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Qb d for biologics
Qb d for biologics
Qb d for biologics
Qb d for biologics
Qb d for biologics
Qb d for biologics
Qb d for biologics
Qb d for biologics
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Qb d for biologics

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  • 1. FOCUS ON... QUALITYQbD for BiologicsLearning from the Product Development and Realization(A-MAb) Case Study and the FDA OBP Pilot Programby Steve Kozlowski, Wassim Nashabeh, Mark Schenerman, Howard Anderson,Ilse Blumentals, Kowid Ho, Rohin Mahtre, Barbara Rellahan, and Victor Vinci,with Lorna McLeodC osponsored by CASSS (an case study and sponsors participating international separation in the FDA Pilot Program provided society) and the FDA, the detailed QbD examples to form the 23rd CMC Strategy Forum basis for workshop discussions. Awas held in Bethesda, MD, on 19–20 number of questions were presented asJuly 2010. For the third time, this a basis for discussion, and they appearforum explored the topic of quality by in bold throughout this text.design (QbD) for biologics. The firstsuch forum was held in July 2007 and Critical Qualityfocused on establishing a general Attributes (CQAs)understanding of QbD terminology In assessing attribute criticality, toand concepts. In July 2008, the second what extent is it appropriate to applydiscussed approaches for submission of prior knowledge from similar-classQbD data and associated regulatory molecules to a new product? When is itimplications. Building on those appropriate to leverage company-previous QbD forums, this third specific and literature information?forum extended the discussion from Leveraging prior knowledge is“what” to “how.” The program particularly valuable at the earliestcommittee intended to cover detailed stages of development before you’veimplementation strategies and had a chance to gain molecule-specificpractical key QbD elements that are www.photos.com data in early development. Priorreadily achievable in the short term. knowledge of molecular structure at In addition, this forum would Group. The companies involved were early stages is useful for highlightingcombine key learning from two Abbott Laboratories, Amgen, specific product variants you need toimportant QbD industry–FDA Genentech, GlaxoSmithKline, Eli look for and targeting the types ofcollaborations: the A-MAb Case Lilly and Company, MedImmune, analytical methodology required toStudy and the FDA OBP Pilot and Pfizer. To ensure free public assess them. As long as its strengthsProgram. The pilot program is still in access and further promote the and weaknesses are understood,its early stages but nonetheless industry-wide discussions that led to information is valuable wherever itprovides concrete examples of the its creation, they provided its case comes from.types of exchange of ideas between study to CASSS and ISPE. Find it Keep in mind that, althoughsponsors and regulators. The case online at www.casss.org/ general assumptions can be madestudy on applying QbD principles in associations/9165/files/Case_Study_ about class-specific attributes (e.g.,development of a monoclonal antibody Press_Release.pdf. MAb terminal heterogeneity),represents the culmination of a two- This forum was set up as three inevitably some molecules will notyear effort by a consortium of workshops covering quality attributes, follow the rules. The value of generalbiotechnology companies collectively design space (DS), and control assumptions depends on the depthknown as the CMC-Biotech Working strategies. Authors of the A-MAb that knowledge can reach — how18 BioProcess International 10(8) S eptember 2012
  • 2. specific it is to your particular There was also discussion about The CMC Strategymolecular structure/function. For which parts of a QbD submission Forum Seriesexample, what about its glycoform constitute regulatory commitmentsstructure does or does not affect Fc The CMC Strategy Forum series and what can be handled through areceptor binding? provides a venue for biotechnology and company’s pharmaceutical quality Is the biotech industry still excited biological product discussion. These system (PQS). There is no definitive meetings focus on relevant chemistry,about QbD, or are anxiety and answer. Early and frequent manufacturing, and controls (CMC)frustration replacing excitement? consultations with regulators are issues throughout the lifecycle of suchInstead of managing risk, are we products and thereby foster recommended, and “negotiations” withbecoming more risk-averse? Some collaborative technical and regulatory the agency are to be expected.consensus was reached that QbD is a interaction. The forum committee In setting and justifying acceptablegood idea in theory, but there is still strives to share information with ranges for CQAs, what information iswork to be done in clarifying what it is regulatory agencies to assist them in required? When are preclinical dataand how it is best used. Although the merging good scientific and regulatory sufficient, and when are clinical dataidea is to have a DS within which practices. Outcomes of the forum required? The value of preclinical datachanges can be made without formally meetings are published in this peer- depends on the animal model used.reporting them to regulators, it appears reviewed journal with the hope that Questions that need to be asked they will help assure thatat present that more documentation regard its relevance to humans, biopharmaceutical products(rather than less) is probably needed. whether the ligand/target has the