Meeting Report

Advancing Product Quality: a Summary of the Second FDA/PQRI Conference

Lawrence X. Yu,1,20 Ilgaz Akseli,2 Barbara Allen,3 Gregory Amidon,4 Tara Gooen Bizjak,1 Ashley Boam,1

Margaret Caulk,1 David Doleski,1 Joseph Famulare,5 Adam C. Fisher,1 Scott Furness,1 Brian Hasselbalch,1

Henry Havel,6 Stephen W. Hoag,7 Robert Iser,1 Bruce D. Johnson,8 Robert Ju,9 Paula Katz,1 Emanuela Lacana,1

Sau L. Lee,1 Richard Lostritto,1 Grace McNally,1 Mehul Mehta,1 Ganapathy Mohan,10 Moheb Nasr,11

Roger Nosal,12 Mary Oates,12 Thomas O’Connor,1 Jim Polli,7 G. K. Raju,13 Mahesh Ramanadham,1

Giuseppe Randazzo,1 Susan Rosencrance,1 Anna Schwendeman,4 Arzu Selen,1 Paul Seo,1 Vinod Shah,14

Ramesh Sood,1 Michael P. Thien,10 Tony Tong,15 Bernhardt L. Trout,16 Katherine Tyner,1 Siva Vaithiyalingam,17

Martin VanTrieste,18 Fionnuala Walsh,3 Russell Wesdyk,1 Janet Woodcock,1 Geoffrey Wu,1 Larisa Wu,1

Louis Yu,9 and Diane Zezza19

Received 25 November 2015; accepted 16 January 2016; published online 9 February 2016

INTRODUCTION

The purpose of the Conference on Advancing ProductQuality, under the sponsorship of the Food and DrugAdministration (FDA) and Product Quality Research Insti-tute (PQRI), is to bring regulators, industry professionals,

and academic researchers together to create a synergizedpath toward enhanced global pharmaceutical quality. The2015 FDA/PQRI Conference consisted of a plenary sessionand 20 breakout sessions arranged in four major tracks: (i)emerging regulatory initiatives; (ii) regulatory submission,assessment, and inspection; (iii) product and process devel-opment; and (iv) manufacturing, risk management, andquality assurance. This report provides a summary of theplenary session followed by each topic, as presented at theconference.

PROGRESS AND CHALLENGESIN PHARMACEUTICAL QUALITY

The FDA regulates pharmaceutical drug products toensure an uninterrupted supply of high-quality, safe, andeffective drugs in the USA. The FDA’s vision is to promote amaximally efficient, agile, and flexible pharmaceuticalmanufacturing sector that reliably produces high-qualitydrugs without extensive regulatory oversight (1). Over thepast decade, we have seen significant progress toward thisvision. However, at the same time, we have encountered newand increasingly complex challenges, which include unaccept-able drug shortages, recalls, and threats to supply quality andreliability. The plenary session and related discussion coveredthe progress and challenges from regulatory, industry, andtechnology perspectives.

Regulatory Progress and Challenges

Since the 2014 FDA/PQRI inaugural Conference onEvolving Product Quality (2), the FDA has made significantprogress in advancing product quality by:

1 Food and Drug Administration, Center for Drug Evaluation andResearch, Silver Spring, MD 20993, USA.

2 Boehringer Ingelheim, Ridgefield, CT 06877, USA.3 Eli Lilly and Company, Indianapolis, IN 46225, USA.4University of Michigan, Ann Arbor, MI 48109, USA.5Genentech/Roche, 1 DNA Way, South San Francisco, CA 94080,USA.

6Havel Biopharma LLC/Nanomedicines Alliance, Indianapolis, IN46220, USA.

7University of Maryland, Baltimore, MD 21201, USA.8 Perrigo Company plc, Allegan, MI 49010, USA.9Abbvie, North Chicago, IL 60064, USA.10Merck and Company, Inc., West Point, PA 19486, USA.11 GlaxoSmithKline, Washington, DC 20001, USA.12 Pfizer, Inc, Eastern Point Road, Groton, CT 06340, USA.13 Light Pharma Inc., Cambridge, MA 02142, USA.14 PQRI, Arlington, VA, USA.15 Teva Pharmaceuticals USA, 223 Quaker Rd, Pomona, NY 10970,USA.

16Massachusetts Institute of Technology, Cambridge, MA 02139,USA.

17 Teva Pharmaceuticals USA, 425 Privet Road, Horsham, PA 19044,USA.

18 Amgen, One Amgen Center Drive, Thousand Oaks, CA 91320,USA.

19 Novartis, East Hanover, NJ 07936, USA.20 To whom correspondence should be addressed. (e-mail:

lawrence.yu@fda.hhs.gov; )

The AAPS Journal, Vol. 18, No. 2, March 2016 (# 2016)DOI: 10.1208/s12248-016-9874-5

5281550-7416/16/0200-0528/0 # 2016 American Association of Pharmaceutical Scientists

& Formally documenting quality risk management inthe quality assessment of abbreviated new drugapplications (ANDAs), biological license applications(BLAs), and new drug applications (NDAs);

& Developing and implementing team-based integratedquality assessment that incorporates review, inspec-tion, policy, research, and surveillance;

& Publishing draft guidance (e.g., on quality metrics,established conditions, dissolution, BCS-basedbiowaivers, and botanical drug development);

& Approving the first drug product utilizing a continu-ous manufacturing process, the first drug productutilizing 3D-printing and the first biosimilar;

& Streamlining question-based review underpinningquality-by-design principles for both NDA andANDA applications.

Of course, the most significant advancement was theformation of the Office of Pharmaceutical Quality (OPQ) inthe FDA’s Center for Drug Evaluation and Research. Standingup, OPQ is a milestone in the FDA’s efforts to assure thatqualitymedicines are available to theAmerican public (3). OPQis organized to streamline regulatory processes, advance regu-latory standards, align areas of expertise, and inaugurate thesurveillance of drug quality. Supporting these objectives is aninnovative and systematic approach to product quality knowl-edge management and informatics. Concerted strategies willbring parity to the oversight of innovator and generic drugs aswell as domestic and international facilities. OPQ promotes andencourages the development and adoption of emerging phar-maceutical technologies to enhance the pharmaceutical qualityand reinvigorate the pharmaceutical manufacturing sector in theUSA. This also applies abroad for drug product and APImanufactured for theU.S. pharmaceutical market.With amottoof BOne Quality Voice,^ OPQ embodies the closer integrationand alignment of review, inspection, surveillance, policy, andresearch for the purpose of strengthening pharmaceuticalquality on a global scale.

Industry Progress and Challenges

Two key dimensions to product quality are supply chainquality and reliability. A lack of drug safety and supplycontinuity is often attributable to quality issues. Solutions toresolve these quality issues can be general or product specific.The general solution focuses on improving the quality riskmanagement, pharmaceutical quality systems, and businessprocesses. Product-specific solutions focus on processes,modalities, and platforms, as well as operational andtechnical/analytical considerations.

Quality does not happen in isolated Bpockets,^ rather itis built end-to-end and is continually challenged (as shown inFig. 1). Quality consists of four phases: plan, source, make,and deliver. The Bplan^ phase includes processes that balanceaggregate demand and supply to develop a course of actionthat best meets sourcing, production, and delivery require-ments. This phase is critical to meeting the needs of the targetpatient population. Despite the comprehensive nature ofquality, the pharmaceutical industry may well need to designsolutions by industry segment. For example, a one-size-fits-allmodel may increase the risk of supply interruption in certain

industry segments. Processes are needed to collaborativelypredict demand and move to a model that incorporatesreplenishment based on true demand instead of forecast.Unfortunately, compared to other manufacturing industries,the pharmaceutical industry has generally poorly integrateddemand into the plan phase (4).

The Bsource^ phase includes processes that procure goodsand services to meet planned or actual demand. The age of aUS-centric, vertically integrated, life science industry has, for themost part, come to an end (5). In the past decade, sourcing andmanufacturing have moved overseas in an effort to lower costs.With these changes, however, came increasing demand onpharmaceutical manufacturers to manage and control theirsupply chains, which are now longer and more complex. Thepharmaceutical industry often fails to incorporate critical aspectsof suppliers (i.e., original manufacturers, shippers, distributors,contract manufacturers, and suppliers) into their internalperformance networks (e.g., specification alignment). Theindustry has insufficient knowledge of its suppliers with respectto quality and reliability, which often contributes to productrecalls and drug shortages. The common practice is to conductperiodic audits of suppliers, which are not sufficient. There is anurgent need to develop metrics to evaluate and monitor thequality and reliability of suppliers.

