10.5731/pdajpst.2017.007575Access the most recent version at doi: 252-25871, 2017 PDA J Pharm Sci and Tech

 sm ), Emma Ramnarine, Ursula Busse, et al.Authors: Members of the PDA Task Force on Post-approval Changes for Innovation in Availability of Medicines (PAC iAM for Managing Post-approval ChangesManagement. Pharmaceutical Quality System Effectiveness PDA Points to Consider: Technical Product Lifecycle  

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PDA PAPERS

PDA Points to Consider: Technical Product LifecycleManagement. Pharmaceutical Quality System Effectivenessfor Managing Post-approval ChangesAuthors: Members of the PDA Task Force on Post-approval Changes for Innovation in Availability of

Medicines (PAC iAMsm)

Emma Ramnarine*, GenentechUrsula Busse, NovartisMarcello Colao, GlaxoSmithKline BiologicalsJulia Edwards, BiogenKevin O’Donnell, Health Products RegulatoryAuthority (HPRA), Ireland

Maik Jornitz, G-Con, LLCMorten Munk, NNE PharmaplanMelissa Seymour, BiogenMihaela Simianu, Pharmatech AssociatesLisa Skeens, PfizerAnders Vinther, Sanofi-Pasteur

Introduction

The International Council for Harmonisation (ICH)Quality Guideline 10 (ICH Q10) describes the phar-maceutical quality system (PQS), indicating it is in-tended to apply throughout a product’s lifecycle, inconjunction with good manufacturing practice (GMP)requirements, in order to achieve quality in a consis-tent and reproducible manner. Implementation of aneffective PQS is essential for a company to achieveproduct realization, establish and maintain a state ofcontrol, and facilitate continual improvement (1).When changes are made during the commercial life ofa product, an effective PQS, product and process un-derstanding, and use of quality risk managementshould ensure that product quality, patient safety, andadequate supply to patients are maintained; this, ac-cording to ICH Q10 —Annex 1, should provide com-panies the opportunity to manage post-approvalchanges (PACs) with reduced regulatory oversight (1).

But what exactly constitutes an effective PQS? Andhow does it support change management for PACs?

This paper intends to answer these questions andguide companies to seize the opportunities outlinedin ICH Q10 —Annex 1, to manage product andprocess changes within the PQS and downgrade the

level of regulatory submission required. This is thesecond of a series of PDA “Points To Consider”papers on technical product lifecycle management;the first paper focused on the technical productlifecycle management strategy including communi-cation and knowledge exchange between MarketingAuthorization Holders and Health Authorities (2).

Background

During the commercial manufacturing phase of the prod-uct lifecycle, specific elements of the PQS are used toidentify and manage PACs. Per ICH Q10, these includemanagement responsibilities, the four quality system el-ements—process performance and product quality mon-itoring (PPPQM), corrective and preventive action(CAPA), change management, management review—and the PQS enablers, knowledge management and qual-ity risk management (QRM). When successfully imple-mented, together these elements will support an effectivechange management system.

ICH Q10 —Annex 1, Potential Opportunities toEnhance Science and Risk Based Regulatory Ap-proaches, states that when companies can demonstratean effective PQS and product and process understand-ing, including the use of QRM principles, they “gainthe opportunity to optimise science and risk basedpost-approval change processes to maximise benefitsfrom innovation and continual improvement” (1). Inother words, companies can manage more changeswithout the need for prior regulatory approval, pro-vided they operate under a framework comprising aneffective PQS, along with sound product and processknowledge and risk management practices. Thisframework should extend to and include PACs in

* Corresponding Author: Emma Ramnarine, SeniorDirector, Head Global Biologics QC, Genentech, Inc.,1 DNA Way, South San Francisco, CA 94080. E-mail:eramnar@gene.com

doi: 10.5731/pdajpst.2017.007575

PDA PAPER DISCLAIMER: The following paper is a special contribution from the Parenteral Drug Association (PDA). Thisarticle was internally reviewed by PDA and the task force members and not peer-reviewed by the PDA Journal of PharmaceuticalScience and Technology. Note: This PDA paper is protected by copyright and unauthorized distribution or use is prohibited.

