Qb d & new process validation guidance


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Qb d & new process validation guidance

  1. 1. FOCUS ON... ComplianceQuality By Design and the NewProcess Validation GuidanceA Report from IBC’s BiopharmaceuticalDevelopment and Production Weekby Cheryl ScottW here were you in 1987, and and the one it replaces, with which what were you doing? I’m everyone should by now be very not too embarrassed to say familiar. that I was beginning mylast year of high school and paying far FDA Sessionmore attention to guitar lessons and During the Monday morning plenarywriting my first novel than what I session on 14 March (shared withmight eventually do for a career. IBC’s sixth annual “TechnologyMeanwhile, the US FDA was Transfer for Biopharmaceuticals” andpublishing a guidance document on seventh annual “Outsourcingprocess validation that the Manufacturing of Biopharmaceuticals”biopharmaceutical industry has relied meetings), three FDA representativeson ever since. I’m willing to bet that literally phoned in their teleconferencequite a few readers of this issue presentations on the Office ofweren’t yet working in the industry at Biological Products (OBP) pilotthat time either — and one or two program for QbD (Patrick Swann,could even have been in the New OBP’s deputy director), the concept ofEngland crowd with me at a Def Analytical laboratories like this one at Roche continuous verification (GraceLeppard concert that year. are vital to process validation. (www.roche.com) McNally, consumer safety officer at A lot has happened since then in the Center for Drug Evaluation and the while, your main source forthe United States: four different Research’s division of manufacturing answers about the FDA’s expectationspresidential administrations dealing and product quality), and risk-based regarding process validation has stayedwith wars and major economic boom- approaches to process understanding the same. It was all about testing,and-bust cycles, a huge federal budget and control (Mansoor Khan, director instrument qualification, and processdeficit turned into a surplus and then of CDER’s division of product quality robustness and repeatability. Nowinto an even larger deficit, the growth research). Anyone who attends a west- finally, as of January 2011, the agencyof the Internet from a niche military/ coast conference has come to expect has finalized an updated guidance (2)academic application to a ubiquitous less FDA participation than can be to bring process validation into theand vital personal and business tool, had on the east coast, so their long- modern era of risk management andand the dawn of a new millennium. distance session was a welcome quality by design (QbD).Biopharmaceutical manufacturers saw addition to the program. It is only fitting, then, that thethe end of the establishment license Pilot Program: The OBP launched primary focus of IBC’s 15th annual(ELA) and product license application its QbD pilot program for biotech “Process and Product Validation”(PLA) processes, the rise of the products in July 2008 with two conference (part of “Biopharmaceuticalbiologics license application (BLA), streams, one for new molecular Development and Production Week”)the birth of the well-characterized entities at the investigational new in Bellevue, WA, 14–15 March 2011biologic, dozens of product approvals drug (IND) or BLA stage and the was the similarities and differences(1), and the coming of biosimilars. All other for postapproval-stage between this new guidance document14 BioProcess International May 2011
  2. 2. Other Guidance Documents The International Conference on Harmonisation of Technical ICH Q10: Pharmaceutical Quality System was adopted by the Requirements for Registration of Pharmaceuticals for Human European Union in July 2008, by the United States in April 2009, Use (ICH) brings together regulatory authorities and and by Japan in February 2010 after the tripartite harmonized pharmaceutical companies from Europe, Japan, and the United ICH guideline had been finalized in June 2008. This document States to discuss scientific and technical aspects of drug applies to pharmaceutical drug substances and drug products registration. Since its inception in 1990, ICH has worked through (including biotechnology and biological products) throughout its global cooperation group to harmonize the increasingly their lifecycles. Companies should apply its elements global face of drug development. Its mission is to help ensure appropriately and proportionately to each stage. The guideline that safe, effective, and high-quality medicines are developed can be downloaded online at www.ich.org/fileadmin/Public_ and registered with the most efficient use of resources. The Web_Site/ICH_Products/Guidelines/Quality/Q10/Step4/Q10_ organization focuses on four main subjects: quality, safety, Guideline.pdf. efficacy, and multidisciplinary guidelines, which include the