The Bmake^ phase consists of processes that transformproduct to a finished state to meet planned or actual demand. Arecent survey by Rita C. Peters from the biopharmaceuticsindustry has shown that Quality by Design (QbD) has improvedthe process understanding (68.4%), improved product quality(66.7%), and reduced variability in product quality (57.9%) (4).Nearly half of the industry reported improved manufacturingefficiency as a result. However, almost 32% of the respondentshad not implemented QbD. Reasons cited for not implementingQbD include a lack of guidance and direction from regulatoryagencies (46.2%), no process or quality advantage to be gained(30.8%), a lack of understanding of the QbD initiative (23.2%),or the perception that it is too costly. Other factors includeprocess robustness, quality risk management maturity, increasedproduct complexity, and lack of international harmonization ofregulations.

The Bdeliver^ phase consists of processes that providefinished goods and services to meet planned or actualdemand, typically including order management, transporta-tion management, and distribution management. The chal-lenges in this stage include supply chain security, productintegrity in transition, and distribution information visibility.

Overall, the pharmaceutical industry needs to internalizethe concept that Bholistic reliability^ (i.e., the ability of a supplychain to consistently deliver) is a critical part of quality. Qualityis not just about process and method. It is also about visibility,information, predictability, and the systems to manage them.The ability to improve reliability comes both from systemicimprovement and product-specific improvement. On the whole,the pharmaceutical industry’s challenges are not unique. Othermanufacturing industries have addressed similar challenges andtheir successes can be leveraged.

Technology Progress and Challenges

Drug makers have used cutting-edge science to discovermedicines, but they have manufactured them using

529Advancing Product Quality: a Summary of the Second FDA/PQRI

techniques dating to the days of the steam engine (6).Pharmaceutical manufacturing processes are falling behindother industries in terms of technology and efficiency. Now,the industry is moving toward a major upgrade from batch tocontinuous production (7) (see also Fig. 2). Under the newapproach, raw materials are fed into a single, continuouslyrunning process. Many other industries adopted such acontinuous approach years ago, because quality can bechecked without interrupting production. This leads to weeksshaved off production times and significant cuts in operatingexpenses. Until recently, pharmaceutical companies havemanufactured drugs the old-fashioned way, mixing ingredi-ents in large vats and in separate steps, often at separateplants, with no way to assess quality until each step is finished.

The significant benefit of a continuous process is theintegration of chemical operation and formulation into onesolution, allowing a constant, fully automated process inwhich raw materials are introduced at one end and productscome out the other. The FDA, once viewed as a potentialobstacle to manufacturing innovation, is actively promotingand supporting moves to continuous processes. The FDA,seeing an opportunity to improve the overall quality andreliability of drug manufacturing, began pushing for suchchange in 2004 (1). Indeed, in 2015, the FDA approved thefirst new drug application that contains a continuousmanufacturing process (8).

During the plenary session, Bernhardt Trout presentedthe first example of an end-to-end, integrated continuousmanufacturing plant for a pharmaceutical product from hisgroup at MIT (9). It starts from a chemical intermediate andperforms all intermediate reactions, separations, crystalliza-tions, drying, and formulation, which results in a formed finaltablet in one tightly controlled process. This plant provides aplatform to test newly developed continuous technologieswithin the context of a fully integrated production system. Inaddition, this plant provides a means to investigate thesystem-wide performance of multiple interconnected units.

In summary, significant progress has been made byregulators, industry, and academia to support and advanceproduct quality. With the creation of OPQ, the acceptance

of QbD by industry, and the technological advancementsin continuous manufacturing processes, the stage is set todeliver pharmaceuticals of unprecedented quality to theAmerican public. If quality is promoted, designed, andbuilt appropriately, this will be a truly rewarding endeavorthat has the potential to benefit the industry and thepatient.

EMERGING REGULATORY INITIATIVES

Biopharmaceutics Classification System (BCS) Biowaivers

In August 2000, FDA issued a guidance for industry onwaiver of in vivo bioavailability and bioequivalence studiesfor immediate release of solid oral dosage forms based onBCS (10). The BCS is a scientific and risk-based frameworkfor classifying a drug substance based on its aqueoussolubility and intestinal permeability (11). When combinedwith the in vitro dissolution characteristics of the drugproduct, the BCS takes into account three major factors thatgovern the rate and extent of oral drug absorption from IRsolid oral dosage forms: solubility, intestinal permeability,and dissolution rate. In 2002, the FDA issued a guidancerecommending that food effect bioequivalence studies werenot needed for BCS Class I drugs dosed in immediaterelease forms that exhibit rapid dissolution (12). To ensureaccuracy and consistency, the FDA formed the BCSCommittee who has the responsibility and authority tomake the determination of BCS classification of new orgeneric drugs. The committee has classified a total of 42drugs as BCS Class I drugs (i.e., rapidly dissolving,immediate-release drug products containing high solubilityand highly permeability drug substances). The determina-tion not only helps to ensure the availability of new orgeneric drugs but also saves sponsors hundreds of millionsdollars of clinical studies. Further, the FDA recentlyreleased a draft guidance extending the biowaiver to BCSClass III drugs (i.e., very rapidly dissolving, immediate-release drug products containing high solubility but lowpermeability drug substances), which will further accelerate

Fig. 1. The four phases of quality. Quality does not happen in Bpockets.^ It is built end-to-end andit is continually challenged. Quality is about more than process and method. Holistic reliability is acritical part of quality

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the development of drugs and reduce the amount of costlyin vivo studies (13). A point highlighted at the conference isthat future efforts in this arena should focus on globalharmonization of classification systems for biowaivers.

Pharmaceutical Product Lifecycle Management—Q12

There are a number of challenges faced by industry andthe FDA (as well as other regulatory authorities) when itcomes to managing post-approval changes. These challengeshave a direct impact on lifecycle management and may leadto (i) a lack of proactive implementation of manufacturing (andother) improvements; (ii) inefficient use of industry andregulatory resources; (iii) incomplete realization of the benefitsand operational flexibility expected by the implementation ofICH Q8–Q11; and (iv) supply chain disruption and potentialdrug shortages.

In 2014, at the ICH Quality Strategy Workshop inMinneapolis, workshop participants reflected on the progresssince publication of ICH Q8–Q11 (14). They proposed a 5-year strategic plan including the development of a vision andstrategy for pharmaceutical product lifecycle management. Atthe ICH 2014 workshop, the ICH Steering Committeeendorsed the proposal to establish an Expert Working Group(EWG) to develop a new guideline, BTechnical and Regula-tory Considerations for Pharmaceutical Product LifecycleManagement–ICH Q12.^ ICH Q12 is a priority for industryand regulators and is intended to bring more focus on the

commercial manufacturing phase of the lifecycle, whilebridging the development phases that were already coveredin the aforementioned guidelines. ICH Q12, as noted in theconcept paper (15), is unique to ICH BQ^ guidelines as it isintended to tackle not only technical challenges in managing aproduct’s lifecycle but also regulatory challenges. Theseregulatory challenges include some complex regulatory pro-cesses that are not always science and risk based. Thesechallenges include clarity on what constitutes regulatorycommitments or established conditions (16) and their rela-tionships to controls (as shown in Fig. 3), best practices forchange and knowledge management as lifecycle managementenablers, as well as exploring opportunities to harmonizeglobal data requirements to support post-approval changes.

At this critical stage, in the drafting of the ICH Q12guideline, feedback received at the conference informs theQ12 EWG on several themes critical to realizing the vision ofthe guideline. These themes include (i) exploring how toprovide FDA (and other regulators) confidence in thereliability of industry’s change management systems; (ii)better utilizing regulatory tools (e.g., a robust PharmaceuticalQuality System (PQS), New Inspection Protocols Project(NIPP), records requests in lieu or in advance of inspection,and enhanced knowledge management); (iii) tying the levelof detail and change management of established conditions torisk and level of product and process knowledge; and (iv)providing a clear pathway for legacy and generic products torealize the opportunities and benefits of Q12.

