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Understanding Quality Paradigm Shifts in the Evolving Pharmaceutical Landscape: Perspectives from the USP Quality Advisory Group

Understanding Quality Paradigm Shifts in the Evolving Pharmaceutical Landscape: Perspectives from... AAPS J (2021) 23:112 Vol(0123456789) https://doi.org/10.1208/s12248-021-00634-5 Commentary Understanding Quality Paradigm Shifts in the Evolving Pharmaceutical Landscape: Perspectives from the USP Quality Advisory Group 1 2,11 3 4 2 Jane Weitzel · Horacio Pappa · Gregory M. Banik · Amy R. Barker · Elizabeth Bladen · 5 6 2 2 7 2 Narendra Chirmule · Joseph DeFeo · Jennifer Devine · Steven Emrick · Taha Kass Hout · Michael S. Levy · 8 9 2 10 Gugu N. Mahlangu · Barbara Rellahan · Jaap Venema · Wesley Workman Received: 17 February 2021 / Accepted: 1 August 2021 Abstract  Recent changes in the pharmaceutical industry have led to significant  paradigm  shifts in the pharmaceutical quality environment. Globalization of the pharmaceuticalindus- try, increasingly rapid development of novel therapies, and adoption of new manufacturing techniques have presented numerous challenges for the established regulatory framework and quality environment and are impacting the approaches utilized to ensure the quality of pharmaceutical products. Regulators, industry, and standards-setting organizations have begun to recognize the need to rely more on integrated risk-based approaches and to create more nimble and flexible  standards to complement these efforts.  They also increasingly  have recognized that quality needs to be built into systems and processes throughout the lifecycle of the product. Moreover, the recent COVID-19 crisis has emphasized the need to adopt practices that better promote global supply chain resilience. In this paper, the USP Quality Advisory Group explores the various paradigm shifts currently impacting pharma- ceutical quality and the approaches that are being taken to adapt to this new environment. Broad adoption of the Analytical Procedure Lifecycle approach, improved data manage- ment, and utilization of digital technologies are identified  as potential solutions that can  help meet the challenges of these quality paradigm shifts. Further discussion and collabora- tion among stakeholders are needed to pursue these and other solutions that can ensure a continued focus on quality while facilitating pharmaceutical innovation and development. KEY WORD Advanced manufacturing · Analytical procedures lifecycle · Digital technologies and performance-based standards · Risk-based quality management systems · Supply chain INTRODUCTION   USP General Chapters–Measurement and Data Quality Expert  Committee, Rockville, Maryland, USA   United States Pharmacopeia, 12601 Twinbrook Pkwy, Rockville,  Defining  expectations for medicine quality and establishing  Maryland 20852, USA conformance to those expectations traditionally has been a    STMatics, LLC, Philadelphia, Pennsylvania, USA joint effort  involving regulators, the pharmaceutical industry,  Eli Lilly and Company, Indianapolis, Indiana 46285, USA pharmacopeias, and other stakeholders. Until recently, this   Symphony Tech Biologics, Bengaluru, Karnataka, India Juran Inc., 160 Main St., Southington, Connecticut 06489, USA was a relatively straightforward exercise: quality standards    Amazon Web Services (AWS), 410 Terry Ave., North Seattle,  were established following product approval, essentially Washington 98109, USA mirroring the specifications  approved by the relevant regu- Medicines Control Authority of Zimbabwe (MCAZ), Harare, latory agency, and quality was determined by testing the Zimbabwe   Amgen, 601 13th Street N.W., 12th Floor, Washington,  end product. Providers and patients have had confidence  in  District of Columbia 20005, USA the medicines they used knowing that the final  product met    USP General Chapters–Biological Analysis Expert Committee,  pharmacopeial standards and other regulatory requirements. Rockville, MD, USA Over the past two decades, however, there have been dra-   To whom correspondence should be addressed. (e–mail: HP@ usp.org) matic and sweeping changes in pharmaceutical development Vol.:(0123456789) Vol(0123456789) AAPS J (2021) 23:112 • The pharmaceutical supply chain has become increas- and the manufacturing environment—changes which are only accelerating as we look into the future. These changes  ingly complex due to operations globalization, local  sourcing, customer accommodation (i.e., variety and are having significant  implications for how we think about  pharmaceutical quality and offer  both opportunities and  customization of products), and managing omnichannel supply chains amid technology turnover and company challenges for better defining  and measuring quality. In 2019, USP formed a Quality Advisory Group to assist mergers (4). Globalization specifically  has introduced  additional points of vulnerability in the supply chain and in exploring the changes in the pharmaceutical development  and the manufacturing environment that have occurred and stakeholders are exploring a number of track and trace  (TnT) type of solutions to help (e.g., blockchain) (5). implications for how regulators, industry, pharmacopeias, and others collaborate to safeguard the quality of medicines. A key challenge in a globalized market is how to safe- guard the quality and consistency of medicines without The purpose of this paper is to share the findings  of the  Advisory Group. More broadly, USP seeks to assist industry, increasing the barriers to access in less developed coun- tries which may lack the resources or technology to meet regulators, and other stakeholders by creating a platform for investigating these quality paradigm shifts, and ulti- or enforce stringent standards. mately, the development and implementation of collabora- tive solutions. Quality expectations need to be managed in a way that  facilitates efficient  drug development, manufacturing, and  distribution on a global scale, while ensuring that provid- ers and patients in all parts of the world can obtain quality medicines. PHARMACEUTICAL INDUSTRY TRENDS New Therapies and Modalities Domestic to Global A second major pharmaceutical industry trend has been In recent years, the pharmaceutical industry has become the introduction of increasingly complex and sophisticated  truly globalized, at all stages of the drug development pro- therapies and