Other Documents: Real-world experiences of companies and MedDRA standardized medical terminology guide and the regulators with the Q8, Q9, and Q10 guidelines made ICH aware common technical document (CTD), a format for submitting of a need for some clarification of key issues. The latest version information for regulatory review in all participating countries. of its resulting questions-and-answers document was finalized ICH celebrated its 20th anniversary in 2010 (www.ich.org/ in November 2010 and can be downloaded online at www.ich. fileadmin/Public_Web_Site/News_room/C_Publications/ org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/ ICH_20_anniversary_Value_Benefits_of_ICH_for_Regulators. Quality/Q8_9_10_QAs/Q-IWG_QAs_Step4/Q8_Q9_Q10_ pdf ). In relation to process validation, four ICH subtopics are Question_and_Answer_R4_step_4_November_2010.pdf. most relevant: Q8, Q9, Q10, and Q11. ISPE has published a guidance document that’s free for its ICH Q8(R2): Pharmaceutical Development was adopted by members and available to nonmembers at a nominal cost: ISPE the European Union in June 2009, by the United States in Product Quality Lifecycle Implementation Guide: Overview of November 2009, and by Japan in June 2010, after having been Product Design, Development and Realization — A Science- and finalized in November 2005. This document is intended to Risk-Based Approach to Implementation. International Society for provide guidelines for drug products as defined in the scope of Pharmaceutical Engineering: Tampa, FL, October 2010; www. Module 3 of the common technical document (CTD), which is ispe.org/ispepqliguides/overviewofproductdesign. According to ICH topic M4. The guideline does not apply to contents of ISPE:, the guide is “the first in a series of product quality lifecycle submissions for drug products in clinical research, but its implementation good practice guides that will describe principles are important to consider during that stage. An annex enhanced, QbD approaches to product realization and is an to the tripartite harmonized ICH text was finalized in November introduction to and an overview of the guides series.” To address 2008 and incorporated into the core document, which was then product and process development, transfer to and renamed Q8(R1). That annex provided further clarification of establishment of commercial manufacture using science- and key concepts and described the principles of QbD. It showed risk-based approaches, the series will cover critical quality how concepts and tools (e.g., design space) outlined in the attributes (CQAs) and critical process parameters (CPPs), design parent document could be put into practice. When a company space, and control strategy. applies QbD and quality risk management (ICH Q9, see below) In addition, ASTM International has published a standard that as part of a pharmaceutical quality system, opportunities arise supports ICH Q8 and Q9 titled ASTM E2537-08: Standard Guide to enhance science- and risk-based regulatory approaches (as for Application of Continuous Quality Verification to described in ICH Q10, see below). The Q8 guideline was revised Pharmaceutical and Biopharmaceutical Manufacturing. According to (R2) in the summer of 2009 to reflect minor corrections, and to ASTM, “The accumulated product and process understanding it can be downloaded online at www.ich.org/fileadmin/Public_ used to identify critical quality attributes (CQAs), together with Web_Site/ICH_Products/Guidelines/Quality/Q8_R1/Step4/Q8_ the knowledge that the risk-based monitoring and control R2_Guideline.pdf. strategy will enable their control, should provide confidence to ICH Q9: Quality Risk Management was adopted by the show validation of each batch manufactured — as opposed to a European Union in January 2006, by the United States in June conventional discrete process validation effort.” 2006, and by Japan in September 2006 after the tripartite ICH Q11: Development and Manufacture of Drug harmonized ICH guideline was finalized in November 2005. This Substances was endorsed as a topic by the ICH Steering guideline provides principles and examples of tools for quality Committee in April 2008. This new guidance is proposed for risk management that can be applied to all aspects of active pharmaceutical ingredients (APIs) harmonizing the pharmaceutical quality including development, manufacturing, scientific and technical principles relating to the description and distribution, and inspection and submission/review. It can be justification of the development and manufacturing process applied throughout the lifecycle of drug substances and (common technical document sections CTD S2.2–S 2.6) of drug medicinal products, biologicals, and biotechnological products substances including both chemical and biotechnological/ and covers the use of raw materials, solvents, excipients, biological entities. The document is only at stage 1 of the ICH packaging, and labeling materials. The document can be process currently, and a concept paper can be found at downloaded at www.ich.org/fileadmin/Public_Web_Site/ICH_ www.ich.org/fileadmin/Public_Web_Site/ICH_Products/ Products/Guidelines/Quality/Q9/Step4/Q9_Guideline.pdf Guidelines/Quality/Q11/Concep_Paper/Q11_Concept_Paper.pdf.16 BioProcess International May 2011