Fig. 2. Road map for pharmaceutical manufacturing. Over the last decade, there has been aparadigm shift in pharmaceutical manufacturing, moving away from fixed processes, where productquality is confirmed solely though end-product testing, to the Quality by Design paradigm (QbD).QbD is a systematic scientific and risk-based approach to pharmaceutical manufacturing wherequality is built-in through product and process understanding. Continuous manufacturingrepresents the next paradigm shift and provides an opportunity, through integration and theapplication of systems-based approaches, to adopt advanced manufacturing process developmentand control systems to produce high quality products. This reduces waste resulting from thegeneration of out-of-specification material. Since in its ultimate manifestation, a continuous processis designed as a whole, the distinction between the drug substance process and the drug productprocess can potentially be eliminated. This blue sky vision can be achieved through the adoption ofnovel process technologies

531Advancing Product Quality: a Summary of the Second FDA/PQRI

Dissolution Testing

BWhat is currently impossible to do in my field but, ifpossible, would fundamentally change it?^ posited the futuristJoel Barker (17). For an important segment of the pharma-ceutical field focused on solid oral dosage forms, the answer isa better, more predictive dissolution test. Dissolution is one ofthe most important quality attributes of a solid oral drugproduct. Dissolution testing serves as a critical tool to ensureconsistent quality and performance of both development andcommercial products. It is also critical for the evaluation ofrelative product performance resulting from changes informulation and/or manufacturing processes. Prior to regula-tory filing, it guides formulation and process development andfacilitates assessment of critical process parameters, designspace, risks, and development of appropriate control strate-gies. Post-approval, it assures batch-to-batch consistency ofproduct and supports proposed changes in formulation andmanufacturing processes. The major problems with currentdissolution methodologies are that they may be over- orunder-discriminating or, at worst, completely irrelevant toin vivo performance.

Standard compendial tests for Boral bioperformance^include the disintegration test adopted in the 1950s, thedissolution apparatus 1 (basket) adopted in 1970, and thedissolution apparatus 2 (paddle) adopted in the 1980s (18).Since then, little advancement has occurred in the field ofdissolution testing despite the breakthrough in modeling andsimulation of oral drug absorption. Future dissolution testingmay well need to transition to multiple dissolution method-ologies for different purposes (e.g., fit-for-purpose dissolutionmethodologies). For quality control purposes, the dissolutiontest needs to be simple, fast, and affordable. However, thedissolution test also needs to reflect the situation in vivo. Avariety of non-compendial dissolution methodologies arecurrently being evaluated and used in academia, industry,and regulatory agencies in pursuit of test methods that moreaccurately represent what is now known of human gastroin-testinal physiology (19). The goal is better assessment ofin vivo performance.

The FDA is keenly interested in modifying dissolutiontesting to be more clinically relevant. As a first step, the FDArecently issued a draft guidance on dissolution testing andspecification criteria for immediate-release solid oral dosageforms containing BCS Class 1 and 3 drugs (20). For drugproducts of these classes, the guidance recommends standardtest conditions (i.e., 100 RPM Basket USP apparatus 1 or 75

RPM Paddle USP apparatus 2), dissolution media (i.e.,500 mL of 0.01 M HCl with no surfactant at 37°C), andacceptance criteria (i.e., Q= 80% in 30 min for BCS Class 1and in 15 min for BCS Class 3). The scientific rationales forthis guidance are that (i) the low risk of patient-relevantdissolution failure, (ii) the more physiologically relevantmedia and volume, and (ii) the need to meet the dissolutioncriteria will likely yield in vivo equivalence.

Investigating in vitro methods generally has one goal:getting the Boptimal^ in vivo release rate and then maintain-ing the desired performance over the life of the product.There is much on-going research within industry to advancein vitro methods predictive of in vivo outcomes and todevelop clinically relevant specifications for extended releaseproducts. Example research includes (i) the use of osmoticsystems to rapidly assess in vivo viability and confirmbiopharmaceutical models; (ii) coupling biopharmaceuticsmodels with digital dosage form design to select extendedrelease formulation composition; (iii) radio labeling andscintigraphy to identify lead formulations and obtain usefulin vivo information; and (iv) conducting chemical analysis toassess matrix effects on dissolution. Remaining challengesinclude addressing disintegration throughout the gastrointes-tinal track. However, the effects of such disintegration are stillnot clear. Depending on the matrix and nature of the drug,other aspects, such as diffusion, may be of more importance.The conference made clear the united viewpoint that,whenever possible, in vitro quality attributes need to link toin vivo performance to minimize risks to patients and assureconsistent oral bioperformance.

Quality Metrics

Quality metrics are expected to play an important role inachieving the desired state of pharmaceutical quality. Qualitymetric programs are used throughout the pharmaceuticalindustry to monitor quality control systems and processes anddrive continuous improvement efforts in drug manufacturing.Since 2013, the FDA has been discussing with stakeholdershow to select a subset of ideal metrics that are mutually usefuland objective. The FDA is committed to supporting themodernization of pharmaceutical manufacturing and expectsthat this program, along with other surveillance programs,will encourage improved behavior and responsibility in thisarea by identifying and rewarding establishments that goBabove and beyond^ the minimum quality standards.

Fig. 3. Established conditions and their relationships to controls. Established conditionsare part of an overall control strategy and are essential to assuring product quality.Established conditions are included in the elements of the control strategy reported in anapplication

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The FDA published a draft guidance on quality metricsin July 2015 (21). This guidance recommends four metrics: (i)lot acceptance rate, (ii) product quality complaint rate, (iii)invalidated out-of-specification rate, and (iv) annual productreview or product quality review on time rate. Optionalmetrics include senior management engagement, correctiveaction and preventive action effectiveness, and processcapability/performance (see discussion of process capabilitybelow under Manufacturing and Quality Assurance). TheFDA intends to use the information in order to provide moreinsight into the state of quality for product and facility;provide more quantitative and objective measures of qualityat the product, site, and system levels; enhance the risk-basedsurveillance inspection scheduling model; improve effective-ness of inspections; and help identify factors leading to supplydisruption. Further, this information may provide a basis toassist in determining the appropriate reporting category forpost-approval manufacturing changes. Multiple internationalpharmaceutical manufacturers have submitted positive com-ments to the docket endorsing a mandatory program. Twomedical gas associations have even suggested the scope beexpanded to include their products. Others, however, haveexpressed concern with the enforcement tone of the draftguidance.

Representatives from both industry and the Interna-tional Society of Pharmaceutical Engineering (ISPE) aresupportive of FDA’s effort in addressing quality metricswhile recognizing that standardization across industry isdifficult. ISPE recommendations start with three of theFDA’s proposed metrics: (i) lot acceptance rate (reportedby site, differentiated by product), (ii) product qualitycomplaints (reported by product only), and (iii) invalidatedout-of-specification rate (reported by site, differentiated byproduct). ISPE recommends deferring annual product reviewor product quality review on time rate. ISPE recommendsreporting by site, differentiated by product, since it is morerepresentative of how industry currently gathers quality dataand therefore may reduce the burden for startup of theprogram.

All of the conference presenters in this session agreedthat the context of each data point and metric matters and asingle metric cannot independently be used to judge quality.Additional areas of discussion included (i) calculating theproduct complaint rate by units and not by lot; (ii) correctiveaction and preventive action effectiveness/retraining rate; (iii)the annual product review on time rate; (iv) supply chainvisibility (e.g., contract manufacturing being part ofreporting); and (v) non-application product complexities(e.g., national drug code numbers may not be differentiateduntil final packaging, challenging upstream metric reportingat this detail in over-the-counter industry). Ultimately, qualitymetric programs will improve patient access to importanttherapies by increasing the quality and reliability of drugsupplies.