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outsourced operations and supplier management toensure that these are also planned, managed, and com-municated appropriately.

Because commercial-scale batches are manufactured fol-lowing license or application approval, initially, manu-facturing process knowledge is limited. As commercialproduction experience and knowledge is gained, adjust-ments are generally needed to improve manufacturingprocesses and control. Changes are thus a natural part ofa product’s commercial lifecycle. When a change clearlygenerates an improvement in terms of (a) reduced risk topatients, (b) improved process capability, (c) enhancedproduct availability, and/or (d) technical innovation andcontinual improvement, these changes should be allowedto be implemented without prior approval or with down-graded notification, provided the risk assessment con-cludes that the changes introduce no additional risk topatient safety, product quality, and/or product efficacy.The PQS must ensure such changes are robust by dem-onstrating change effectiveness. This is consistent withcontinued process verification concepts and providesmore data to establish confidence in risk managementdecisions.

As a result, regulators should accept that the PQS iscapable of an appropriate degree of self-governance inensuring product quality and safety. This would allowmost PACs to be managed under the PQS, without re-quiring prior review and approval by the regulator. In theevent the PQS is subsequently found to be ineffective,restrictions on the ability to make changes with down-graded notification to regulatory authorities may be putin place.

Building an effective PQS is the responsibility of thecompany, one that extends beyond having a license ora GMP certificate to manufacture medicines.

PQS Effectiveness for Post-approval Changes

Management responsibilities and the four specific el-ements of PQS outlined in ICH Q10, enabled by QRMand knowledge management, when applied to PACswill support an effective change management system.The key elements that characterize an effective PQSare described in more detail below.

Management Responsibilities

Company management is ultimately responsible for en-suring that an effective PQS is in place for managing

PACs. This includes defining and communicating roles,responsibilities, and authorities for PACs (for internaland outsourced operations) and providing adequate re-sources and budget for effective PAC implementation.

Management develops the overall strategy of PACs for aproduct. Consequently, it needs to ensure that appropri-ate internal audit and self-audit mechanisms enable pro-active assessment and mitigation of compliance risks inthe PQS, including any issues that might be introducedby the PACs. Management is accountable for drivingtimely improvements when significant variation or majorfailure modes are detected.

Management needs to promote and support the appli-cation of QRM and knowledge management activitiesas key enablers of an effective PQS for PAC manage-ment. And finally, management is responsible for de-veloping the desired quality culture at all levelsthroughout the company to ensure the sustainability ofPQS effectiveness.

Process Performance and Product Quality Monitoring(PPPQM)

An effective PPPQM program provides for proactivemonitoring of processes and product quality to confirmthat the control systems are performing as intended,that the desired state of control is maintained, and thatnew knowledge is captured in a structured way. Sys-tems should be in place for the early detection of processdrifts and unexpected variability and trends, as well asfor the effective handling of adverse events, complaints,and defects. Systems should identify PACs needed toensure an ongoing state of control and product availabil-ity, and to drive continual improvement. An effectivePPPQM program further includes formal continual im-provement programs, as needed, for products, processes,and the control strategy.

Corrective and Preventative Actions (CAPA)

An effective CAPA program monitors and managesunintended risks and consequences of PACs, and itshould enable identification of root cause(s) so thatappropriate actions can be taken to correct problemsand prevent their recurrence. The program alsomonitors and verifies the effectiveness of anyCAPAs associated with PAC initiatives. Designedto deliver low rates of deviation and emphasize theneed to learn from deviations, deviation trends, andcomplaint/recall incidents, an effective CAPA pro-

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gram focuses on preventive measures rather thancorrective actions.

Change Management

An effective change management system is characterizedby change implementation per the product lifecycle man-agement strategy (including plans and protocols),achievement of change objectives, and high success ratesfor PAC approvals by regulatory authorities. It ensuresmaintaining conformity of products and manufacturingprocesses with regulatory filings and established condi-tions. It also includes the development and maintenanceof a comprehensive system for reliable control of PACsin outsourced operations and the effective managementof suppliers. Effective change management relies on adata-driven, science- and risk-based assessment ofchanges that takes into account the potential impact onall relevant aspects of the product and process, estab-lished conditions, and any unintended consequences.Such an assessment will ensure that changes are imple-mented in a timely manner and objectives of the changewill be achieved. Through the application of good sci-ence in PAC-related risk assessments, effective changemanagement provides assurance that any potential risksassociated with PACs are identified and managed ade-quately.