  3. 3. molecules. The pilot program has which falls into line with ICH Q8provided an opportunity for the (see the “Other Guidance” box).biopharmaceutical industry and the During early product and processFDA to evaluate and identify best development, process design buildspractices for key QbD elements of criteria for testing, qualification, andtarget product profiles, critical quality setting specifications later on. “Theattributes (CQA), risk assessment, commercial manufacturing process isprocess characterization for design- defined during this stage based onspace definition, CQA-focused control knowledge gained throughstrategies, and expanded change development and scale-up activities” Enhance Cell Productivityprotocols. This builds on the concept (2). Process qualification encompasses Enhance Cell Productivity Deliver Scalable Resultsof well-characterized biologicals (a.k.a. many validation concepts familiar to Deliver Scalable Reproducible Make Processes Resultsspecified biologics), which came about in those who have been working with thethe late 1990s when it was recognized previous guidance document all along: Make Processes Reproduciblethat analytical methods had improved Manufacturing equipment, tooling,to the point at which biologics could and instrumentation, and utilitiesbe analyzed and described well must be qualified using standardenough to separate their identities validation protocols along with an Please visit us at:from their processes, at least associated validation master plan, risk ESACT 2011 Please visit us at:somewhat (3–5). A few years later, assessment, and requirements ESACT 2011 Vienna 15 – 18 May,CDER took over responsibility for specifications. “During this stage, the 15 – 18 May, Booth #216 Viennathose well-characterizable products process design is evaluated to Booth #216from the Center for Biologics determine if the process is capable ofEvaluation and Research (CBER). reproducible commercial The OBP pilot program offers manufacturing.” (2).individualized examination of QbD Continued process verification, theinitiatives submitted in market final stage, was the focus of Graceapplications for biotech therapies for a McNally’s presentation. “Ongoingnumber of original and supplemental assurance is gained during routinebiologic license and new drug production that the process remains inapplications. Manufacturers — such a state of control” (2). McNallyas Genentech, an early program emphasized the “life-cycle approach”participant — voluntarily provide that makes process validation anchemistry, manufacturing, and ongoing activity — not something acontrols (CMC) information in an company can do and then move on.expanded change protocol describing “Criticality” (as of quality attributes) istheir implementation of QbD and risk a continuum, she pointed out, not anmanagement. Their candidate either–or question. McNally alsoproducts are monitored by trhe OBP pointed to several other sections of thethroughout product development and Code of Federal Regulations that cantesting after early discussions with help those working to implement theseFDA reviewers about R&D issues. concepts into their manufacturing process development: 21 CFR Part For the pilot, the Office of 100a, 110a, 110b, 160b3, 165a, 165d, Compliance (OC) will be part of 180e, 211.42, 211.63, and 211.68. review communication, so there is a need to transfer information among Panel Discussion OBP, OC, and the field. Ideally, Parallel Bioreactor Systems for Unparalleled Results. After the FDA presentations, we product reviewers should be present Parallel Europe Bioreactor Systems for Unparalleled Results. followed session chair Victor Vinci at initial QbD-type inspections. +49 2461 Europe 9800 (director of purification development The Office of Compliance will play info@dasgip.de +49 2461 9800 and viral safety in bioproduct R&D, a key role in understanding the role info@dasgip.de US East Coast LRL, at Eli Lilly & Co.) to a smaller of quality systems in QbD filings +1 800 531 9462 US East Coast ballroom for process validation biotools@dasgip.com and their control strategies. (6) +1 800 531 9462 strategies and case studies from biotools@dasgip.com US West Coast Continuous Verification: According Acceleron Pharma, Amgen, +1 510 799 6105 US West Coastto Swann, the new guidance describes Genentech, Hospira, MSD Biologics, tombruggman@dianovainc.com +1 510 799 6105three stages of process validation and Pfizer. The next day — along tombruggman@dianovainc.comduring the lifecycle of a drug product, with sessions covering analytical