treatment modalities. cess. Greater than 40% of finished  drugs and 80% of active  pharmaceutical ingredients sold are produced outside of • In a review article examining the drug development  the USA (1). Medicines are now developed and manufac- pipeline in 2017, approximately three-quarters (74%) of  tured with a global mindset, with manufacturers focused on clinical-phase projects were potentially first-in-class  (6). optimizing manufacturing across multiple production sites Combination products are becoming increasingly com- in countries with highly variable technical and regulatory mon, including drug-device and diagnostic-drug products capacities. This trend will only continue in the future, as  that allow medicines to be better targeted and delivered. pharmaceutical manufacturers look to a global market fueled • Digital therapeutics, which use technology to help man- by expansion in “pharmerging” countries (e.g., China, Bra- age, monitor, and prevent illness, are rapidly being intro- zil, Russia, India, and South Korea) (2) as well as aging duced and implemented both as an alternative and sup- demographic trends in developed countries (3). plement to conventional medicines. Recently, the COVID-19 pandemic has exposed numer- • Personalized or precision medicine, which can tailor ous vulnerabilities and challenges created by the globali- products to individual patients based on genetic char- zation of the pharmaceutical industry. While concern over acteristics and predicted outcomes, is a promising and the lack of security and robustness of the supply chain has quickly growing area of cell and gene therapies. been growing over the past two decades, the impact of the • Advances in engineering and software technologies have COVID-19 pandemic has made it starkly apparent that this is transformed the drug development process, from gene a critical issue that needs to be promptly addressed. It is now sequencing, process engineering, and analytical tech- recognized more than ever the need to establish and evolve nologies to data modeling and analytics. Ensuring qual- quality standards to reflect  the global nature of the pharma- ity standards in this fast-paced environment with rapid ceutical supply chain to help ensure quality medicines and technological advances will require close alignment with avoid potentially harmful consequences. As a result of this industry, regulators, and other stakeholders. globalization: These new advanced therapies and modalities require new  • There is a need for greater harmonization of quality  thinking about how quality can be evaluated and determined. standards and requirements, so that manufacturers are not Traditional quality expectations—identity, strength, quality,  faced with conflicting  and/or duplicative requirements  and purity—may need to be re-defined  for new modalities to  across countries that add cost without providing value. AAPS J (2021) 23:112 Vol(0123456789) establish consistent and appropriate expectations for these  including federal regulations regarding testing and release products to help ensure their quality. for distribution (11), was a key driver of product decisions and created a focus on end-product testing, with a binary New Manufacturing Approaches pass/fail result (12). There is a recognition that the goal is  not compliance per se, but rather the ability to ensure qual- Driven by goals such as increased efficiency,  a desire for a  ity as products move through development and manufactur- ing through the use of mature quality systems and metrics. smaller environmental impact, reduced risk of drug product quality issues, and shorter time to production, the pharma- The binary pass/fail result is enhanced and supported with  increased product knowledge and understanding. As a result: ceutical industry is starting to move to new and alternative technological and manufacturing approaches. • The pharmaceutical industry and regulators are explor- • Pharmaceutical manufacturing is transitioning from the ing pathways toward identifying and mitigating risks throughout the lifecycle of medicines (13). traditional “batch” process—in which finished  products  are made in an intermittent series of steps—to more effi - Industry increasingly is employing statistical and sci- entific  techniques to analyze and address risk, to help  cient approaches and control strategies for manufactur- ing drug substances and drug products (e.g., continuous prevent failures instead of detecting them after the fact. • Predictive analytics are being used to better understand manufacturing, “on-demand” manufacturing, role of  automation) (7). and anticipate areas of risk and vulnerability. • • The pharmaceutical industry is using science and risk- Improved data and analytical technologies are available to measure more components and intermediates; each based approaches to establish patient-centric control strategies. with increasingly more accuracy. • In silico modeling approaches, such as digital twins, use As data aggregation and analytical capabilities continue of electronic-data capture, analysis, and monitoring sys- tems are being used. to expand, the ability to better identify risk and target oppor- • tunities for quality improvement will also continue to grow New manufacturing trends continue to emerge such as 3D  printing and single-use/disposable equipment that allow mod- and should be leveraged. For adoption of risk-based control strategies to be successful, industry needs to demonstrate the ularized manufacturing to scale up capacity with potentially no changes to manufacturing facilities or equipment (8). rigor and applicability of these strategies, while regulatory pathways and guidelines need to provide flexibility  and clear  As technology continues to advance, these novel expectations for implementation of such approaches. approaches to manufacturing will continue to gain traction in the industry. It will be critical to have regulatory pathways Paradigm Shift #2: from Prescriptive Approaches that provide clear expectations for how to introduce and sup- to Flexible Performance and Outcome‑Based Standards port new technologies to facilitate timely implementation. Establishment of guidance and best practices for adoption of Given the increasing rate of innovation in pharmaceutical these technologies will also be necessary to facilitate their therapies and manufacturing methods, as well as the need to efficient  and economical