Effective change management further relies on thequality of a company’s post-change monitoring activ-ities. These monitoring activities may be short- orlong-term, as appropriate, and based on pre-definedcriteria.

Effective change management improves product quality,process performance, state of control, and/or productavailability, and lowers residual risks. It delivers com-pelling and documented examples of continual improve-ment and results in adequate control and management ofrisks to product quality and availability as well as topatient safety.

Knowledge Management (PQS Enabler)

An effective knowledge management system leveragesexisting and newly achieved/newly identified productand process knowledge for change management. Thiscomprises innovation and technology advancements, aswell as knowledge gained from PPPQM, deviations,trends, complaints, recalls, annual product review/prod-uct quality review (APR/PQR), and management re-views. Through the use of robust testing and monitoring

plans, it captures new product and process knowledgegained over time and during change implementation, andfosters knowledge-sharing between internal and out-sourced operations.

Effective knowledge management ensures that theright knowledge is used by the right people at the righttime, to allow for effective decision-making. Such asystem better provides for the tacit knowledge held byindividuals to be converted into explicit, documentedknowledge that can be made accessible and under-standable to others involved at each stage of the prod-uct lifecycle. The existence of active expert networks,sharing of best practices/lessons learned at definedstages (e.g., after a PAC), ongoing risk management—and a company culture that allows for open commu-nication, collaboration, and learning from near missesand mistakes—are all signs of effective knowledgemanagement.

Quality Risk Management (PQS Enabler)

An effective QRM system provides for a risk-baseddecision-making framework and ensures that system-atic and proactive risk-based and data-driven decision-making is used for all PACs. Such a system willenable identification of changes that reduce the risk ofquality failures and manufacturing problems and im-prove process capability. It distinguishes changes thatrequire regulatory reporting or notification fromchanges that can be managed solely in the PQS. Incertain cases, the risk assessment can be shared anddiscussed with regulators in a post-approval changemanagement protocol (PACMP) (3).

Furthermore, an effective QRM system assesses therisk level before and after implementation of the PACto ensure that the PAC presents no increase in risk toproduct quality and/or patient safety.

Management Review

Effective management review of process performance,product quality, and the PQS should include a review ofPAC initiatives, their timely implementation, intendedobjectives, and outcomes. Where the objectives of PACinitiatives are not achieved, effective management re-view ensures that formal CAPA action plans are devel-oped and implemented, and that lessons learned arecaptured and incorporated into future PAC activities.

Effective management review assesses strategies forPAC implementation to identify opportunities for con-

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tinual improvement, ensures appropriate internal cat-egorization of PACs, and increases the probability ofapproval by regulatory authorities.

Effective management review also monitors regula-tory inspection and internal audit observations relatedto PACs, and includes a regular review of the perfor-mance of the PQS elements that support effectivechange management. It ensures products and pro-cesses are continually improved, new knowledge isadequately managed within the PQS, and regulatoryfilings are maintained.

Measuring PQS Effectiveness

The extent to which the different PQS elements areimplemented and maintained reflects the maturityand robustness of a company’s PQS, and can indi-cate that the company sustainably operates in a stateof control with respect to PAC management. Mea-surement of PQS effectiveness therefore represents

another important aspect of providing assurance thatthe PQS is adequate and effective in providingoversight of PACs to ensure product quality andadequate supply. In addition, ongoing measurementand associated actions ensure continuous improve-ment of the PQS.

Effectiveness of a PQS can be monitored using appro-priate key performance indicators (KPIs) based onabsolute data and trends. These should be meaningful,simple, and not subject to interpretation. Figure 1illustrates some KPIs that can be useful in assuring theeffectiveness of the PQS for PACs. Alternative KPIsmay be used as deemed appropriate by Quality andsenior management.

The Role of Quality Culture in Enabling PQSEffectiveness

For sustained effectiveness, the PQS needs to be em-bedded in the company’s quality culture—a set of

Figure 1

PQS elements relevant for PAC and examples of related KPIs.