Botanical Drug Development and Quality Standards

There is a renewed interest in the discovery of noveltherapeutic molecules from botanical sources, especially afterDr. Youyou Tu was awarded the Nobel Prize in Physiology orMedicine in 2015 for her contribution to the initial discovery

of artemisinin and its use in the treatment of malaria (22). Incontrast to artemisinin, which is highly purified, botanicaldrug products generally consist of naturally-derived complexmixtures of vegetable materials, which may include plantmaterials, algae, macroscopic fungi, or combinations thereof.These mixtures contain many different chemical componentsand exhibit considerable variability (e.g., in phytochemicalprofile) that is inherent from natural variations at theorganism level. Due to the uncertainty of the active compo-nent(s) in a botanical mixture, the FDA generally considersthe entire mixture as the active ingredient for botanical drugsderived from a single botanical raw material. New botanicalsintended to be marketed as drugs in the USA are expected tomeet the same standards as non-botanical drugs for quality,safety, and efficacy. As a result, while botanicals could be animportant source for new drugs, their development remains agreat challenge due to their inherent complexity. Therefore,they have not been in the mainstream development of thepharmaceutical industry.

To facilitate the development and regulatory evaluationof botanical drugs in the USA, the FDA published its firstguidance on Botanical Drug Products in 2004 (23) and issueda revised draft guidance on Botanical Drug Development in2015 (24). The 2015 draft guidance provides recommenda-tions on quality, nonclinical, clinical, and other unique aspectsassociated with botanical new drug development through theinvestigational new drug (IND) and new drug application(NDA) processes. Most importantly, the draft guidancedescribes the Btotality-of-evidence^ approach for qualitycontrol of botanical drugs that overcomes the limited abilityto characterize the entire botanical mixture or its activecomponents by analytical means. In addition to conventionalCMC data, this integrated approach considers other evidenceincluding raw material control, clinically relevant bioassay(s),and other non-CMC data. The degree of reliance on theseother data for ensuring consistency of quality depends on theextent to which the botanical mixture can be characterizedand quantified. Using this approach, the FDA approved thefirst botanical NDA for Veregen (sinecatechins) in 2006 andthe second botanical NDA for Fulyzaq (crofelemer) in 2012.These two NDA approvals show that new therapies derivedfrom natural complex mixtures can be developed to meetmodern FDA standards of quality, safety, and efficacy.

Despite the approval of two botanical products under theNDA pathway, more research is still needed to addresschallenges related to the characterization and quality controlof botanical raw materials, drug substances, and drugproducts. For botanical raw materials, fast, simple, and fit-for-purpose screening methods should be developed foraccurate plant species identification. There is also a need forcataloging possible environmental contaminates (e.g., pesti-cides and heavy metals) related to the plant source. For drugsubstances and products, analytical methods should beimproved to better characterize the heterogeneity andvariability of botanical mixtures in relation to harvestingtechniques and/or manufacturing conditions (e.g., extraction).A better scientific approach should also be developed toassess drug substance stability and understand its impact onbotanical drug quality, safety, and efficacy. This will requirecollaborative efforts among the industry, academia, andgovernment agencies.

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REGULATORY SUBMISSION, ASSESSMENT,AND INSPECTION

Breakthrough Therapy—CMC Challenges

The FDA Safety and Innovation Act (2012) Section 901and 902 introduced fast track and breakthrough therapydesignations. Breakthrough therapy designation is for seriousand life-threatening conditions and granted based on prelim-inary clinical evidence using a risk-based approach (e.g.,obtained during phase 1 or phase 2). For breakthrough drugs,the FDA allows reduced research, development, manufactur-ing, and processing timelines while not reducing CMC qualityexpectations. As such, several flexible approaches areemployed during the review process including rolling submis-sions, supplements, postmarket requirements, and postmarketcommitments. For example, agreements have been reachedon submitting less stability data at initial application withsubmission of data as it becomes available.

Accelerated filing and review are challenging for bothFDA and industry. For FDA, there are (i) fewer available CMCdata (e.g., safety, stability, processing, and manufacturing); (ii)additional amendments during the application lifecycle; (iii)needs for earlier identification and inspection of facilities; (iv)increased treatment protocols/expanded access submissions;and (v) increased postmarket requirements and postmarketcommitments to cover residual risk. For industry, it requires(i) high clinical demands; (ii) detailed product lifecycle planning;(iii) pre-approval inspection readiness; (iv) establishment ofmeaningful specifications; and (v) development of robustmanufacturing processes. The key tomitigating risks and solvingunexpected issues is early, open, and increased communicationsbetween the sponsor and the FDA. Sponsors have found thattimely and meaningful communications with the FDAare essential when issues arise. When working collaboratively,FDA and sponsors are able to explore, troubleshoot, andresolve unexpected issues throughout the lifecycle ofbreakthrough drugs. At the conference, it was evident thatindustry is hoping to establish clear, consistent, predictable, andtransparent policies and processes. These should be developedwith stakeholder input that aligns the pharmaceutical develop-ment and commercial manufacturing programs to applicableregulatory pathways.

Pre-Approval and Surveillance Inspection

FDA conducts inspections of manufacturing operationsfor two primary reasons: (i) to evaluate a manufacturingoperation before granting approval and (ii) to verify, throughperiodic evaluation of all manufacturing facilities, thatmanufacturing is in a state of control. To this end, a pre-approval inspection (PAI) may be performed. The PAI, as itsname implies, is part of the application review process toevaluate the (i) site readiness for commercial manufacturing,(ii) conformance to the marketing application, and (iii) datagenerated at the site for authenticity, reliability, and accuracy.The decision to conduct a PAI depends on facility, process,and product risks.

The PAI inspection can give FDA valuable informationand assurance on behalf of patients that any new drug will bemanufactured in a manner that assures its demonstrated

safety and efficacy. A PAI can (i) more efficiently andeffectively resolve certain review issues identified during theapplication’s off-site review, (ii) improve the reviewers’understanding of the process and product, and (iii) enablesubstantive discussions about the process and control strategy(including any PAT-based monitoring, model maintenance,and decision trees). A PAI also provides FDA experts with anopportunity to more fully assess information not containedwithin the standard application that relates to general facilityissues. In particular, this includes how the proposed new drugwill be incorporated in an existing non-dedicated facility,including discussions on trending, continued process verifica-tion, and risk management. The FDA may also inspect afacility after granting approval and soon after distribution toverify that the commercial-scale manufacturing operation,including control strategy, results in the drug as it wasdesigned and approved. The most significant discussions atthe conference regarding PAIs resulted in the recommenda-tions that (i) application reviewers from different disciplinesparticipate in inspections more often, (ii) the same inspectionteam perform inspections of all manufacturing facilities citedin the application, (iii) the FDA increases its coordinationwith other regulators performing facility inspections, (iv) theFDA not issue a written notice of observations (FDA 483) atthe end of a PAI, and (iv) the FDA submit questions inadvance of a facility inspection.

A surveillance inspection is performed to verify thatdrugs, both active ingredients and finished products, aremanufactured according to the FDA’s regulations governingminimum quality standards (i.e., current good manufacturingpractices). Surveillance inspections also provide industry anopportunity to learn from the observations, assess whethercurrent practices align with recommendations in FDAguidance, and provide the FDA with current information onindustry practices. Current surveillance inspections focus onCGMP violations and generally result in a determination ofthe need for further regulatory action (e.g., warning, seizure,import alert, and injunction). A possible different approachdiscussed at the conference would be determining a facility’soverall quality capability along a scale (low to high) toprovide for suitable regulatory intervention at lower func-tioning facilities and reduced regulatory activities at higherfunctioning facilities.

The ideal surveillance inspection to assure productquality might better recognize and encourage the twofundamental elements of good quality management, whichare that (i) risk is systematically understood and mitigatedand (ii) risk management and efforts to assure robust drugquality are promoted and incentivized. This would require aholistic and collaborative approach between industry andregulators. The concerns with current surveillance inspectioninclude (i) the lack of apparent incentives for the proactiveenhancement of manufacturing quality, (ii) limited use of risk-based approaches by regulators resulting in inefficient use ofindustry (and regulatory) resources, (iii) inconsistencies inregulatory inspections (and other review and enforcementdisciplines), and (iv) a lack of harmonization among regula-tory agencies. Recommendations for future approachesinclude (i) incentivizing high-functioning manufacturing op-erations, (ii) developing a shared quality problem reportingsystem adapted from the aviation safety reporting system, and

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(iii) considering certain standards for quality such as in theseafood hazard analysis critical control point program. TheFDA is developing a more structured and question-basedinspection program supporting a more objective categoriza-tion of each facility’s quality management system (i.e., Bnewinspection protocol project^).