  4. 4. Figure 1:  QbD development and product lifecycle (7); no temporal relationship is intended Prior Clinical Animal In Vitro Input Material Controls Knowledge Studies Studies Studies Process Controls Co nt i nu o u s Pr o ce ss Ve r i fi c at i o n High-Criticality Attributes Procedural Controls Control Strategy Elements Safety and (1) Quality attributes Efficacy Data to be considered Process Parameter and/or controlled by Controls the manufacturing Process Process process Targets for Development Design Testing Product Criticality and Quality Space Quality Assessment (2) Acceptable Characterization In-Process Testing Attributes Attributes ranges for quality attributes to ensure drug Specifications safety and efficacy Characterization and Attributes that do not Comparability Testing need to be considered or controlled by the Process Monitoring manufacturing process Low-Criticality Attributes PR O D U C T U N D E R S TA N D I N G PR O CE SS U N D E R S TA N D I N Gmethods validation and transfer and associated with every unit operation in pudding is not in the first three bites,”drug product validation from the a manufacturing process. Calcott emphasized. “It’s eating theAmerican Society for Quality, Repetto told us that mature whole thing.”Amgen, Centocor (Johnson & companies have in recent years done A company must be able toJohnson), Genentech, Hyde “a pretty thorough job” of integrating adequately explain and defend theEngineering, Novartis, Pfizer, and risk management and QbD into their choices that it makes. “It’s the data,”ProBioGen — we were treated to a process validation activities. But not said Repetto, “not the number of lots.”fascinating panel discussion with every company can employ dozens of For some, three lots may be enough; forVinci, Robert Repetto (Pfizer’s statisticians and risk experts so may be others, thee may not be anywhere neardirector of external affairs), and less experienced with the new science enough; and for companies with a greatconsultants Peter Watler (Hyde and risk based approach. The one- deal of process knowledge andEngineering and Consulting) and time rule of thumb for running three understanding about its platformPeter Calcott (Calcott Consulting). verification lots is no longer so process three runs may be more than is Calcott said that process validation straightforward; it depends on the necessary. “I can foresee a day whenis transitioning “from a check-box level of product and process routine periodic oversightactivity to value-added.” Everyone knowledge the company has acquired demonstrating ongoing process control,emphasized the interplay between raw from development studies. could become a more valuable tool tomaterials, process controls, and final “Is this a new paradigm?” Watler the agencies than coming in to inspectoutcomes (drug products). The new asked. “I hope it is; we really do need everything at one time.guidance documents what thought- one.” He and others emphasized that An audience member commentedleaders have talked about for a few three lots run early in the lifetime of a that such an approach seems to lendyears now: the team-oriented, life- product cannot be expected to itself well to products that aren’t scaledcycle approach linking QbD and represent its process a decade later — very large (e.g., personalized medicineproduct/process development with risk or beyond. The new guidance and higher-titer production, high-assessment. Calcott described a “four document is not prescriptive; it is a concentration formulations), forDs” approach: design (for standard framework for conversations between example with the commercial scalerequirements), demonstrate (by companies and the FDA, as well as similar to that of clinical trial materialexperimenting), document (using among departments and colleagues production. “For this approach to workgood science and good manufacturing within those organizations. Caldwell you need development data that ispractice, GMP), and determine (with warned that such conversations, representative of your full scale process.ongoing monitoring). The old DQ/ however, can end up pushing product If that can’t be done for a uniqueIQ/OQ/PQ approach doesn’t licensing later as the agency asks for production system you will still need todemonstrate process; equipment more information — unless a demonstrate process control, so yourfunction is barely half the story. There company begins with the necessary process validation plan would reflectare raw materials and inputs, process data and understanding to keep that the lower level of process knowledge. ”controls, and product attributes from happening. “The proof of the said Repetto. As companies move18 BioProcess International May 2011