adoption, which in turn will sup- accommodate a diverse global marketplace, overly prescrip- port and encourage broader adoption and improve quality. tive approaches to determining product quality may impede innovation and slow patient access to needed new therapies. • Standards should accommodate and facilitate develop- QUALITY PARADIGM SHIFTS ment of new products and therapies, and lower barriers to innovation and access. Associated with these major industry trends, and in many Standards need to account for wide variations in techno- cases resulting from them, are fundamental and interrelated logical capabilities and resources of industry and regula- shifts in how industry, regulators, and standards-setting bod- tors globally. ies are approaching and assessing quality. • Standards should be designed to offer stakeholders options to achieve the same or better-quality products by focusing on performance and outcome-based standards. Paradigm Shift #1: from Compliance‑Driven to Integrated Risk‑Based Approaches The challenge is to ensure that even as standards become  more flexible,  they will continue to provide the same assur- In the past, the need to show regulatory compliance to ance of medicine quality and consistency for providers and current good manufacturing practices (CGMP) (9, 10), Vol(0123456789) AAPS J (2021) 23:112 patients in all parts of the world. Moreover, to be effective,   vulnerabilities are driven by greater complexity of the upstream  these approaches should be implemented as a coordinated supply chain and include reliance on “just-in-time” manufactur- effort  between regulators around the globe via harmoniza- ing, lack of redundancy in suppliers, increased outsourcing of tion and alignment of requirements and standards. ingredients, and even final  product manufacturing. In addition,  there is a lack of transparency of the supply chain, which can Paradigm Shift #3: from Testing Products to Building limit the ability of stakeholders to take mitigative action before it is too late. All of these risks can contribute to a supply chain Product Quality that lacks resilience and the ability scale-up to meet demand or absorb supply shocks. In addition to increased risk of drug There is an increasingly prevalent view that quality needs  shortage, the global nature of the market has also increased the to be built into systems and processes instead of “tested in”  risk of adulterated raw materials and finished  products entering  to products at the end (14). the market and has provided opportunities for data fraud (20). Recently, the COVID-19 pandemic brought these vul- • The pharmaceutical industry and regulators are increasingly  nerabilities into sharp focus, leading to calls to bring back embracing Quality by Design (QbD) approaches, which com- domestic manufacturing of products and increase the diver- prise a system of knowledge that enables pre-defined  attrib- sity and redundancy of the supply chain (21). These solu- utes for process control and product quality as outlined in ICH tions are likely to be politically popular, but ultimately, mar- guidelines Q8–11. Integrating QbD into the development and ket pressure will continue to encourage overseas production manufacturing process helps ensure consistent product quality of pharmaceuticals and their components to areas with the by understanding and controlling formulation and manufactur- lowest manufacturing costs. ing variables and critical quality attributes (15). More fundamental solutions are needed to ensure a resil- • QbD and process analytical technology (PAT) can enable  ient supply chain that has the capacity to absorb the shocks real-time process adjustments within predefined  ranges  of acute disruptions and ensure the quality of raw materials, of quality and in a manner that can be applied across drug components, and finished  drug products. Creation of  products and facilities. These in-process control deci- a framework that incentivizes quality, supply chain robust- sions can provide an increased level of quality assurance ness, and to sufficiently  address the challenges of the new  compared to traditional end-product testing and allow for global supply chain could be achieved by: real-time release testing of drug products (16). There is a recognition that quality needs to extend beyond  • Development of standards to help ensure data integrity systems and processes to the organization itself. Increas- and provide the foundation needed to facilitate effective   ingly, pharmaceutical manufacturers are seeking to estab- remote auditing and inspections. lish a “culture of quality” in which all employees feel  Development of standards and best practices that support responsible for quality (17, 18). supplier qualification  and improved evaluation of raw  materials. The shift toward QbD and an organization-wide commit- • Adoption of guidelines and best practices that encourage ment to quality is already underway, and compendial and manufacturers to conduct risk assessments to determine regulatory approaches must continue evolving to support potential weaknesses in their supply chain, such as relying and help advance this transformation. on a single source for raw materials and intermediates or utilization of “just-in-time” manufacturing, and develop- Paradigm Shift #4: Need to Ensure Supply Chain ment of corresponding solutions to mitigate these risks (22). Resilience in a Quality Environment • Increased harmonization and alignment of standards between regulatory agencies and pharmacopeias around The globalization of the pharmaceutical industry and supply  the globe. chain has benefited  patients by providing increased access  Adoption of methods and standards for tracking of drug to medicines—particularly low-cost generics—both in the components throughout the drug development process USA and around the world. Unfortunately, this shift leads to from raw materials to delivery of finished  drug products. a global supply chain that has numerous vulnerabilities and increased risks to the quality of drugs. Specifically,  one of the main risks created by the global sup- ply chain is an increase in the potential for drug shortages of EFFORTS TO ADDRESS PARADIGM SHIFTS many critical medicines. The complexity of the global supply  chain can create logistical and regulatory challenges which While it is useful to understand and recognize the quality make it difficult  for drug manufacturers to quickly ramp up  