Risk-Based Regulatory Approach

The desired state of the risk-based regulatory approachinvolves open communication between the industry andFDA. Beyond open communication on an ongoing basis,applications provide additional transparency regarding riskuncertainty as well as design, development, and robustness ofthe quality control strategy for a particular product. In thespirit of transparency, industry should be open to sharing riskassessments or their approach to risk assessment with theFDA, but this openness should not be penalized. In addition,both the industry’s and the FDA’s focus should be on risk andquality, not merely compliance.

The current state of the risk-based approach for ensuringproduct quality is far from perfect. There are an unacceptablenumber of product recalls and drug shortages, and there isnot enough transparency from industry or regulators. TheFDA would like to know how the industry performs riskassessments. Meanwhile, the industry is concerned withinconsistencies in regulatory assessments/inspections andglobal divergence. Better understanding of product qualityand control strategies will increase FDA confidence in theindustry’s ability to manage quality.

Barriers to transform from the current to the future stateinclude (i) cultural inertia; (ii) insufficient incentives; (iii) lackof standardization of tools, techniques, and systems for riskassessment; (iv) lack of trust between the industry andregulators; (v) lack of open communication and mutualrecognition; (vi) lack of lifecycle focus; and (vii) cumbersomesubmission formats. The short-term goal is to improve thetransparency on both sides by (i) providing clear expectationsto industry, (ii) ensuring appropriate control strategies are inplace, (iii) distinguishing risk from characterizing uncertainty,(iv) sharing risk assessment techniques to improve the FDA’sconfidence in data, and (v) determining and confirmingpredictability of risk assessment techniques. The long-termgoal is to build a collaborative relationship between industryand the FDA. Transparency from both sides will increaseconfidence and trust and standardize risk assessments.However, both sides need to have the same intentions (e.g.,operations, vision, creativity, and quality standards). Bothsides should focus on patient safety and work together tocreate robust assessment tools and systems.

Quality Risk Management

Risk management drives the focus of Quality Manage-ment Systems (QMSs), helps define the level of effort ofthose activities, and supports risk-based decisions of qualitymanagement. Integration of risk management into QMSs canhelp to drive efficiency and effectiveness and reduce injuryrate, backlog, inventory, capital, and losses (as shown inFig. 4). A QMS includes development, evaluation of quality

defects, auditing and inspection, periodic product reviews,and change control.

Quality risk management (QRM) is used to guide thedevelopment of a robust control strategy that ensures criticalquality attributes are established and attained (i.e., riskassessment). The capability of the process and robustness ofthe control strategy to reproducibly deliver quality productshould be evaluated periodically to ensure continued suitabil-ity (i.e., risk review). Risk management is incorporated intomanufacturing governance by:

& Orthogonal reviews of product, site, and system toobtain comprehensive assessment of risks and main-tain a risk file;

& Updates based on production (e.g., nonconformities,process changes, and supplier changes), market (e.g.,complaints, adverse events, and customer inquiries),and changes in industry and regulation (e.g., newrequirements and information on similar marketedproducts);

& Planning activities for the long-term (e.g., businessstrategy, policy, portfolio, and enterprise goals), mid-term (e.g., operational strategy, key objectives, globalgovernance, and performance targets), and short-term (e.g., resource deployment, shop floor execu-tion, process control, and monitoring);

& Management involvement, escalation, decision mak-ing, and auditing.

The QRM scope should include worst-case situationsprospectively, resulting in the generation of knowledge tounderstand risks and/or implement controls to mitigate risks.In particular, leadership should (i) focus on risks associatedwith human behavior; (ii) fully understand the perspective ofindividuals manufacturing the product; and (iii) implementappropriate levels of authority, incentives, and controls tomitigate quality issues.

The importance of QRM in remediation of complianceissues after regulatory actions have occurred is paramount.QRM should be integrated across systems to ensure orthog-onal reviews of the entire manufacturing process (e.g., setupevery site the same to maintain the level of quality control).This integration should reduce confusion and streamline thefunctionality of QMS using common quality practices. QRMcan be aided by continuing to improve quality controlstrategies based on common deficiencies and creating globalstandards to have more accountability throughout the pro-cess. It is clear that governance is very important to thesuccess of QRM.

FDA Integrated Quality Assessment

OPQ has developed and implemented a team-basedIntegrated Quality Assessment (IQA). This approach maxi-mizes each team member’s expertise and provides alignedpatient-focused and risk-based drug product quality recom-mendations, inclusive of drug substance, drug product,manufacturing process, and facilities (as shown in Fig. 5).An IQA team is designed to work in a highly collaborativemodel within PDUFA/GDUFA timelines. Reviewers in theIQA team focus on quality risks as they relate to patientneeds and communicate information requests or deficiencies

535Advancing Product Quality: a Summary of the Second FDA/PQRI

in terms of mitigating risks to clinical performance. Thereview is done with the consideration of clinical andregulatory frameworks with lifecycle approaches. Opencommunication and dialogues of quality risk and link to thepatient are critical to the success of the IQA approach.

The team-based IQA approach emerged from both newand generic drug reviews. For new drugs, it evolved from theQbD pilot and team-based reviews on breakthrough submis-sions. For generic drugs, it progressed from the integration ofdrug substance/drug product pilot in 2010. It advanced as partof OPQ reorganization and GDUFA implementation alongwith the use of real-time communication. All new and genericapplications as well as CDER-managed biologics licenseapplications (BLAs) submitted after October 1, 2014 havebeen reviewed using the IQA approach. In fact, the recentapprovals of the continuous manufacturing drug product and3D-printed drug product applications are outcomes of theIQA approach (8,25).

The purpose and benefit of the FDA IQA are clearlyunderstood and supported by the industry. Reviews of approvedNDAs from 2011 to 2015 revealed that common areas fordeficiencies were process control and specifications (together60% of deficiencies). As a result of implementation of IQA,consistent drug product quality assessments have been ob-served. There exists improved alignment in areas such ascriticality, process description, and control strategy. Still, thereare opportunities for further dialog. Industry participants notedthat information requests should be considered deficiencies ininformation provided in a submission, not necessarily a defi-ciency in a firm’s development program. For ANDAs, there hasbeen an observed increase in total number and diversity of

questions (i.e., questions have apparently been generated by ateam, compared to the more focused questions of the single-reviewer approach). These questions are fundamental in naturewith respect to both product and process understanding. ANDAsponsors have observed very high expectations for mitigationstrategy on all risks. Implementation of QbD principles isneeded for all ANDAs.

FDA and industry are aligned in desiring drug productquality on behalf of the patient. More effective, transparent,and risk-based communication linking quality to clinicalperformance is expected. Further discussion is needed onmaking quality management system information transparentto regulators to build trust and on managing blurred linesbetween reviewers and inspectors. At the conference, sug-gested improvements to the IQA process included:

& FDA communication through IRs/deficiencies shouldmake clear the rationale behind the question.

& Application team leads should have a stronger role inconsolidating questions and ensuring applications areproperly supported.

& Keeping and expanding on the dialog between FDAand industry. Can FDA provide best practices and/orexpectations for risk assessments (e.g., how muchinformation to provide and where to provide it)?

& A potential for a face-to-face meeting shortly afterstarting submission review for NDAs.

& Encouraging industry to ask for clarity regardingquestions that are unclear, appear unsupported, ormight generate an unexpectedly voluminousresponse.

Fig. 4. Quality risk management and process capability. By focusing on integrating quality risk management into qualitymanagement systems and pursuing process capability, Lilly has delivered improvements including reductions to the injuryrate by 50% and to the deviation rate by 40% from 2007 to 2013

536 Yu et al.

PRODUCT AND PROCESS DEVELOPMENT

Characterization of Complex Drug Formulations ContainingNanomaterials

FDA is receiving and approving an increasing number ofapplications for complex drug formulations containingnanomaterials. These products are regulated and reviewedin the same manner as drug products not containingnanomaterials. Challenges to both industry and regulatorsalike for the development and regulation of these productsoften stem from ensuring appropriate and adequate charac-terization in order to maintain product quality. In particular,determining which methods will be used for characterizationis a subject of much debate.