  5. 5. • gather with QbD helps you make QbD — can happen without those decisions,” Watler added. knowledgeable analytical personnel But Calcott emphasized, “Don’t using dependable equipment to gather data for data’s sake.” There perform robust and reproducible “QbD is not only should be a purpose behind annual laboratory methods behind the the buzzword product reviews, trend charting, and manufacturing scenes. for 2011, but it other scheduled reviews; companies A presentation from Keith A shouldn’t continually “tweak” their Davis, a busy senior scientist from represents a major processes based on every little issue. Pfizer’s bioprocess characterization step forward in the Only real problems should be and analytical support laboratory in way FDA regulates addressed with process changes: St. Louis described several therapeutics. QbD Remember, you’ll have to justify these technological advances that have things to regulators with good science improved productivity and the quality will make a huge and common sense. of data his laboratory can gather. difference in product “As we learn more about these Cross-trained groups of analysts such safety for years to products and molecules,” Repetto said, as Davis described are increasingly come.” —Nancy “we’ll know better how to proceed.” tasked with supporting development And Calcott pointed out that the very of robust manufacturing processes. Chew, MS, RAC, nature of a CQA as critical makes it Among the vendors and instruments FRAPS important to investigate every he thanked for stepping up to help associated failure and issue related to them succeed are it. Over time, however, “clinical • the Octet platform from ForteBio experience may lessen the importance “for accurate, rapid MAb titerforward, they’ll have to be looking at or criticality of some CQAs.” In the determination,” which formerlythe overall process picture through early days of process validation, involved protein A high-performancetrending and base their decisions on Repetto reminded us, a company liquid chromatography (HPLC) ordata. The A-Mab case study published might never know or care whether enzyme-linked immunosorbent assaysby CASSS was identified as a good something shifted within (ELISAs)example of modeling for predictability specifications. With continued process • ProA PreDictor plates from GE(7). monitoring, “it may be something you Healthcare for MAb sample “I think the agency can get past want to look at.” By studying trends preparation using protein Ahaving things set in stone,” said over time, companies may be able to purificationCalcott, and let companies use data discover real problems earlier than • the Processor Plus automated geland science to explain why they they might have otherwise — early staining and blot processing system,shouldn’t be right away. Experience at enough to prevent process failures, also from GE Healthcarelarge scale shows that things may need product losses, and expensive mistakes. • the iBlot dry blotting systemadjusting as time goes on. Those from Invitrogenworking with platform technologies — The Importance • Nanodrop spectrophotometrice.g., monoclonal antibodies (MAbs) — of Analytical Methods products from Thermo Scientificget a head start because they have lots After the “Process and Product • Kingfisher-96 systems (also fromof data to begin with. Validation” final sessions focused on Thermo Scientific) for automated What about continuous analytical methods validation and DNA extraction and qPCR analysisverification? That’s a major focus of transfer, IBC’s inaugural “Analytical • HPLC systems from Agilentthe new guidance. If a process Technologies for Biopharmaceutical Technologies for amino-acid analysischanges over time, will its critical Development” meeting packed a small • The BioScale ViBE bioanalyzerquality attributes (CQAs) do so as hall on 16–18 March, often with some for host-cell protein and protein Awell? For now, there’s no easy answer. attendees standing in the back of the quantitation“How we choose CQAs will be in room. With the new process • SpotFire data managementflux as we figure out how to interpret validation paradigm, it’s never been software.these guidances,” said Watler. (ICH more apparent just how vital process Critical quality attributes, as PaulQ11, “Development and Manufacture analytical technologies (PATs), Motchnik of Genentech described inof Drug Substances” is only at the statistical design of experiments, his presentation the morning offirst stage of international work, so it bioassays, and data management are to Wednesday 16 March 2011, arestill has a ways to go.) If an the success of a biotherapeutic product identified through analytical testingopportunity to change a process arises in development. None of the defining, with a solid basis in platform(e.g., biosimilar competition) a evaluating, trending, and monitoring knowledge and scientific literature.company will certainly want to revisit described in the new guidance — and Tools such as multidimensionaleverything. “All the knowledge you all the other documents relating to chromatography (discussed by Methal20 BioProcess International May 2011