manufactured in a regulatedAs one regulator pointed out, “If we environment will continue to be safe same properties as in humanshad total trust in a DS, we wouldn’t and efficacious. The CMC Strategy (including PK and PD effects). Howneed regulatory agencies.” Forum is organized by CASSS, an does the disease state in humans affect It was generally agreed that we International Separation Science how you interpret and use the data?need an adaptable way of assessing Society (formerly the California Do immunogenic responses in animalsreportability criteria with a common Separation Science Society), and is affect your evaluation? Although anunderstanding of what needs to be cosponsored by the US Food and Drug advantage of preclinical testing is inprovided, both in a filing and in terms Administration (FDA). exposing animals to purified variants,of changes. How much can be clinical data are still the gold standardhandled by a company’s quality pharmacokinetics (PK) or as long as patient variabilitymanagement system (QMS), or pharmacodynamics (PD) often considered. Extracting product frompharmaceutical quality system (PQS) depends on a number of factors: e.g., serum samples is very valuable andaccording to ICH Q10? How much the scope and significance of class- informative for PK.documentation will ensure regulators’ specific knowledge and the availability However, the utility of clinical datacomfort level? of meaningful models. Other factors for PD depends on available markers As far as enthusiasm goes, it was to consider are different dosing (e.g., increasing blood-cell levels arenoted that QbD needs to have regimens (e.g., intravenous or easier to measure than tumor size/s orinherent value to a company to make subcutaneous), chronic or single overall survival). Again, althoughit worthwhile. It is a good, progressive dosing, patients’ disease state general assumptions can be made (e.g.,idea, but companies need to including whether patients are MAb terminal heterogeneity),understand its value to them and see it immunosuppressed, and so forth. inevitably a case will arise withmaking sense from both science and When changing a molecule’s molecule-specific differences, andbusiness perspectives to maintain their indication, you must revisit your CQA ranges for those will need to beenthusiasm. Regulatory relief (one of risk assessment. justified. CQA ranges depend onQbD’s original drivers) is still a future This question remains: At what manufacturing process capabilities,prospect. point can we accept an attribute as patient populations, dose strategies, How much additional molecule- noncritical for all class-specific and so on. It seems difficult to justifyspecific information would be molecules? Regulators are at present a single range for a particular CQArequired to support an assessment reluctant to allow such an assumption across a whole class of molecules; onlybased on prior knowledge? It is across the board, so justification is DNA and endotoxins seem to haveunlikely that the criticality of quality required case by case. One participant achieved that from a safetyattributes for a given molecule will be put it very succinctly: “Literature and perspective. However, it appears thatidentical to that of another molecule. knowledge can be a wealth of data if the CQA risk-assessment tool nowSo it is worthwhile in investigating the data are relevant to your used across the industry is seen as anthe unique aspects of a molecule to molecule.” Proving that literature is effective mechanism for incorporatingconfirm assumptions about “class- relevant is important for the comfort prior knowledge. But “noncritical” orspecific” knowledge. Whether to of regulators and for ensuring that “less critical” QAs must still becheck all relevant attributes while your product is truly safe and considered in relation to CPPs andlooking at their effects on efficacious. their related control strategy with20 BioProcess International 10(8) S eptember 2012
  • 3. justification as to how they were Forum Cochairs As in previous QbD forums, thereconsidered (not forgotten). is still a good deal of uncertainty Kowid Ho discussed how the Steve Kozlowski (director of the office of about terminology. ICH Q8R defines biotech products at FDA/CDER inEuropean Union (EU) PAT team is QbD as “a systematic approach to Bethesda, MD)and is not implementing QbD development that begins withconcepts. One complication in Europe Wassim Nashabeh (global head of predefined objectives and emphasizes technical regulatory policy and strategyis the existence of two entities — the product and process understanding at Genentech, a member of the RocheCouncil of Europe and the European and process control, based on sound Group, in South San Francisco, CA)Union — which include different science and quality risk management.” Mark Schenerman (vice president ofcountries and do not always agree Some commenters consider that analytical biochemistry at MedImmuneabout issues related to drug definition to be too vague. In in Gaithersburg, MD)applications. The European Medicines addition, there is still a wide range ofAgency (EMA) represents the EU’s 27 working definitions of CQAs,member nations and has taken on the greater numbers of smaller lots early in particularly at the earliest stages oftask of regulating how drugs can move development. Using lots enriched for a development. One company calls themacross national borders. So the answer specific variant early in development is “provisional” CQAs; other terms haveto “what is required” can vary another route toward understanding been discussed