Although critical quality attributes for any product areultimately product specific, size distribution is a much-citedattribute for the characterization and control ofnanomaterials. The size distribution of different formulationscontaining nanoscale materials has been demonstrated toimpact the product performance and is thus often measuredduring product development, as well as in release andstability specifications. Dynamic light scattering (DLS) is themost common sizing technique seen by both industry andFDA. However, for determining size distributions, thistechnique must be supplemented with another complemen-tary method to adequately characterize the size distributionof the nanoscale materials. The FDA and industry agree thata comprehensive particle size control strategy is essential forproducts containing nanoscale materials.

Size is not the only critical quality attribute for drugproducts containing nanomaterials. Other attributes (includ-ing non-nanoscale attributes) such as morphology, drugrelease, and surface charge often impact product perfor-mance. The determination of the critical quality attributes willultimately be product specific, and discussions between theindustry and FDA are recommended to clarify critical qualityattributes and their measurement in order to accelerate thedevelopment and approval of these complex formulations.

Biosimilar Product Assessment—How Similar is Similar?

The Biologics Price Competition and Innovation Act, apart of the Patient Protection and Affordable Care Actsigned into law on March 23, 2010, amended the PHS Act bycreating a licensure pathway for biological products demon-strated to be biosimilar to, or also interchangeable with, anFDA-licensed biological reference product. The FDA issueda series of guidance documents to aid the development ofbiosimilar products. On March 6, 2015, FDA approved thefirst biosimilar product, Sandoz’s Zarxio, biosimilar toAmgen’s Neupogen (26). Nevertheless, challenges in thedevelopment of biosimilar products were presented anddiscussed by FDA and industry representatives.

Development of the product is a continuum, thus,analytical similarity should be evaluated at every stage (e.g.,pre-IND, IND-enabling, pharmacokinetic/pharmacodynamicstudies, and supporting licensure). Multiple reference lots, insome examples 20–30 lots, were used, spanning a period of 4–5 years. Lots that are used in pivotal clinical studies should bepart of the analytical similarity assessment. Issues that ariseduring product development may relate to potential shifts inquality attributes of the reference product. Therefore, if theshift occurs during early development of the biosimilar, it ispossible to integrate the new lots in the development programand adjust the process to match the quality attributes of thereference product. For a mature program, the industryperspective was that the biosimilar should maintain theoriginal target profile. The recommendation was to engagethe FDA in discussion as such issues arise. Another potentialissue is the analytical drift that can be introduced byinstrument or personnel changes. This drift is mitigated bythe use of reference standard and appropriate assay suitabil-ity criteria, highlighting the importance of consistent refer-ence standard materials and of a two-tier reference standardsystem.

The use of statistical tools to evaluate the analyticalsimilarity was another discussion topic at the conference. TheFDA goal is to make the program successful and inspire

Fig. 5. FDA team-based integrated quality assessment. Team-based integrated qualityassessment consists of discipline reviewers of drug substance, drug product, process, andfacility. Formal risk assessment is used to enhance the efficiency and effectiveness of reviewand inspection. Integration of review with inspection produces more informed decisions onfacility acceptability and application approvability

537Advancing Product Quality: a Summary of the Second FDA/PQRI

confidence in the public and health care provider communi-ties. Industry representatives highlighted some of the chal-lenges. The number of lots used in the analytical similarityassessment is important, as a small number of lots may not besufficient to capture the variability of the product. The FDArecommends a statistical approach based on risk ranking ofquality attributes, with risk levels linked to statistical tiers(i.e., tier 1—equivalence testing, tier 2—quality ranges, andtier 3—visual comparison). Not all highly critical qualityattributes will be assigned to tier 1. The risk assessment isproduct specific, as is the assignment of attributes to bespecific statistical tiers. In terms of equivalence testing, it isdifficult for industry to target manufacturing ranges when theequivalence margins are very tight. In conclusion, there is aneed for FDA guidance on statistical evaluation of analyticalsimilarity.

Palatability and Swallowability

Patient acceptance of the drug product and adherence tothe prescribed therapy are critical for achieving the intendedtherapeutic benefit. The mouthfeel is a critical qualityattribute for oral drug products and includes a spectrum ofassessments such as texture, taste, smell, palatability, andswallowability. Mouthfeel is especially important in pediatricpopulations where patient acceptance of the dosage form maybe more difficult to achieve as compared to adults. Mouthfeelassessments can be performed in taste panels (e.g., sensorymethods in adults and pediatric patients) and also performedin vitro using specific tools and techniques.

The session highlighted the possibility of learning andleveraging opportunities from the methods applied fordescribing and improving mouthfeel of foods. It focused ontribology which captures processes that contribute to mouth-feel and the use of electronic sensors (e.g., electronic tongue)in formulation development for palatability and taste-masking. Since the 1960s, a significant body of knowledge,expertise, and techniques continue to be developed forunderstanding consumers’ perception of mouthfeel of foodsand beverages. This knowledge has been used for designingand optimizing foods (including liquids) that are acceptable toconsumers. The fundamental measures (e.g., hardness, vis-cosity, elasticity, and shear stress) used in foods forquantifying and translating into consumer experience (27)are also measured in pharmaceutics for assessing drugproduct attributes.

In food engineering, tribology helps to understand theoral processing of food as well as texture and mouthfeel(28,29). Tribology captures the physical basis of mouthfeelconsisting of processes such as viscosity, saliva interactions,adsorption, surface properties, and wear. It serves as animportant tool to assess the in vitro oral breakdown trajectoryof foods and beverages. Complexity of taste perception andcontributors to palatability/taste cover a wide spectrumranging from factors directly related to the drug product toextrinsic factors such as cultural background and dietarypreferences. While taste panels can address certain sensoryaspects, routine testing of formulations in taste panels,particularly in special populations such as pediatrics andgeriatrics, will be difficult to conduct. An electronic tongue (e-tongue) was first developed in late 1980s/early 1990s to

support formulation development/improvement (30). Typicalareas of use for the e-tongue are taste masking andformulation development, comparative studies evaluatingpredictive ability, and bitterness assessment and attenuation.In addition, the e-tongue is used for characterizing tastemasking attributes of solid oral dosage forms (e.g., tastemasking as a function of time) and as a tool to determine theduration of formulation taste masking (31). The e-tongue’sapplication in the food and pharmaceutical industries iscontinuing to grow as evident by the increase in interest andpublications over time despite challenges (e.g., sensor re-sponse, reference standards, differences in the volume ofliquid for electronic tongue/taste sensor vs. mouth, etc.).

Several key messages and recommendations werediscussed at the session. With respect to discussions onscience and methods for assessing mouthfeel (e.g., textureand tribology) and palatability (e.g., taste masking and e-tongue), information obtained with in vitro methods is mostvaluable in early formulation development (i.e., screening).Further, no single method can replace in vivo assessments.While all methods are complementary, methods/tools bringmost value when they are used correctly and users manageexpectations. There are opportunities for trans-disciplinarylearning for formulation development that can be harnessedwith continued dialog with other industries (e.g., food,consumer, human, and animal healthcare), academia, andregulatory agencies. There is a need for more venues for opendiscussion and sharing of knowledge and experiences. Thereis also a need for continued research and collaboration onhow to further apply in vitro methods for understanding andimproving mouthfeel and taste.

Content Uniformity

Uniformity of dosage units (UDU) can be demonstratedby content uniformity (CU) or weight variation based on drugloading in the products. Proper methods to ensure CU are ofparticular interest for products with low drug loading and/ornarrow therapeutic indices. The draft BGuidance for Indus-try–Powder Blends and Finished Dosage Units—Stratified In-process Dosage Unit Sampling and Assessment^ was with-drawn in 2013 because it no longer reflects the FDA’s currentthinking. The United States Pharmacopoeia (USP) <905>Uniformity of Dosage Units only provides limited assuranceof the tested batch due to the lack of a statistical samplingplan. Therefore, there is an urgent need for alternatives to theexisting CU methodology and stratified sampling.