paradigm shifts in the evolving pharmaceutical landscape, production in response to increases in demand (19). Additional AAPS J (2021) 23:112 Vol(0123456789) the question remains as to how these changes should be as the United States Pharmacopeia (USP) and British Phar- addressed. Beyond just recognizing these issues, it is much macopoeia. In several Stimuli Articles, USP has presented more challenging to determine the consequent transfor- examples of how QbD approaches could be used to support  mations that need to occur to address these rapid changes flexible  yet robust strategies for analytical procedure life- and meet the diverse needs of patients and industry. While cycle development. (25–33). Recently, in September 2020, industry and science evolve organically, subsequent changes USP also proposed a new general chapter ⟨1220⟩ Analytical to guidance, standards, and regulations require purposeful Procedure Life Cycle in the Pharmacopeial Forum (33). action and periodic evaluation to ensure they are aligned The APL approach is based on and focuses on the reality  with contemporary and future needs. If standards and regu- that an analytical procedure must be demonstrated to be fit   lations fail to evolve to meet these needs, they may become for its intended purpose and provides mechanisms to move increasing detrimental and hinder rather than support from prescriptive to more flexible  approaches. The purpose  improvements needed to ensure quality. of applying lifecycle principles to analytical procedures is Regulators, industry, academia, pharmacopeias, and other to holistically align analytical procedure variability with the stakeholders have recognized the need for this evolution and requirements of the product to be tested and to improve the are pursuing new regulatory and standards approaches that reliability of the procedure by understanding, reducing, and will help ensure quality while facilitating access to afford- controlling sources of variability. Enhanced understand- able as well as novel therapies. Organizations such as the ing of variables that affect  the performance of an analytical  National Institute for Pharmaceutical Technology and Edu- procedure provides greater assurance that the quality attrib- cation (NIPTE), the American Association of Pharmaceuti- utes of the tested product can be reliably assessed. The APL  cal Scientists (AAPS), and the Product Quality Research approach provides a framework for defining  the criteria for  Institute (PQRI) reflect  broad collaborative efforts  among  and development of an analytical procedure that meets the these stakeholders to explore and advance emerging regu- acceptance criteria. The procedure then becomes part of a  latory science topics relating to the quality and efficiency   continuous verification  cycle to demonstrate that it meets the  of pharmaceutical research, development, and manufac- predefined  criteria over the life of the procedure. turing. The US Food and Drug Administration (FDA) has  In addition to the APL approach, improved data manage- been working to find  ways to accelerate and support indus- ment and increased use of digital technologies could also try adoption of advanced manufacturing technologies, and provide many potential solutions which could allow industry recently entered a memorandum of understanding (MOU) and regulators to adapt to the current paradigm shifts. Some with the National Institute of Standards and Technology  of these advances in the digital space, such as assisted intel- (NIST) to further this work (23). ligence and machine learning, are driving paradigm shifts on As an outcome of its Pharmaceutical Quality for the their own. Currently, only the surface has been scratched of twenty-first  Century Initiative, the FDA recently introduced  the potential benefits  that digital technologies could provide  a new Quality Maturity Model (QMM) (24). The FDA’s  if fully utilized and integrated throughout the pharmaceuti- interest QMM builds on ICH Guidance Q10: Pharmaceuti- cal manufacturing process. cal Quality System, which moves beyond CGMP and tradi- Applications of improved data use could include embed- tional quality management systems to the notion of an eeff c - ding of standards content software that defines  methods and  tive pharmaceutical quality system that facilitates innovation interfaces with lab instrumentation. Likewise, establishment and continuous improvement throughout the entire product of systems to ensure data integrity and automatic transfer lifecycle. Like Q10, QMM emphasizes management’s essen- to regulatory agencies could allow for added trust between tial responsibility for establishing a company-wide commit- industry and regulators. Adoption of data integrity and data ment to quality and investing in people and resources. QMM sharing along with other quality processes could be incen- recognizes that today’s complex and dynamic pharmaceu- tivized by allowing for reduction in inspections and provid- tical environment requires a multi-faceted and proactive ing for streamlined approval of products. This could benefit   approach to quality that includes risk management, predic- manufacturers who establish mature quality management tive analytics, robust quality metrics, and a focus on continu- capabilities and allow regulatory agencies to focus their ally improving performance and outcomes. efforts  on facilities at greater risk for quality issues. A step  USP’s Quality Advisory Group has identified  two funda- in this direction is FDA’s Knowledge-aided Assessment and  mental solutions that can complement these efforts  and help  Structured Application system (KASA), which uses struc- advance the transformation of quality frameworks. These are  tured data and information capture, predefined  rules, and  the broad adoption of the Analytical Procedures Lifecycle algorithms, and computer-aided analyses improve the qual- (APL) approach and increased utilization of digital technolo- ity, efficiency,  consistency, and objectivity of FDA’s regula- gies. The APL approach, which includes Analytical Quality  tory actions by evaluating risks in a more systematic fashion. by Design (aQbD), is being developed by organizations such The FDA’s commitment to KASA represents a significant   Vol(0123456789) AAPS J (2021) 23:112 regulatory paradigm shift, leveraging digitalization and of digital technologies are just two examples of potential  structured data for