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shared values, beliefs, and behaviors that supportproduct quality—and patient-centric decision-making.

A company can achieve the desired quality culturewhen its management clearly demonstrates leadership,commitment, and engagement of the entire organiza-tion. In this environment, management shares a com-mon vision, fosters transparent, open and “no-blame”communication throughout the company based ontrust, and invests in employee education and trainingto ensure a proficient and knowledgeable workforce.Employees engage in activities that emphasize qualityperformance and continual improvement across allfunctional areas, and a rewards and recognition pro-gram drives the desired quality culture with a strongfocus on the patient.

Organizational changes can affect company cultureand thus affect PQS effectiveness. Changes in seniorleadership; major organizational changes such asmergers, acquisitions, or joint ventures; or changes inbusiness or governance models can generally result incultural changes. When companies undergo thesechanges, the potential impact on PQS effectivenesswill need to be considered, assessed, and appropriatelyaddressed.

Conclusion

The U.S. FDA Office of Pharmaceutical Quality’sWhite Paper: FDA Pharmaceutical Quality Oversight,One Quality Voice identified one of the challenges forregulators:

The number of post-approval supplements re-ceived for review has increased over the pastdecade, in part owing to our current practiceof “locking in” an applicant’s manufacturingprocess before it is fully optimized. A bur-densome regulatory framework requires man-ufacturers to submit supplements as theystrive for process optimization (4).

ICH Q10 —Annex 1 offers a solution to this challenge,recognizing that potential opportunities for risk-basedregulatory approaches exist and can be leveraged toreduce regulatory burden. An effective PQS providesan appropriate framework— one grounded in science-and risk-based decisions and knowledge manage-ment—to determine which PACs do not require priorapproval and could be handled solely within the com-pany’s PQS, potentially without prior notification.

ICH Q12, Technical and Regulatory Considerationsfor Pharmaceutical Product Lifecycle Management,proposes that several PACs can be managed in thePQS, or via “do and tell” notification, without the needfor regulatory approval prior to implementation (3).Based on the PQS framework described in ICH Q10,this paper describes elements specifically related toeffectiveness of the PQS in managing such PACs.

The regulatory framework for PACs needs to be sim-plified globally, allowing companies to innovate; con-tinually improve their processes, methods, and facili-ties; and ensure product quality and availability. PDAbelieves that industry is responsible for effectivelymanaging products through their entire lifecycle. Es-sential to that undertaking is ensuring that the PQSeffectively covers many PACs that currently requireregulatory approval prior to implementation or notifi-cation. This change of focus will enable industry toachieve the desired state described in FDA’s “Pharma-ceutical Quality for the 21st Century Initiative” andfurther articulated by Dr. Janet Woodcock, director ofFDA CDER, of a “maximally efficient, agile, flexiblemanufacturing sector that reliably produces high-qualityproducts without extensive regulatory oversight” (5).

Glossary

Change Management: A systematic approach to pro-posing, evaluating, approving, implementing, and re-viewing changes (ICH Q10).

Continual Improvement: Recurring activity to en-hance performance (ISO 9001:2015).

Control Strategy: A planned set of controls, derivedfrom current product and process understanding, thatassures process performance and product quality. Thecontrols can include parameters and attributes relatedto drug substance and drug product materials andcomponents, facility, and equipment operating condi-tions, in-process controls, finished product specifica-tions, and the associated methods and frequency ofmonitoring and control (ICH Q10).

Enabler: A tool or process that provides the means toachieve an objective (ICH Q10).

Established Conditions: The description of the prod-uct, manufacturing process, facilities and equipment,and elements of the associated control strategy, asdefined in an application, that assure process perfor-

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mance and quality of an approved product (Draft FDAGuidance on Established Conditions, May 2015).

Established Conditions for chemistry, manufacturing,and controls are legally binding information defined inan approved Marketing Authorization Application(MAA).

Innovation: The introduction of new technologies ormethodologies (ICH Q10).

Knowledge Management: Systematic approach to ac-quiring, analyzing, storing, and disseminating infor-mation related to products, manufacturing processes,and components (ICH Q10).