at previous forums. Itdepending on which agency is involved. QA criticality. However, keep in mind is difficult to work within definitions In setting and justifying acceptable whether you can justify patient you aren’t clear about.CQA ranges, what information is exposure to potentially negative affects What aspects should be consideredrequired? How does stability fit in? resulting from levels of attributes when assessing interactions betweenStability must be considered for beyond what is normally designed into quality attributes? Can the interactioncomparing levels of attributes present dose-escalation studies. of noncritical attributes render themat time zero with those that may How does a company broaden CQA critical? What information would bechange over time until expiry. Thus ranges based on safety and efficacy required to establish an absence ofpatient exposure to end of expiry considerations? The assumption is interactions? You could use the DS ofmaterial must be considered when that a “critical quality attribute” will fermentation, for example, to get anestablishing ranges (especially if used affect safety and efficacy. So you have idea of the true “DS” in relation toin clinical studies). You also must to understand at what point an effect relative levels of QAs being producedaccount for the appearance of new is relevant to patients (e.g., aggregates). before needing extensive interactionattributes as a product degrades over Shed light on this question by studies of QAs that are nottime, which could necessitate adding leveraging preclinical and clinical realistically manufactured at differentquality attributes (and setting an serum samples for detecting variant levels by your process. Some attributesappropriate ranges) to your clearance over time and for on their own may not appear criticalpreliminary quantitative risk maximizing assessment of dose- but then interact and become critical,assessment (PQRA) that are not ranging studies. Linking QA levels to although no specific examples werepresent at time zero. immunogenicity, safety, and efficacy is mentioned. You can use forced In setting and justifying acceptable challenging. Most current clinical degradation to create high levels of aCQA ranges, what information is studies are not designed to link particular QA (e.g., oxidation) andrequired? How do we reconcile the specific levels of attributes to patient examine its impact on another (e.g.,value of establishing broader clinical outcomes. If possible, strategies for aggregation) to determine whetherexposure to product variants with the better correlating quality attributes their interaction is raising thegoals of product development, which and clinical data would be valuable. criticality level. It will require creatingcontinually drives toward Epitope mapping can be useful if a range of purified molecules withcomparability, consistency, and higher you see an immune response. By each QA at specified levels and testingpurity? Producing “more variable” introducing increased levels of them in animals or in vitro (if feasible)product lots early in development can attributes into an appropriately to show a lack of impact on PK/PDprovide patient exposure information powered preclinical study, you can (and maybe safety). But that can beand help you understand the impact of discover what levels have an effect. extremely costly and time consuming.different levels of attributes on PK/ Relevant in vitro studies can showPD (and maybe safety). But such limits that do or do not affect PK/PD Design Spacevariability may not reflect commercial (e.g., Fc receptor binding, potency What types of information/dataprocess capability, especially at the assays, and so on). Data derived from can be used to define a DS (e.g.,time of licensure, although it may be the clinic may lead to attempts to manufacturing data, design ofimportant for future changes and reduce the levels (or strengthen experiments, platform/priorprovides for an expanded CQA “DS.” control) of a given attribute if the link knowledge)? Manufacturing data fromThere is, of course, an increase in cost of safety/efficacy to a QA can be made pilot-scale runs, engineering runs, andand time associated with producing after the original risk assessment. full-scale clinical and/or commercial22 BioProcess International 10(8) S eptember 2012
  • 4. runs can be used in defining DS. commitment, but those are filed in the Program Planning CommitteeDesign of experiments (DoE) and development section. Companies mustprocess characterization are also Howard Anderson (biologist in the consider ranges for parameters notuseful, as is platform or prior division of therapeutic proteins at FDA/ included in a DS. At some point, aknowledge including both internal CDER in Bethesda, MD) process/parameter can be great enoughand published (external) data. Ilse Blumentals (director of global to have an impact, even if it is veryFormulation development will yield regulatory affairs at GlaxoSmithKline in extreme. Such ranges may be based onuseful data, as will stability and King of Prussia, PA) limits that have been tested beyondcomparability studies. All those Kowid Ho (quality assessor at AFSSAPS normal operations — “knowledgeproduct-related data should be in Saint Denis Cedex, France) space” — although justification ofincluded in assigning criticality to Rohin Mahtre (vice president of wider ranges may be based on priorquality attributes. biopharmaceutical development at knowledge. Literature should be used carefully. Biogen Idec, Inc. in Cambridge, MA) After much discussion aboutIn-house data are more