  6. 6. Albarghouthi of MedImmune), As always, the first place youhydrogen-deuterium exchange with should go is to the guidance documentmass spectrometry detection (described itself. But we hope to offer up someby Steven Berkowitz of Biogen Idec), expert advice in our pages over the Westfalia Separator® capitalcareisoelectric focusing (explained by Brian months (and years) to come.Hosken of Genentech), miniaturized Comprehensive Protectionimmunoassays (presented by Mats Acknowledgments for Your InvestmentInganäs of Gyros AB in Sweden), I’m grateful to Peter Calcott, Nancy Chew (Regulatory Affairs, North America, Inc.),microchip assays (addressed by Xiaoyu Robert Repetto, Victor Vinci, and Peter WatlerChen of Novartis), laboratory for their review of this report.automation (the focus of presentationsby Martin Vanderlaan of Genentech Referenceand Susanne Demarco of Pfizer), and 1 Scott C. US-Approved Recombinantnew-era mass spectrometry (reported Cell Culture Products, 1980–2010. BioProcesson by several speakers to close out the Int. 7(10) 2009: supplemental wallchart.Analytical Technologies meeting on 2 CDER/CBER/CVM. Guidance forFriday 18 March 2011) are helping Industry: Process Validation — General Principles and Practices. US Food and Drugcompanies answer the questions Administration: Rockville, MD, January 2011;regulators will ask when it comes time www.fda.gov/downloads/Drugs/for product review. GuidanceComplianceRegulatoryInformation/ A New Way of Thinking: When I Guidances/UCM070336.pdf. You are pursuing a clear objectiveworked for BioPharm magazine in the 3 CDER/CBER. Guidance for Industry: with your investments: a high levellate 1990s, I remember numerous Content and Format of Investigational New Drug of performance at minimum cost. Applications (INDs) for Phase 1 Studies of Drugs,discussions of the confusion over We have customized our range of Including Well-Characterized, Therapeutic,terminology: The word validation only Biotechnology-Derived Products. US Food and services to take full account of thisapplied to processes, whereas throughout the entire life cycle Drug Administration: Rockville, MD, of your centrifugal technology.qualification applied to November 1995; www.fda.gov/downloads/ Westfalia Separator ® capitalcare isinstrumentation, and neither would Drugs/GuidanceComplianceRegulatory Information/Guidances/UCM071597.pdf. the modern, appropriate responseapply to products themselves. to your growing needs for process 4 CBER/CDER. Guidance for Industry:Design qualification (DQ ), installation efficiency and availability of your Changes to an Approved Application for Specifiedqualification (IQ ), operational quali- Biotechnology and Specified Synthetic Biological plant. Our tailor-made servicefication (OQ ), and performance qual- Products. US Food and Drug Administration: products mean you benefit fromification (PQ ) — none of these appear Rockville, MD, July 1997; www.fda.gov/ the competence and experience ofin the new guidance. Repetition of the downloads/Drugs/GuidanceCompliance the technology leader: RegulatoryInformation/Guidances/phrases process qualification and product UCM124805.pdf. Field servicevalidation illustrates the fact that in 5 Apffel A, et al. Application of New Original spare partsmany ways, this is a whole new world. Analytical Technology to the Production of a Repairs Peter Watler told me after the “Well-Characterized Biological.” Dev. Biol. Condition monitoringmeeting that he heard Grace McNally Stand. 96, 1998: 11–25. Trainingmake a specific point that the IQ/ 6 Mire-Sluis A, et al. Quality by Design: Service level agreementsOQ/PQ/DQ terms were industry The Next Phase: Potential Regulatory Applied consulting Implications and Filing of QbD Data.terminology rather than the FDA’s. “I BioProcess Int. 7(1) 2009: 34–42.have certainly heard folks make an 7 CMC Biotech Working Group. A-Mab:issue out of the terminology,” he said, A Case Study in Bioprocess Development. CASSS, Your direct route to 24 / 7 service:“which is really quite silly. The focus an International Separation Science Society: www.westfalia-separator.com / serviceshould be on what a study says, not Emeryville, CA; www.casss.org/associations/ pdf. •about what it is called. And the FDA 9165/files/A-Mab_Case_Study_Version_2-1.is clear on this. This has caused somein industry to divert validation effortsaway from a scientific understanding Cheryl Scott is senior technical editorto strict adherence of terminology and of BioProcess International.protocol. Fortunately the newguidance does away with thatnonsense so industry can put resources To order reprints of this article, contact Liquids to Valueinto science and understanding rather Rhonda Brown (rhondab@fosterprinting.com) 1-800-382-0808. Download a low-resolutionthan protocol and definitions.” PDF online at www.bioprocessintl.com. GEA Mechanical Equipment GEA Westfalia Separator Group Werner-Habig-Straße 1 · 59302 Oelde (Germany) SE-2-60-002 Phone +49 2522 77-0 · Fax +49 2522 77-2089 www.westfalia-separator.com