improved access to historical data (e.g., broad solutions that could help achieve these goals. drug flings)  related to similar products already approved on  Further dialog and engagement with industry, regulators, the market, more objective risk assessment, and greater con- and other stakeholders are needed to explore these avenues  sistency in decision-making by regulators who are reviewing and identify additional approaches that could be utilized to an ever-increasing number of filings  (34). meet the challenges of the current paradigm shifts. USP and Moreover, increased use of applications such as artifi- its Quality Advisory Group are committed to collaborat- cial intelligence and predictive analytics can provide tools ing with stakeholders to develop the best solutions to these that could allow for identification  of potential quality risks  pressing issues. before they even occur. For example, predictive analytics  Acknowledgements  The authors would like to thank additional par- could alert a formulator to the potential presence of a pre- ticipants and contributors to the work including Vincent Antonucci viously unexpected impurity, preventing potential product  and Dan Snider who both participated in discussions as independent recalls that could have a negative impact on the global drug experts. Your contributions are gratefully acknowledged. supply and public health. To realize the full potential of digital solutions, standards  Author Contribution • Jane Weitzel – Drafting the work or revising it critically for important intellectual content, substantial contributions will be needed to establish parameters that would allow for to the conception or design of the work, approval of final  content data sharing and interoperability among various digital plat- • Horacio Pappa – Substantial contributions to the conception or forms, including analytical equipment, software platforms design of the work, approval of final  content, drafting the work or  that analyze process/instrumentation data, and risk manage- revising it critically for important intellectual content, approval of final   content. Corresponding author. ment platforms used by regulators that would rely on these • Gregory M. Banik – Substantial contributions to the conception data. Given the global nature of the pharmaceutical market, or design of the work, approval of final  content even greater benefits  could be gained if this interoperabil- • Amy Barker – Substantial contributions to the conception or ity can be facilitated among regulatory agencies around the design of the work, approval of final  content • Elizabeth Bladen – Substantial contributions to the conception globe. or design of the work, drafting the work or revising it critically for important intellectual content • Narendra Chirmule – Substantial contributions to the conception  or design of the work, approval of final  content • Joseph DeFeo – Substantial contributions to the conception or CONCLUSION design of the work, approval of final  content • Jennifer Devine – Substantial contributions to the conception or Changes in the pharmaceutical industry are causing fun- design of the work, approval of final  content, drafting the work or  revising it critically for important intellectual content, approval of final   damental shifts in traditional quality paradigms. Success- content fully navigating through these shifts will require new and • Steven Emrick – Substantial contributions to the conception or innovative thinking, as well as greater collaboration across design of the work, approval of final  content. an increasingly global and diverse set of stakeholders. This  • Taha Kass-Hout – Substantial contributions to the conception or  design of the work, approval of final  content includes not just regulators, industry, and pharmacopeias, • Michael S. Levy – Approval of final  content but also new stakeholders such as data technology com- • Gugu N. Mahlangu – Substantial contributions to the conception  panies, who can help harness data and analytics to better or design of the work, approval of final  content understand and drive quality. • Jaap Venema – Approval of final  content • Wes Workman – Substantial contributions to the conception or The adoption of more flexible, agile, and iterative  design of the work, approval of final  content approaches to public standard development and delivery will also be required. Historically, standards-setting has been a static and reactive process. Given the rapid rate Funding Development of this paper was funded by the United States of change in products and technologies, standards-setting Pharmacopeia. bodies and regulators will need to employ more proactive Declarations and nimble ways of introducing, evolving, and adopting standards. Conflict of Interest  The authors declare no competing interests. Working together, with a shared recognition of both the opportunities and challenges created by this rapidly evolving environment, we can develop approaches that help ensure a continued focus on quality and continuous improvement while supporting and facilitating important advances in Please submit any input on the perspectives presented in this paper therapies and technologies. Increased adoption of an Ana- to Horacio Pappa, Director, General Chapters, United States Pharma- lytical Procedures Lifecycle Approach and an increased use copeia, email hp@usp.org. AAPS J (2021) 23:112 Vol(0123456789) Open Access  This article is licensed under a Creative Commons  13. Zhang L, Mao S. Application of quality by design in the current Attribution 4.0 International License, which permits use, sharing, drug development. Asian J Pharm Sci 2017;12(1):1–8. https:// adaptation, distribution and reproduction in any medium or format, www. scien cedir ect. com/ scien ce/ artic le/ pii/ S1818 08761 63005 75 as long as you give appropriate credit to the original author(s) and the  14.  Zacché M, Andersson M. The advantages of a ‘quality by design’  source, provide a link to the Creative Commons licence, and indicate approach in pharma drug development. Pharma Manufacturing. if changes were made. The images or other third party material in this  2020. https:// www. pharm amanu factu ring. com/ artic les/ 2019/ the- article are included in the article’s Creative Commons licence, unless  advan tages- of-a- quali ty- by- design- appro ach- in- clini cal- and- indicated otherwise in a credit line to the material. If material is not comme rcial- pharma- devel opment/. Acessed April 2021. included in the article’s Creative Commons licence and your intended   15.  International Conference on Harmonisation of Technical Require- use is not permitted by statutory regulation or exceeds the permitted  ments for Registration of Pharmaceuticals for Human Use. 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Understanding Quality Paradigm Shifts in the Evolving Pharmaceutical Landscape: Perspectives from the USP Quality Advisory Group