valuable than Barbara Rellahan (product quality team handling non-CPPs, non-CQAs, andpeer-reviewed published literature leader in the division of monoclonal all things noncritical, one audiencebecause they can be backed up and antibodies at FDA/CDER in Bethesda, MD) member asked whether we trulytheir history verified. The quality of Victor Vinci (director of purification believe in our risk-assessment tools —data in published papers varies development and viral safety at Eli Lilly and if so, why are we so worried aboutsignificantly. Conclusions based on & Company in Indianapolis, IN) what is not critical. However,literature, in-house or otherwise, regulators are concerned about theshould be confirmed for a new universal definition may not be concept of a “limitless DS” andmolecule. Some assumptions can be possible. There is concern that the complete lack of control for elementsmade safely, particularly for a platform definition of criticality depends heavily deemed noncritical. One commenterproduct. But anything unexpected on the operating range studied. summed up the industry’s stance:must be investigated. Changes beyond that particular Although the QbD paradigm provides Should a DS consist of CPPs only, or operating range need to be managed for noncritical quality attributes,should noncritical parameters be appropriately. nothing is left to chance. Everythingincluded? When might the latter be Someone commented that “DS is is well-controlled and monitoredappropriate? DS should include all not defined by CPPs alone. Assurance because that’s good science andrelevant parameters required for of quality defines DS. Regardless of common sense.assurance of product quality, not just the risk assessment instruments, What actions should be taken if aCPPs. If a DS were based solely on terms, or definitions you use, your DS unit operation response is not asCPPs, defining them would require a must provide an acceptable level of expected either at pilot ormuch greater level of understanding. If assurance that it will produce safe, manufacturing scale? This may meanyou include some control of non-CPPs efficacious drug product — and that that prior knowledge of the function— or include them somehow into the your QMS will adequately handle all or operation of a given unit and/or itsDS — then data requirements may be movements within the DS.” impact on the product is incorrect. Itlower. If the DS includes CPPs only, Someone else mentioned that to depends on the stage of developmentthen a thorough data package will be diminish and eventually eliminate at which this occurs. The earlier suchneeded to convince regulators that you “endless negotiations” regulatory a deviation occurs, the more likely itscan ignore controls or inclusion of agencies, the industry must come to impact can be rectified easily. Late-non-CPPs. But non-CPPs should still some common understandings of stage failures or unexpected resultsbe controlled in a manufacturing definitions, requirements, and so forth may require a more comprehensiveprocedure; it is how they are — and we are not there yet. evaluation of assumptions and data onmonitored, what their ranges are, how Experience is the only way to get which DS (or process understanding)deviations are dealt with, and so forth there, and companies willing to garner is based. In either case, all datathat will be different. Because each that experience are paving a road for relating to a unit operation should becompany can use different risk- the rest of the industry. reassessed in light of the failure.acceptance profiles to define How should companies handle Depending on those results, other unitcriticality, it will be difficult for parameters that are not included in operations, risk assessments, or processregulators to accept a risk assessment the DS? Do we apply an infinite range? quality attribute (PQA) assessmentswithout in-depth review. Parameters not included in a DS might need revisiting. It is still unclear how to should be controlled within the overall DS, many forum participantsdifferentiate between a statistically quality system. Examples include stressed, is an iterative process. It issignificant CQA effect from a manufacturing parameters (MPs), bound to change as more data arepractically significant impact. That process monitoring, change control collected and the knowledge spacedetermination currently appears to be assessments, risk assessments, and so increases. It is desirable to identifyin the eye of the beholder, and a forth. That’s not a regulatory necessary changes early in the process, S eptember 2012 10(8) BioProcess International 23
  • 5. of course, but it is possible that justification of small-scale–model there should be a continuous processsituations will occur such as the failure qualification against large scale. The verification protocol, changeof a unit operation at pilot or DS description applies only to the area management protocol or stabilitymanufacturing scale. At a minimum, in which a CQA is affected. You protocols. But you do need toall data then would have to be should describe the linking of demonstrate that your DS model isreassessed. individual steps across your process to not affected by a particular change. How might a DS change across the ensure CQA control. One person asked how regulatorslife cycle of a product? What types of It is still unclear exactly what deal differently with a “regular BLA”new information could identify a new parameters to include in a filing (the compared with one based on QbD.DS limit? Knowledge gained over time CPP and non-CPP argument) and