Management: Coordinated activities to direct andcontrol an organization. Management can include es-tablishing policies and objectives, and processes toachieve these objectives. The word managementsometimes refers to people, i.e., a person or group ofpeople with authority and responsibility for the con-duct and control of an organization (ISO 9001:2015).

Organization: Person or group of people that has itsown functions with responsibilities, authorities, andrelationships to achieve its objectives (ISO 9001:2015).

Performance: Measurable result. Performance can re-late either to quantitative or qualitative findings. Per-formance can relate to the management of activities,processes, products, services, systems, or organiza-tions (ISO 9001:2015).

Performance Indicators: Measurable values used toquantify quality objectives to reflect the performanceof an organization, process, or system, also known asperformance metrics in some regions (ICH Q10).

Pharmaceutical Quality System (PQS): Manage-ment system to direct and control a pharmaceuticalcompany with regard to quality (ICH Q10 based onISO 9000:2005).

Product Lifecycle: All phases in the life of a productfrom the initial development through marketing untilits discontinuation.

Product Realization: Achievement of a product withthe quality attributes appropriate to meet the needs ofpatients, health care professionals, and regulatory author-

ities (including compliance with marketing authoriza-tion) and internal customers’ requirements (ICH Q10).

Post-approval Change Management Protocol(PACMP): A regulatory tool that enables planning offuture change(s). It describes the change(s) an appli-cant/Marketing Authorization Holder (MAH) wouldlike to implement during the lifecycle of a product,how these would be prepared and verified, includingassessment of the impact of the proposed CMCchange(s), and the proposed (usually lower) reportingcategory in line with regional requirements. ThePACMP also identifies specific conditions and accep-tance criteria to be met.

Process Capability: Ability of a process to realize aproduct that will fulfill the requirements of that prod-uct (ISO 9001:2015).

Quality: The degree to which a set of inherent prop-erties of a product, system, or process fulfills require-ments (ICH Q9).

Quality Risk Management: A systematic process forthe assessment, control, communication, and review ofrisks to the quality of the drug (medicinal) productacross the product lifecycle (ICH Q9).

Risk: The combination of the probability of occur-rence of harm and the severity of that harm (ICH Q9,ISO/IEC Guide 51).

Senior Management: Person(s) who directs and con-trols a company or site at the highest levels with theauthority and responsibility to mobilize resourceswithin the company or site (ICH Q10 based in part onISO 9001:2015).

State of Control: A condition in which the set ofcontrols consistently provides assurance of continuedprocess performance and product quality (ICH Q10).

Conflict of Interest Declaration

The authors declare that they have no conflicts of interest.

References

1. Quality Guideline Q10: Pharmaceutical QualitySystem; International Conference on Harmonisation:Geneva, Switzerland, 2008 [http://www.ich.org/products/guidelines/quality/article/quality-guide-lines.html (accessed August 28, 2016)].

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2. PDA Points to Consider: Technical Product Life-cycle Management: Communication and Knowl-edge Exchange between Marketing AuthorizationHolders and Health Authorities. PDA J. Pharm.Sci. Technol. (accepted article January 2017)[journal.pda.org (accessed January 23, 2017)].

3. Quality Guideline Q12: Technical and RegulatoryConsiderations for Pharmaceutical Product Life-cycle Management, concept paper and businessplan; ICH: Geneva, 2014.

a. Concept paper: [http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q12/Q12_Final_Concept_Paper_July_2014.pdf (ac-cessed December 2016)].

b. Business plan: [http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/

Q12/Q12_Final_Buisness_Plan_July_2014.pdf(accessed December 2016)].

4. White Paper: FDA Pharmaceutical Quality Oversight,One Quality Voice; Office of Pharmaceutical Quality,U.S. Food and Drug Administration, U.S. GovernmentPrinting Office: Washington, DC, 2015 [http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM442666.pdf (accessed January 6, 2017)].

5. Final Report on Pharmaceutical cGMPs for the 21stCentury—A Risk Based Approach; U.S. Food andDrug Administration, September, 2004 [http://www.fda.gov/downloads/drugs/developmentapprovalprocess/manufacturing/questionsandanswersoncurrentgoodmanufacturingpracticescgmpfordrugs/ucm176374.pdf (accessed January 23, 2017].

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