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AAPS J (2021) 23:112 Vol(0123456789) https://doi.org/10.1208/s12248-021-00634-5 Commentary Understanding Quality Paradigm Shifts in the Evolving Pharmaceutical Landscape: Perspectives from the USP Quality Advisory Group 1 2,11 3 4 2 Jane Weitzel · Horacio Pappa · Gregory M. Banik · Amy R. Barker · Elizabeth Bladen · 5 6 2 2 7 2 Narendra Chirmule · Joseph DeFeo · Jennifer Devine · Steven Emrick · Taha Kass Hout · Michael S. Levy · 8 9 2 10 Gugu N. Mahlangu · Barbara Rellahan · Jaap Venema · Wesley Workman Received: 17 February 2021 / Accepted: 1 August 2021 Abstract  Recent changes in the pharmaceutical industry have led to significant  paradigm  shifts in the pharmaceutical quality environment. Globalization of the pharmaceuticalindus- try, increasingly rapid development of novel therapies, and adoption of new manufacturing techniques have presented numerous challenges for the established regulatory framework and quality environment and are impacting the approaches utilized to ensure the quality of pharmaceutical products. Regulators, industry, and standards-setting organizations have begun to recognize the need to rely more on integrated risk-based approaches and to create more nimble and flexible  standards to complement these efforts.  They also increasingly  have recognized that quality needs to be built into systems and processes throughout the lifecycle of the product. Moreover, the recent COVID-19 crisis has emphasized the need to adopt practices that better promote global supply chain resilience. In this paper, the USP Quality Advisory Group explores the various paradigm shifts currently impacting pharma- ceutical quality and the approaches that are being taken to adapt to this new environment. Broad adoption of the Analytical Procedure Lifecycle approach, improved data manage- ment, and utilization of digital technologies are identified  as potential solutions that can  help meet the challenges of these quality paradigm shifts. Further discussion and collabora- tion among stakeholders are needed to pursue these and other solutions that can ensure a continued focus on quality while facilitating pharmaceutical innovation and development. KEY WORD Advanced manufacturing · Analytical procedures lifecycle · Digital technologies and performance-based standards · Risk-based quality management systems · Supply chain INTRODUCTION   USP General Chapters–Measurement and Data Quality Expert  Committee, Rockville, Maryland, USA   United States Pharmacopeia, 12601 Twinbrook Pkwy, Rockville,  Defining  expectations for medicine quality and establishing  Maryland 20852, USA conformance to those expectations traditionally has been a    STMatics, LLC, Philadelphia, Pennsylvania, USA joint effort  involving regulators, the pharmaceutical industry,  Eli Lilly and Company, Indianapolis, Indiana 46285, USA pharmacopeias, and other stakeholders. Until recently, this   Symphony Tech Biologics, Bengaluru, Karnataka, India Juran Inc., 160 Main St., Southington, Connecticut 06489, USA was a relatively straightforward exercise: quality standards    Amazon Web Services (AWS), 410 Terry Ave., North Seattle,  were established following product approval, essentially Washington 98109, USA mirroring the specifications  approved by the relevant regu- Medicines Control Authority of Zimbabwe (MCAZ), Harare, latory agency, and quality was determined by testing the Zimbabwe   Amgen, 601 13th Street N.W., 12th Floor, Washington,  end product. Providers and patients have had confidence  in  District of Columbia 20005, USA the medicines they used knowing that the final  product met    USP General Chapters–Biological Analysis Expert Committee,  pharmacopeial standards and other regulatory requirements. Rockville, MD, USA Over the past two decades, however, there have been dra-   To whom correspondence should be addressed. (e–mail: HP@ usp.org) matic and sweeping changes in pharmaceutical development Vol.:(0123456789) Vol(0123456789) AAPS J (2021) 23:112 • The pharmaceutical supply chain has become increas- and the manufacturing environment—changes which are only accelerating as we look into the future. These changes  ingly complex due to operations globalization, local  sourcing, customer accommodation (i.e., variety and are having significant  implications for how we think about  pharmaceutical quality and offer  both opportunities and  customization of products), and managing omnichannel supply chains amid technology turnover and company challenges for better defining  and measuring quality. In 2019, USP formed a Quality Advisory Group to assist mergers (4). Globalization specifically  has introduced  additional points of vulnerability in the supply chain and in exploring the changes in the pharmaceutical development  and the manufacturing environment that have occurred and stakeholders are exploring a number of track and trace  (TnT) type of solutions to help (e.g., blockchain) (5). implications for how regulators, industry, pharmacopeias, and others collaborate to safeguard the quality of medicines. A key challenge in a globalized market is how to safe- guard the quality and consistency of medicines without The purpose of this paper is to share the findings  of the  Advisory Group. More broadly, USP seeks to assist industry, increasing the barriers to access in less developed coun- tries which may lack the resources or technology to meet regulators, and other stakeholders by creating a platform for investigating these quality paradigm shifts, and ulti- or enforce stringent standards. mately, the development and implementation of collabora- tive solutions. Quality expectations need to be managed in a way that  facilitates efficient  drug development, manufacturing, and  distribution on a global scale, while ensuring that provid- ers and patients in all parts of the world can obtain quality medicines. PHARMACEUTICAL INDUSTRY TRENDS New Therapies and