Regulators said that they are stillduring development can influence how much detail: Should non-CPP figuring that out. So far, they areassumptions or back up existing data limits be tested?. However, we do looking very closely at QbDin modifying a DS — either know that process steps with DS are applications because they sometimesexpanding or contracting it. Processes part of license claims with parameter seem ambiguous, and regulators’ levelnearly always undergo change, and ranges and mathematical models. We of comfort requires close scrutiny. Onenew or altered processes can provide don’t yet know whether to include criterion specifically mentioned is thenew data that influence the DS: e.g., graphical representations and/or data clarity of the CQA and CPPcomparability data, stability data, and summaries. We need to ensure a definitions used in a filing. ICHtesting at different limits/conditions. balance between more data required Q8-R2 defines both terms, andAdditional manufacturing, preclinical, and flexibility for change without regulators are most comfortable withor clinical data could enhance product reporting — and discern data for sponsor definitions that hold closest toknowledge, turning CQAs into non- filing from data to be available on those ICH definitions. However, RonCQAs or vice versa. Process/product inspection. Taticek pointed out in hisimpact may become evident with more Your description of manufacturing presentation, “It is not clear how tomanufacturing experience at scale. and process controls should be filed in interpret the ICH definition of critical How can DS modifications be filed Section 2.2. Again, there are still process parameters: A CPP is athroughout the life cycle of a product? questions about what to include and parameter that has both a statisticallyIt depends on when the DS is initially where: CPPs, non-CPPs; CQAs, non- significant and a practical (nontrivial)“fixed.” If changes are made between CQAs. What must be included in the impact on the CQAs.”then and the license application, then DS description? How much detail Regulators will also look closely atthose changes would be described in needs to be included about input ranges and the strength of data usedthe marketing application (MA), variables, process parameters, and to support them. Are noncriticalbiologics license application (BLA), or QAs covered by DS and about input parameters still within the ranges youother filling. Should changes occur material controls and process controls? actually studied? If not, how can youafter approval, then filing them should Should you include model be sure that they are still noncritical?be related to the extent and type of representations, equations, and/or a How do you propose to handlechange (annual report, changes-being- combination of ranges? noncritical parameters and qualityeffected, prior approval supplement, Control of materials (Section 2.3) attributes after approval? What do youtype II, or type I variations). This should include detailed input material propose to cover in your QMS, andfiling strategy can be preapproved in a controls and CQAs for starting what is reportable? Again, theprotocol as part of the market materials. Control of critical steps and consensus among regulators seems toauthorization and built into the intermediates (Section 2.4) should be, “It depends. . .” Constrainingquality system. A common include input controls. Development CPPs would be less cause forunderstanding is needed — in the (Section 2.6) will need to include regulatory alarm than expanding themUnited States and elsewhere — of development strategy, CQA and CPP but might still cause regulatorywhat must be submitted in regards to selection, QRM, prior knowledge, concern.description of the QMS and how that DoE, multi- and univariate analysis, How can movement at the edges ofwill influence the need to file design- lot and process history, and a DS be justified/implemented (e.g.,space modifications. comparability. Process validation and/ “adaptive” control strategy or or evaluation (Section 2.5) should statistically justified)? Statistical limitsRegulatory or Submission Impact include evaluation of operating units, can be bound into a DS (e.g.,How should the DS be described in a storage/hold times, column lifetime, statistical boundaries and CPKs) tosubmission? Your DS description must compatibility, viral safety, and so provide a level of confidence whenprovide justification of parameter forth; evaluation of DS, validation, approaching edges of DS. When at itsscoring from the risk assessments used and confirmation of consistency (in limits, the qualification of small-scaleto design process characterization process and end product); and models (with edges defined) is evenexperiments, including data on how movement toward continuous process more essential. You could increasedecisions were made. It should include verification. It is unclear as to whether testing as you approach the DS edges24 BioProcess International 10(8) S eptember 2012
