltrainedarethepersonnel?Isitaroutineorfrequenttask?

Whatisthepathwayforexposure?Inhalation,ingestion,orskintransdermalabsorption?






Whenisexposuremostlikelytooccur?Doworkersneedtodirectlyinterveneintheprocessforsampling,atprocessbreakdown,cleandown,orproductchangeover?

3.6.2.3 ControlofExposure

Aretheexposuresadequatelycontrolled?

Informationthatisalreadyavailableshouldbereviewedtohelpdeterminehowwellexposureiscontrolled:

Isthereexperiencewiththematerialunderreview?Haveanyadversehealtheffectsbeenreported?Doesthenatureofthematerial(e.g.,wet,lumpy,solid)ortheprocess(e.g.,closed)suggestthatriskisunlikelytobehigh?

Arethereanyharddata?Arethereanymonitoringdataavailable?Aretheresimilaroridenticalprocessesbeingoperatedinotherfacilities?

Whatisknownabouttheexposureprofileforthespecificproductandprocessasitisoperatedormightbeoperatedinaparticularfacility?

Thecontrolsthatareappliedshouldbecommensuratewiththeriskandshouldbeconsideredinthecontextofalltherequirementsofthemanufacturingprocess.Forexample,whetheraparticularengineeringcontrolwouldmakeitdifficulttointerveneiftheprocessrunsoutofcontrolormakeitverydifficulttocleanwithoutaffectingefficientplantutilization.

3.6.2.4 ProcessChanges

Iselimination,substitution,orprocesschangepossible?

Whileprocessorformulationchangesareoftendifficulttomakewithestablishedproducts,theopportunitytoreduceexposurepotentialbythismeansisfeasibleifconsideredearlyenoughintheproductdevelopmentprocess.Exampleswherethishasbeenshowntobeeffectiveinclude:

1. removalofasolidrecoverystepbetweenstagesinachemicalprocess

2. changetoawetgranulationprocessfromadirectblendprocessfortabletmanufacture

3. additionofafilmcoattoatabletinordertoreducetheriskofexposureduringpacking

4. formulateasaliquid/semi-solidinacapsuleratherthanasaconventionaltabletorpowderfilledcapsule

Eachoftheseexamplesaddressesonlyonestepinaprocesschainandpotentialforexposuremaystillexistinothersteps.

3.6.2.5 Selection of Engineering Controls

Onceriskfactorshavebeeninvestigated,controlmeasurescanbeconsidered.Thecorrectcontrolsystemshouldbedeterminedandshouldconsidersuchfactorsascost,feasibility,ergonomics,cleanability,andfailuremodeoperation,i.e.,whattodoifthecontrolmeasurefails.

Thoughtneedstobegivenaboutconvertingtheknowledgeonexposurepotentialintotheperformancerequirementsforengineeringcontrols.HowmuchconfidencecanbeplacedonAssignedProtectionFactors(APFs)?Whatexperienceistherein-houseofusingsimilarcontroloptions?






3.6.2.6 LevelofExposureRisk

Istheexposureriskstilltoohigh?

Havingselectedacontroltoaddressameasuredexposure,whathappensiftheexposureriskisstillatanunacceptablelevel?Isitreasonabletoaddinasecondarysystem,suchasanextractsystem,toreducetheexposurepotentialtoanacceptablelevel?

IsroutineuseofPersonalProtectiveEquipment(PPE)acceptableforanactivityofshortduration?Thereisnoclearanswerandsuchoptionsshouldbediscussedwithoperatingpersonnel,plantmanagement,andHSEspecialists.Insomecases,operatorsmaypreferPPEifamorepermanentrigidbarriermakestheprocessstepdifficulttoperformfromanergonomicperspective.

3.6.2.7 EmergencyRecovery

Isemergencyrecoveryrequired?

Whathappensiftheprimarycontainmentsystemfails?Whatknowledgeisthereofthepossiblefailuremodesandtheirfrequencyforagivensystem?Isfailureacceptableunderanycircumstances?Suchfactorsshouldbeconsideredaspartoftheriskassessment.

Whatwillneedtoberecovered,howandbywhom?

Whatsupportinginfrastructurewillberequired?Forexample:

- WouldPPEneedtobeprovided?

- Wouldchangeareas,showers,storageareasforPPEberequired?

- WouldaseparateairsupplyberequiredtoserviceanyPPE?

3.6.2.8 SecondaryPPE

IssecondarycontrolorPPErequired?

Whereavailable,therationalefortheuseofsecondaryPPEshouldbewellunderstoodanddocumented.Isitprovidedtosupplementaprimarycontrolmeasureandreduceanassessedexposurepotentialtoanacceptablelevel?Isitprovidedforemergencyuseonly?

3.6.3 Consequences of Control Strategy

Theconsequencesofadoptinganyparticularexposurecontrolstrategyshouldbere-checkedagainsttheGxP/regulatorylogictoensureplantoperabilityisnotcomprised.





4 Risk Assessment





ISPE Baseline Guide: Page 31Risk-Based Manufacture of Pharmaceutical Products Risk Assessment

4 Risk Assessment RiskassessmentasdescribedinICHQ9(Reference28,Section15.1)encompassesthreesteps;riskidentification,

risk analysis, and risk evaluation. Each of the three steps helps to answer the three fundamental questions:

Whatmightgowrong?

Whatisthelikelihood(probability)itwillgowrong?

Whataretheconsequences(severity)?

Figure 4.1: Risk Assessment

Theriskassessmentstepsmaybeconsideredthemostimportantaspectsofanoverallqualityriskmanagementprocess.Iftherisksarenotidentified,analyzed,andevaluatedproperly,thedecisionsonhowtocontroltheriskcannot be made adequately.

Thecriteriaforjudgingacceptabilityofriskforcross-contaminationandoperatorexposuresdiffer,althoughGxPandIHconsiderationsarelinkedbecausetheysharethesameunderlyingtoxicologicaldataasthestartingpointfromwhich they are derived. In addition, the application and interpretation of the criteria in the risk assessment process will be different.

Partoftheriskassessmentprocessistoconsideriftherearerealisticallyanyplausiblepathwaysthatmightgiverisetoanincreasedriskofexposure.Forexample,thefollowingriskquestionsshouldbeasked:





Page 32 ISPE Baseline Guide:Risk Assessment Risk-Based Manufacture of Pharmaceutical Products

Cancross-contaminationfromanairbornepathwayoccur?Specifically,canproductAbedirectlydistributedviatheairstreamorre-suspendedbackintotheair(afterbeingdeposited),inroom/suite/facility,andthensettleorgetre-depositeddirectlyintoproductBorontocontactpartstobeusedforthemanufactureofproductB?

Canthis