Modalities Domestic to Global A second major pharmaceutical industry trend has been In recent years, the pharmaceutical industry has become the introduction of increasingly complex and sophisticated  truly globalized, at all stages of the drug development pro- therapies and treatment modalities. cess. Greater than 40% of finished  drugs and 80% of active  pharmaceutical ingredients sold are produced outside of • In a review article examining the drug development  the USA (1). Medicines are now developed and manufac- pipeline in 2017, approximately three-quarters (74%) of  tured with a global mindset, with manufacturers focused on clinical-phase projects were potentially first-in-class  (6). optimizing manufacturing across multiple production sites Combination products are becoming increasingly com- in countries with highly variable technical and regulatory mon, including drug-device and diagnostic-drug products capacities. This trend will only continue in the future, as  that allow medicines to be better targeted and delivered. pharmaceutical manufacturers look to a global market fueled • Digital therapeutics, which use technology to help man- by expansion in “pharmerging” countries (e.g., China, Bra- age, monitor, and prevent illness, are rapidly being intro- zil, Russia, India, and South Korea) (2) as well as aging duced and implemented both as an alternative and sup- demographic trends in developed countries (3). plement to conventional medicines. Recently, the COVID-19 pandemic has exposed numer- • Personalized or precision medicine, which can tailor ous vulnerabilities and challenges created by the globali- products to individual patients based on genetic char- zation of the pharmaceutical industry. While concern over acteristics and predicted outcomes, is a promising and the lack of security and robustness of the supply chain has quickly growing area of cell and gene therapies. been growing over the past two decades, the impact of the • Advances in engineering and software technologies have COVID-19 pandemic has made it starkly apparent that this is transformed the drug development process, from gene a critical issue that needs to be promptly addressed. It is now sequencing, process engineering, and analytical tech- recognized more than ever the need to establish and evolve nologies to data modeling and analytics. Ensuring qual- quality standards to reflect  the global nature of the pharma- ity standards in this fast-paced environment with rapid ceutical supply chain to help ensure quality medicines and technological advances will require close alignment with avoid potentially harmful consequences. As a result of this industry, regulators, and other stakeholders. globalization: These new advanced therapies and modalities require new  • There is a need for greater harmonization of quality  thinking about how quality can be evaluated and determined. standards and requirements, so that manufacturers are not Traditional quality expectations—identity, strength, quality,  faced with conflicting  and/or duplicative requirements  and purity—may need to be re-defined  for new modalities to  across countries that add cost without providing value. AAPS J (2021) 23:112 Vol(0123456789) establish consistent and appropriate expectations for these  including federal regulations regarding testing and release products to help ensure their quality. for distribution (11), was a key driver of product decisions and created a focus on end-product testing, with a binary New Manufacturing Approaches pass/fail result (12). There is a recognition that the goal is  not compliance per se, but rather the ability to ensure qual- Driven by goals such as increased efficiency,  a desire for a  ity as products move through development and manufactur- ing through the use of mature quality systems and metrics. smaller environmental impact, reduced risk of drug product quality issues, and shorter time to production, the pharma- The binary pass/fail result is enhanced and supported with  increased product knowledge and understanding. As a result: ceutical industry is starting to move to new and alternative technological and manufacturing approaches. • The pharmaceutical industry and regulators are explor- • Pharmaceutical manufacturing is transitioning from the ing pathways toward identifying and mitigating risks throughout the lifecycle of medicines (13). traditional “batch” process—in which finished  products  are made in an intermittent series of steps—to more effi - Industry increasingly is employing statistical and sci- entific  techniques to analyze and address risk, to help  cient approaches and control strategies for manufactur- ing drug substances and drug products (e.g., continuous prevent failures instead of detecting them after the fact. • Predictive analytics are being used to better understand manufacturing, “on-demand” manufacturing, role of  automation) (7). and anticipate areas of risk and vulnerability. • • The pharmaceutical industry is using science and risk- Improved data and analytical technologies are available to measure more components and intermediates; each based approaches to establish patient-centric control strategies. with increasingly more accuracy. • In silico modeling approaches, such as digital twins, use As data aggregation and analytical capabilities continue of electronic-data capture, analysis, and monitoring sys- tems are being used. to expand, the ability to better identify risk and target oppor- • tunities for quality improvement will also continue to grow New manufacturing trends continue to emerge such as 3D  printing and single-use/disposable equipment that allow mod- and should be leveraged. For adoption of risk-based control strategies to be successful, industry needs to demonstrate the ularized manufacturing to scale up capacity with potentially no changes to manufacturing facilities or equipment (8). rigor and applicability of these strategies, while regulatory pathways and guidelines need to provide flexibility  and clear  As technology continues to advance, these novel expectations for implementation of such approaches. approaches to manufacturing will continue to gain traction in the industry. It will be critical to have regulatory pathways Paradigm Shift #2: from Prescriptive Approaches that provide clear expectations for how to introduce and sup- to Flexible Performance and Outcome‑Based Standards port new technologies to facilitate timely