  • 6. to assure product quality. Not all minimum to keep the agency as “sterile” might be included in aedges are equal; some may be a cliff, informed. If a deviation reveals that a license, but all the details of achievingothers just a gradual difference, so non-CPP is in fact a CPP, then the and maintaining sterility would not bestatistical limits can be applied as DS and other related systems (e.g., included. The intent of “sterility” isappropriate. A QMS may treat risk, small-scale model qualification) met through environmentaldifferent excursions differently would need revising through a QMS monitoring and personnel practices asdepending on their potential product change-control procedure. well as validation and testing. So theimpact. You could file a strategy What role does the quality system output (sterility) is a regulatorydescribing how such excursions would play in approaching CPPs and non- commitment; it doesn’t describe everybe handled (more studies, based on CPPs regarding planned movement detail of how that is to beexisting knowledge, risk assessment, within the DS or approved protocol? A accomplished.and so on) or how a QMS will deal QMS should be able to handle What is the role of the QMS inwith uncertainties associated with movement within an approved DS approaching CPPs and non-CPPs aftermovement near the edges. through preapproved enhancements to approval? How should a system A DS system is asymmetric. A such systems as change control or manage and document oversight ofchange near the middle might have process monitoring that ensure the continuous monitoring process,greater or less effect on the resulting appropriate documentation, process and how should processproduct than the same change near control, and product monitoring to improvements or optimization bethe boundaries. Although the prevent shifts in process capability or implemented and communicated toassumption at filing is that a sponsor product quality. Obviously the level of the agency? A QMS can be enhancedknows the CQAs for a given product, change management will be different to include improved processuncertainty remains. Could the for non-CPPs than for CPPs as far as monitoring (e.g., holistic monthlysponsor be missing “the rest of the how the system handles movement product review), statistical trending,iceberg?” Negotiations with regulators (level of assessment, testing data and appropriate actions should trendsshould be expected with a QbD filing required, postchange monitoring, be found. Such enhancements can beuntil their comfort level has increased reportability, and so on). A non-CPP filed. The management of processwith the process and a sponsor’s movement beyond the range that improvement filings can be predefinedability to work within it. defined its criticality would require as part of change control depending enhanced scrutiny. Perhaps a defined on the level of change; they can alsoQMS and Life-Cycle Implications limit to movement within a range be filed (e.g., as part of a changeWhat is the role of a QMS in (e.g., 50%) would be a compromise to protocol). But could Section 2.2approaching critical and noncritical allowing totally free movement. include a commitment to update DSprocess parameters, especially in Aspects of the QMS enhancements equations, for example, through anregard to deviations or excursions? A required can be filed whereas others annual product review (APR)?QMS change-management program is are made available on inspection. We discussed a number ofessential to assure both a Forum participants brought up a questions, including what level ofmanufacturer and regulators that number of specific testing methods changes within acceptable rangeschanges within a DS will be dealt and discussed their desired frequency, might require reporting. The guidancewith appropriately and may not have specificity, and other questions. ICH indicates that “nontrivial, significant,to be reported (or can be reported in a Q1D (Bracketing and Matrixing and impactful” changes should bereduced category). Deviations and Designs for Stability Testing of New reported, which industry considers tooexcursions should be dealt with Drug Substances and Products) makes vague. So questions remain. Onenormally, with enhancements required clear that many factors need to be person suggested that such changesto ensure adherence to a DS and/or taken into account when designing might be included in Section 2.5.expanded change protocols (eCPs). complex testing strategies. TheThe effect of a deviation on a information necessary for regulators to Control Strategy,non-CPP may not require the same accept such approaches in designing a Life-Cycle Managementlevel of investigation as deviation to a QbD control strategy remains unclear. How would control strategies lookCPP depending on the nature of the Again, the industry generally different for traditional and QbDdeviation (e.g., within the knowledge agrees that non-CPPs and non-CQAs submissions? A QbD control strategyspace). This is not too different from will be controlled within a QMS. is based on a holistic, comprehensivethe current system of going within or Questions remain as to what becomes assessment of the criticality of qualitybeyond validation limits. part of the regulatory commitment attributes, linking that to how they Deviations that require DS revision and what does not — and thus what affect a process and defining process(either shrinking or expanding) may requires a report to the agency and controls and product testing to assurerequire some sort of a filing (level what does not. quality, safety, and efficacy. Thedetermined according to the type of Someone pointed out that under strategy includes risk assessments,change) to “reapprove” it or at a the current paradigm, attributes such prior knowledge, and enhanced26 BioProcess International 10(8) S eptember 2012