The industry wants flexible sample size and acceptancecriteria, especially considering the increased adoption ofprocess analytical technology (PAT) and continuousmanufacturing. The zero tolerance criteria prescribed byUSP <905> are unproductive. USP recognizes these needsand challenges and is actively exploring how to considermanufacturing data that indicates high probability of finalproduct compliance. For instance, USP expert panels andcommittees were formed to discuss real-time release testingand large BN^ sampling.

In the meantime, ISPE has proposed a frameworkfollowing the guideline prescribed by ASTM E2709/E2810.Such a framework offers (i) increased confidence that futuresamples drawn from the batch will comply with USP <905>

538 Yu et al.

and (ii) linkage of blend and content uniformity covering allthree phases of the manufacturing process (i.e., processdesign, process qualification, and continued process verifica-tion). In addition, research has shown the significant advan-tage of using PAT to ensure and enhance blend and contentuniformity. PAT tools cannot only provide in-depth productand process understanding, but also facilitate appropriatesampling and enhance statistical confidence. Regardingstatistical considerations for sampling and defining acceptancecriteria, different sampling strategies are available (e.g.,simple random sampling, stratified sampling, and systematicsampling). It is important to note that random sampling maynot be able to provide the estimation of between/withinlocation variability. Distribution of the data needs to bedetermined because it will dictate the data analysis method.The acceptance criterion should be clinically relevant; itneeds to fit the required product quality level. For instance,the acceptance criterion for a low drug loading and highpotency product may be different from that of a high drugload product. It is important to discuss content uniformityacceptance criteria and sampling plans with regulatoryauthorities early on. Once deemed acceptable, such accep-tance criteria and sampling plans may be updated or revisedthroughout the lifecycle of the product when more advancedmanufacturing and process controls are adopted.

Science of Tech Transfer/Scale-Up

Moving from lab and pilot scale development work tocommercial manufacturing scale can proceed on schedule andwithin budget or it can turn into an expensive set-back.Unexpected costs, delayed launch, lost revenue, and drugshortage may occur if process control and product qualityproblems arise. However, the likelihood of successful scale upand tech transfer to the commercial plant can be greatlyincreased by employing a multidisciplinary approach focusedon fundamental pharmaceutical science, engineering exper-tise, innovative materials science methodology, and advancedcomputer-based predictive tools.

At the conference, case studies demonstrated effectiveuse of mechanical and predictive modeling and simulations inareas such as powder and particle behavior, as well as unitoperations such as fluid bed granulation, bi-layer tabletcompression, and pan coating. Models and simulations insupport of root cause analysis during the product lifecycle andrisk mitigation strategies were also presented.

Full scale Design of Experiments (DOEs) to achievemechanistic product and process understanding can beexpensive and impractical when numerous variables arepresent. Scale up and scale down rules, as well as identifica-tion of scale-independent parameters, are useful. Addition-ally, the application of mathematical modeling, simulation,and advanced analytics can provide insight into behaviors ofmaterials and structures that enable cost effective design andoptimization of manufacturing processes. Instead of largescale DOE runs involving more than ten operating parame-ters for example, commercial runs can validate modelpredictions. Thus, scale up risk is mitigated.

Cost savings are realized as less material is used in themodeling experiments and commercial plant time is reducedwhile commercial process parameters are predicted.

However, effective use of modeling and simulation requiresskilled staff. The pharmaceutical industry could recruit fromother sectors that routinely use these techniques to bring inthe essential skill sets. From a regulatory perspective, thesetechniques are highly encouraged. The use of predictivemodels and simulation is acceptable approaches to productand process development, as well as in manufacturing tosupport real-time release testing (RTRT) and innovativetechnologies like continuous manufacturing.

By providing sufficient information and data in supportof the scaled up process, regulatory review is more efficientand IR cycles are minimized. Sponsors should consultregulatory guidance about the type and extent of modelinformation to include in regulatory submissions. An exampleof such information is in the FDA-EMA QbD material (32).Standardization of models is not common in the pharmaceu-tical industry, but sharing models and developing modelstandards could aid industry development work and facilitateregulator review of submission. Greater adoption of multi-disciplinary approaches using predictive modeling and simu-lation in research and development will improve the scientificproduct and process understanding. Ultimately, this will leadto cost-effective, successful tech transfer and scale-up, andincreased confidence in the manufacturing system overall.

MANUFACTURING AND QUALITY ASSURANCE

How to Prevent, Detect, and Respond to Data IntegrityEvents

Data integrity is the degree to which a collection of datais complete, consistent, and accurate. Data integrity providesthe foundation of pharmaceutical quality. Without reliabledata, the twenty-first century vision that manufacturersproduce high quality drugs without extensive regulatoryoversight cannot be realized. Breaches of data integrity erodeconfidence of regulators and the public. Two main areas ofconcern regarding data integrity are (i) supplying data to ahealth authority as a result of an inspection and (ii) providingdata as part of a regulatory submission. Data integrity issuescan occur at any time and in any place to any company. Datamay be unreliable due to sloppiness and inadvertent errors. Apattern of errors can raise questions about the overallreliability of the data. Common causes of data integrityproblems include:

& Quality system does not have adequate controls andoversight of manufacturing operations and processes;

& Business and performance pressure such as timepressure, inventory demands, and desire to meetmetrics/goals;

& Cultural pressure such as deliberated attempt to hideerrors and desire to deflect accountability;

& Inadequate processes and technology such as inse-cure computer systems and lack of training.

In responding to the data integrity problems, the firmneeds to conduct comprehensive investigations to uncoverroot causes, determine the effect of deficient documentationpractices on the quality of the drug product released fordistribution and develop a management strategy to detail thefirm’s global corrective action and preventative action plan.

539Advancing Product Quality: a Summary of the Second FDA/PQRI

At the end, the FDA may re-inspect the firm to prevent thereoccurrence of data integrity problems.

In summary, the firm should maintain accuracy, reliabledesign, consistent intended performance of record systems,and both paper document systems and computerized systems.Both paper and electronic data should be controlled to ensureauthenticity, integrity, confidentiality, retrievability, accuracy,consistency, and completeness throughout the data lifecycle.Hand-written and electronic signature controls should be inplace to ensure legal binding. Ultimately, effective qualitysystems and management governance assure data integrity.

Continuous Manufacturing

Continuous manufacturing is an emerging technologythat offers opportunities for all stakeholders: patients, regu-lators, and industry. Potential benefits include (i) reducedvariability and increased reliability through the adoption ofprecise control; (ii) reduced costs due to the reduction inequipment footprints and increased process efficiency; (iii)reduced processing time per unit dose (minutes vs. days); (iv)elimination of scale-up bottlenecks leading to more agile andresponsive supply chains; and (v) increased capability torapidly respond to drug shortages, emergencies, and patientdemand to ensure a consistent supply of high qualitymedicines. The implementation of continuous manufacturingdoes present challenges to both industry and regulatory

bodies, but quality risk management provides a frameworkfor identifying and communicating approaches for addressingthese challenges.

Deep process understanding provides a basis for identi-fying and evaluating hazards and failure modes and thescientific foundation for designing controls to mitigate theserisks. One of the key areas of understanding in process designand control strategy development is the understanding ofmaterial flow. Knowledge of system dynamics can be used topredict how disturbances propagate through the process. Inthis way, knowledge of system dynamics can be used to trackand separate conforming and non-conforming product. Cap-turing the understanding of system dynamics may include thedevelopment of process models.

The control strategy for a continuous process should bedesigned to mitigate product quality risks in response topotential variations over time. Criteria for establishing a stateof control will depend on the control strategy implementationoptions (Fig. 6). For continuous manufacturing, the controlstrategy may need to integrate more advanced approaches tomitigate the identified risks such as (i) the establishing criteriafor state of control (e.g., start up and shutdown); (ii) in-process monitoring (including PAT); (iii) process controls(including model-based controls); (iv) material tracking anddiversion schemes for non-conforming product; (v) analysis oflarge data sets for trending and continuous improvement; and(vi) real-time release testing. The design of the controlstrategy should ensure uniform character and quality within

Fig. 6. Control strategy implementation options (33). There are three levels of controlstrategy implementation: Level 1—active control system with real time monitoring ofprocess variables and quality attributes (reliant on active process controls system); level2—operation within established ranges (multivariate) and confirmed with final testing orsurrogate models (reliant on process monitoring and diversion of nonconforming material);and Level 3—unlikely to be operationally feasible for addressing natural variance incontinuous manufacturing without significant end product testing

540 Yu et al.

specified limits over a range of production time periods,amount of material processed, or production variation (e.g.,different lots of feedstock). Thus, the control strategyprovides flexibility for the proposed batch definition. Manu-facturers have been able to apply a variety of batchdefinitions based on specific processes and drivers and arestill able to comply with the applicable regulations.