  • 7. molecule and process understanding to immunogenicity operating space for a Permanent Advisoryleverage preclinical and clinical data vaccine? In determining a vaccine’s Committee for These Forumswith testing capabilities. So in-process immunogenicity operating space, youcontrols, specifications (product and Siddharth Advant (Imclone) need to understand how the molecularraw materials), and stability programs John Dougherty (Eli Lilly and Company) fragments and three-dimensionalwill be based on criticality of quality Christopher Joneckis (CBER, FDA) structure truly affect the immuneattributes and probably be more system — e.g., stimulating only what Rohin Mhatre (Biogen Idec Inc.)streamlined, with fewer items (or we want to because we want a natural, Anthony Mire-Sluis, chair (Amgen, Inc.)fewer with high stringency) than a protective immune response. Thattraditional approach. Wassim Nashabeh (Genentech, a may require designing additional A QbD control strategy should Member of the Roche Group) studies to further examine how theconsider how unit operations affect Anthony Ridgway (Health Canada) product works. You may need to goproduct across the manufacturing Nadine Ritter (Biologics Consulting beyond the traditional potency assayprocess (and interactions among those Group, Inc.) to better characterize and predictoperations). A QbD control strategy Mark Schenerman (MedImmune) response. Immune response ismoves control to the process for Keith Webber (CDER, FDA) certainly a biomarker for vaccines, butdelivering high-quality product — it may not reflect efficacy. Anrather than testing quality into a understanding of patients’ responses toproduct. This control strategy also however, it is up to a sponsor (once its a vaccine is also important. It seemsincludes the concepts of continuous product has been approved) to decide clear that QbD can be applied toverification (e.g., increased whether and when a movement within vaccines and that it is important tomultivariate analysis) and continuous a DS should be reported. But the know how to manufacture the productimprovement. This is the life-cycle agency is uncomfortable with that and and how it works. Ensuring aapproach. The strategy would will request reports when inspectors continuous supply for vaccines is noinevitably include more data and deem it necessary. So a clear and different than for any other product.justification in process understandable guidance is still What studies would be needed tocharacterization, process control, and needed; so far, Q11 does not appear to justify an “immunogenicity operatingjustification of specifications sections be it. Someone asked whether and space” for a therapeutic protein, forof a filing. A QbD control strategy how it might be rewritten to provide which immunogenicity is undesirable?also needs to deal with different levels useful guidance for both regulators First and foremost it is necessary toof uncertainty for a DS. and industry. understand what actually causes How would parameters that are What additional considerations — immunogenicity for a particularunspecified in the license be handled, beyond criticality of a given attribute product. You can use epitope mappingand what is the agency’s involvement? — factor into control strategy of antibodies to identify where in aUnspecified parameters such as development? An attribute that molecule they bind. It can also beprocess monitoring, change control, indicates process consistency (e.g., useful to monitor which lot of materialand noncriticals should be handled by glycosylation) but cannot be easily each patient gets and to control thea QMS. How that system deals with measured through another parameter levels of quality attributes those lotsthose parameters (noncritical process may need to be considered as part of get — and take into account patient-parameters, inputs and outputs, and process monitoring or on specific responses (e.g., majorquality attributes) can be described in comparability, but not necessarily in histocompatibility complexa filing or be made available on routine lot release or stability. An contributions). You can use preclinicalinspection. attribute that provides data about the or nonclinical studies to understand We recommend an annual report as ability to supply patients (e.g., yield) the immunogenic potential of yourthe best way to report such changes. would require some form of product (e.g., in silico or in vivoOne regulator asked, “If validation assessment (in-process). testing). A thorough understanding ofand DoE have been done and included Are the FDA’s eCPs and the product variants and process-relatedin the filing, why does the agency European Union’s postapproval impurities is necessary, and all priorneed to see that again in an annual change management protocols knowledge could prove useful.report?” Another stated that (PAMPs) the same? If not, what are the Several elements of QbD can bemovement within a DS is not a key differences? Because both eCPs applied across multiple product typeschange, so there is no need to and PAMPs are very new, we don’t yet and associated systems. Whatcommunicate that to the agency. know what their key features will be essential components can be appliedAnother, however, pointed to or how they will be implemented. most generally? Some essential“cascading uncertainty” at the edges components include planning andand was of the opinion that changes QbD for Other Products design (e.g., molecule design,toward those edges should be What challenges would come in equipment, and facility), executionreported. According to guidelines, justifying the described (training, clear SOPs, streamlined28 BioProcess International 10(8) S eptember 2012