It was noted though that regulatory expectations are thesame for continuous manufacturing as for traditional batchmanufacturing regarding the science and risk-based ap-proaches and control of processes. Dialog and alignmentbetween industry and regulators are important for successfulimplementation, and there are multiple opportunities forearly engagement with the FDA. While significant progresshas been made, some regulatory and quality aspects are stilldeveloping so there is still work to be done, such as:

& Application of continuous process verification versusvalidation campaigns;

& Integrated product specifications and dossier contentfor integrated end-to-end processes (i.e., raw mate-rials to drug product);

& Application of existing specific guidance needs to beevaluated (e.g., SUPAC guidance);

& Determination of the start of shelf life.

How to Monitor, Control, and Improve Product Quality usingProcess Capability

A high quality drug product has been defined as aproduct free of contamination and reproducibly deliveringthe therapeutic benefit promised in the label. Free ofcontamination is largely a CGMP focus while reproduciblydelivering the therapeutic benefit promised in the label isessentially the QbD focus. Therefore, the pharmaceuticalquality could be considered a function of QbD (science) and

CGMP. The objectives of QbD include (i) achieving mean-ingful product quality specifications based on assurance ofclinical performance and increased process capability and (ii)reducing product variability and defects by enhancing productand process design, understanding, and control (33).

Process capability is defined as the natural or undisturbedperformance after extraneous influences are eliminated. A stateof statistical control (i.e., stable state) means that the processexhibits no detectable patterns or trends and hence the variationseen in the data is due to random causes and is inherent to theprocess. Process capability is a leading, useful indicator ofproduct quality. It represents how well a given process couldperform when all special causes have been eliminated. Processcapability also bears a relationship to supply chainmanagement.It can be used as an indicator for supply chain dependability andto inform inventory management.

Measuring and achieving robust process capability re-quires systematic approaches. As articulated in ICH Q10, thequality system supports the objectives to achieve productrealization, establishes and maintains a state of control, andfacilitates continual improvement (34). A philosophy ofcontinuous improvement has been described as operationalexcellence. The foundation of achieving operational excel-lence is a focus on quality, which subsequently deliversbenefits in dependability, speed, and ultimately cost.

Firms recognize the benefits of understanding andcontrolling the variability in processes and product.Manufacturing in many different industries can be analyzedusing the number of standard deviations between the processmean and the nearest specification limit. This measure ofprocess capability is often given the value of sigma. Thepharmaceutical industry historically manufactured at one totwo sigma, with a significant focus on compliance and meetingspecifications. However, spurned by recent quality initiatives,six sigma are now possible in the pharmaceutical industry.Indeed, some companies, such as Lilly and Amgen, are eitherachieving or working toward six sigma. Firms are realizing

Fig. 7. The benefits of six sigma performance. By driving six sigma performance, Amgen reduced error rateby 96% and realized $400 M cumulative saving

541Advancing Product Quality: a Summary of the Second FDA/PQRI

benefits in fewer errors, faster cycle times/more productivity,and less waste/loss (as shown in Fig. 7). Achieving high sigmaperformance takes time and requires persistent support fromleadership on improving poor performing products andprocesses. Developing deep technical understanding andcontrol and working on flawless execution and human errorprevention are key contributors to success. There arechallenges in achieving high sigma including regulatoryspecification limits that were often set based on limitedprocess capability data, the small number of lots that allowthe determination of steady state, and investments andregulatory changes to manufacturing processes and analyticalmethods. Strong partnerships between industry and regula-tory agencies to remove barriers are an important part ofachieving the vision of maximally efficient pharmaceuticalmanufacturing.

How to Identify Critical Quality Attributes and CriticalProcess Parameters

In the determination of what is really critical in a process,one has to Bbegin with the end inmind^ starting with theQualityTarget Product Profile (QTPP). The QTPP prospectivelysummarizes elements of drug quality, safety, and efficacy andthus forms the basis for development of the Critical QualityAttributes (CQAs). CQAs are then used to make design andoptimization decisions and to identify critical material attributes(CMAs), critical process parameters (CPPs), and refine thecontrol strategy through a continuum of risk assessment andstructured experimentation.

Recent case studies by industry have focused onidentification of CPPs based on CQAs and mechanisticprocess and product understanding. Those studies haveshown that focusing on one product and process unitoperation to assess control space can be misleading, and bestresults have been achieved in striving for deeper mechanisticunderstanding of the product and process. Other industryefforts have focused on development of approaches utilizingstatistical tools for consistency, while still incorporatingscientific judgment and a holistic view of the control strategy.In utilizing such statistical approaches, it is important todetermine that the CPP-CQA relationship is not onlystatistically significant, but also practically significant. Genericdrug sponsors are usually faced with completely differenttimelines and drivers as compared to NDA product develop-ment. In the generic industry, where leveraging documentedprior knowledge is advantageous, QbD implementation hasbeen shown to be both scientific and strategic and should befully integrated in product development.

Drug sponsors who claim that Bnone of the drug qualityattributes are critical because of fixed material attributes andprocess parameters for all key processing steps^ will oftenhear the FDA respond that Ball material attributes andprocess parameters are potentially critical as a result oflimited characterization of the sources of variability andinadequate understanding of the impact of CMAs and CPPson the drug product CQAs.^ By contrast, sponsors that haveimplemented significant control of the CQAs with in-processor at-line measurements (e.g., via NIR spectroscopy) will findthat the FDA will focus the review on the control of criticalsteps and intermediates (e.g., using the NIR test method).

SUMMARY

The October 2015 FDA/PQRI Conference on Advanc-ing Product Quality provided a forum for the exchange ofideas focused on drug product quality between regulatoryagencies, the pharmaceutical industry, and academia. Keytopics of the 2015 conference were (i) emerging regulatoryinitiatives; (ii) regulatory submission, assessment, and inspec-tion; (iii) product and process development; and (iv)manufacturing, risk management, and quality assurance.Key discussion points and recommendations for each trackand session have been captured. With powerful advance-ments in product quality encompassing regulatory, industrial,and technological elements, an era of rapidly improvingpharmaceutical quality is underway. At the conference, onetheme prevailed through all sessions: regulators, industry, andacademia are aligned in their desire for drug product qualityon behalf of the ultimate stakeholder–the patient.

3D three dimensional, ANDA abbreviated new drugapplication, API active pharmaceutical ingredient, ASTMAmerican society for testing and materials, BCSbiopharmaceutics classification system, BLA biological li-cense application, CGMP current good manufacturing prac-tice, CMA critical material attribute, CMC chemistrymanufacturing and controls, CPP critical process parameters,CQA critical quality attribute, CU content uniformity, DLSdynamic light scattering, DOE design of experiment, EMAEuropean Medicines Agency, EWG Expert Working Group,FDA Food and Drug Administration, GDUFA generic druguser fee amendments, HCl Hydrogen Chloride, ICH Interna-tional Conference on Harmonisation of Technical Require-ments for Registration of Pharmaceuticals for Human Use,IND investigational new drug, IQA integrated quality assess-ment, IR immediate release, IR information request, ISPEInternational Society for Pharmaceutical Engineering, MITMassachusetts Institute of Technology, NDA new drugapplication, NIPP new inspection protocols project, NIRnear-infrared spectroscopy, OPQ office of pharmaceuticalquality, PAI pre-approval inspection, PAT process analyticaltechnology, PDUFA prescription drug user fee act, PHSpublic health service, PQRI Product Quality ResearchInstitute, PQS pharmaceutical quality system, QbD qualityby design, QMS quality management system, QRM qualityrisk management, QTPP quality target product profile, RPMrevolutions per minute, RTRT real time release testing,SUPAC scale-up and post-approval changes, UDU uniformityof dosage units, USP U.S. Pharmacopeial Convention.

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