  • 8. processes/methods), monitoring (e.g., and specific regulatory risks including questions — such as defining CQPs,statistical process control and patient population and indication. The CPPs, and DS — are beginning to getmultivariant analysis), continuous framework might also include material answered. The answers are becomingimprovement (e.g., corrective and demand: Will treatment be chronic or more consistent across projects andpreventative actions), and risk acute, high or low potency, and does it companies. Plenty of work remains toassessments. Some elements of QbD involve high or low plant use? be done, but our progress is clear andare becoming regulatory expectations. Global acceptance of QbD by inspiring. •Forum participants mentioned that we regulators is one barrier to holistichave been doing “QbD light” for years implementation. How are companies Steve Kozlowski is director of the office of(e.g., process/product interactions, managing global filings? The two biotech products at FDA/CDER in Bethesda,criticality of in process controls) and options expressed at the forum were MD; Wassim Nashabeh is global head ofthat CGMP is an expectation (better essentially producing two different technical regulatory policy and strategy atjustification for reassessment of files or “file all data and wait for Genentech, a member of the Roche Group,specifications and in-process controls, questions.” in South San Francisco, CA; Markrisk assessments, good science, and What are the main concerns Schenerman is vice president of analyticalcommon sense). companies have in implementing biochemistry at MedImmune in What elements of QbD appear to be QbD? Although it certainly benefits Gaithersburg, MD; Howard Anderson is athe most difficult, costly, and/or time molecular design and process biologist in the division of therapeutic proteins at FDA/CDER in Bethesda, MD;consuming? Forum participants development, companies worry about Ilse Blumentals is director of globalmentioned DoE, data accumulation, QbD’s effect on time and expense of regulatory affairs at GlaxoSmithKline inand reporting of DS as potential developing products. They wonder King of Prussia, PA; Kowid Ho is a qualitybarriers. Multiple risk assessments are whether QbD will really allow for assessor at AFSSAPS in Saint Denis Cedex,clearly time-consuming. Another more rapid development if platform France; Rohin Mahtre is vice president ofbarrier is developing extensive eCPs knowledge is applied. Some people are biopharmaceutical development at Biogenrather than one-off comparability concerned that questions from Idec, Inc. in Cambridge, MA; Barbaraprotocols. Because QbD is not globally regulators will increase as more data Rellahan is product quality team leader inaccepted, using it can lead to different are provided in filings. Companies the division of monoclonal antibodies atfilings in different jurisdictions, which wonder whether the cost and time of FDA/CDER in Bethesda, MD; Victor Vinci iscan be both costly and time QbD will be recognized from a cost of director of purification development and viral safety at Eli Lilly & Company inconsuming. However, QbD is still goods perspective as opposed to a Indianapolis, IN. Lorna McLeod is aworthwhile. Many aspects of it are better process and product contributing editor for BioProcessvery cost effective — molecular design understanding. Will QbD have Internationaland CQA understanding, for example inherent value to the industry? Does it— and can be applied by companies actually prevent multiple failures thatregardless of size, product, or process. might occur under the traditional Disclaimer How are companies making approach? Are QbD-based products of The content of this manuscript reflectsdecisions over how much (if any) QbD better quality than before? Concern discussions that occurred during thewill be applied to a particular product, continues to be focused around DS, CMC Strategy Forum workshop inespecially considering early phase, efforts to create it, and what addition to personal viewpoints andlate-phase, and licensed products? For regulatory and/or QMS relief will experiences of the authors. Thisreasons such as attrition of molecules come (if any). document does not represent officiallythrough development and the cost and Apart from process and product, on sanctioned FDA policy or opinions andtime to carry out specific aspects of what other applications can QbD have should not be used in lieu of publishedQbD, it may not be financially viable an impact? The answers to this FDA guidance documents, points-toto apply to all molecules. We need to question include equipment design, consider documents, or direct discussions with the agency.establish a strategic framework to implementation, and execution;guide the circumstances in which to facility design and utilities; rawapply QbD. Such a framework might materials; containers; transport; andinclude probability of success based on QMSs. To order reprints of this article, contactknowledge of the biological pathway, Rhonda Brown (rhondab@fosterprinting.com)availability of clinical data, and Advancing with Caution 1-800-382-0808. Download a low-resolutionmarket position. It might also include Although many questions remain, PDF online at www.bioprocessintl.com.process/product complexity, taking collaborations between the FDA andinto account whether or not you are industry are bringing QbD ever closerworking with a platform, whether to realizing the potential of buildingyour drug product is lyophilized or quality into biopharmaceuticalliquid, whether you are working with products rather than controlling itan established or a new technology, after development. Many early S eptember 2012 10(8) BioProcess International 29

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