implementation. Establishment of guidance and best practices for adoption of Given the increasing rate of innovation in pharmaceutical these technologies will also be necessary to facilitate their therapies and manufacturing methods, as well as the need to efficient  and economical adoption, which in turn will sup- accommodate a diverse global marketplace, overly prescrip- port and encourage broader adoption and improve quality. tive approaches to determining product quality may impede innovation and slow patient access to needed new therapies. • Standards should accommodate and facilitate develop- QUALITY PARADIGM SHIFTS ment of new products and therapies, and lower barriers to innovation and access. Associated with these major industry trends, and in many Standards need to account for wide variations in techno- cases resulting from them, are fundamental and interrelated logical capabilities and resources of industry and regula- shifts in how industry, regulators, and standards-setting bod- tors globally. ies are approaching and assessing quality. • Standards should be designed to offer stakeholders options to achieve the same or better-quality products by focusing on performance and outcome-based standards. Paradigm Shift #1: from Compliance‑Driven to Integrated Risk‑Based Approaches The challenge is to ensure that even as standards become  more flexible,  they will continue to provide the same assur- In the past, the need to show regulatory compliance to ance of medicine quality and consistency for providers and current good manufacturing practices (CGMP) (9, 10), Vol(0123456789) AAPS J (2021) 23:112 patients in all parts of the world. Moreover, to be effective,   vulnerabilities are driven by greater complexity of the upstream  these approaches should be implemented as a coordinated supply chain and include reliance on “just-in-time” manufactur- effort  between regulators around the globe via harmoniza- ing, lack of redundancy in suppliers, increased outsourcing of tion and alignment of requirements and standards. ingredients, and even final  product manufacturing. In addition,  there is a lack of transparency of the supply chain, which can Paradigm Shift #3: from Testing Products to Building limit the ability of stakeholders to take mitigative action before it is too late. All of these risks can contribute to a supply chain Product Quality that lacks resilience and the ability scale-up to meet demand or absorb supply shocks. In addition to increased risk of drug There is an increasingly prevalent view that quality needs  shortage, the global nature of the market has also increased the to be built into systems and processes instead of “tested in”  risk of adulterated raw materials and finished  products entering  to products at the end (14). the market and has provided opportunities for data fraud (20). Recently, the COVID-19 pandemic brought these vul- • The pharmaceutical industry and regulators are increasingly  nerabilities into sharp focus, leading to calls to bring back embracing Quality by Design (QbD) approaches, which com- domestic manufacturing of products and increase the diver- prise a system of knowledge that enables pre-defined  attrib- sity and redundancy of the supply chain (21). These solu- utes for process control and product quality as outlined in ICH tions are likely to be politically popular, but ultimately, mar- guidelines Q8–11. Integrating QbD into the development and ket pressure will continue to encourage overseas production manufacturing process helps ensure consistent product quality of pharmaceuticals and their components to areas with the by understanding and controlling formulation and manufactur- lowest manufacturing costs. ing variables and critical quality attributes (15). More fundamental solutions are needed to ensure a resil- • QbD and process analytical technology (PAT) can enable  ient supply chain that has the capacity to absorb the shocks real-time process adjustments within predefined  ranges  of acute disruptions and ensure the quality of raw materials, of quality and in a manner that can be applied across drug components, and finished  drug products. Creation of  products and facilities. These in-process control deci- a framework that incentivizes quality, supply chain robust- sions can provide an increased level of quality assurance ness, and to sufficiently  address the challenges of the new  compared to traditional end-product testing and allow for global supply chain could be achieved by: real-time release testing of drug products (16). There is a recognition that quality needs to extend beyond  • Development of standards to help ensure data integrity systems and processes to the organization itself. Increas- and provide the foundation needed to facilitate effective   ingly, pharmaceutical manufacturers are seeking to estab- remote auditing and inspections. lish a “culture of quality” in which all employees feel  Development of standards and best practices that support responsible for quality (17, 18). supplier qualification  and improved evaluation of raw  materials. The shift toward QbD and an organization-wide commit- • Adoption of guidelines and best practices that encourage ment to quality is already underway, and compendial and manufacturers to conduct risk assessments to determine regulatory approaches must continue evolving to support potential weaknesses in their supply chain, such as relying and help advance this transformation. on a single source for raw materials and intermediates or utilization of “just-in-time” manufacturing, and develop- Paradigm Shift #4: Need to Ensure Supply Chain ment of corresponding solutions to mitigate these risks (22). Resilience in a Quality Environment • Increased harmonization and alignment of standards between regulatory agencies and pharmacopeias around The globalization of the pharmaceutical industry and supply  the globe. chain has benefited  patients by providing increased access  Adoption of methods and standards for tracking of drug to medicines—particularly low-cost generics—both in the components throughout the drug development process USA and around the world. Unfortunately, this shift leads to from raw materials to delivery of finished  drug products. a global supply chain that has numerous vulnerabilities and increased risks to the quality of drugs. Specifically,  one of the main risks created by the global sup- ply chain is an increase in the potential for drug shortages of EFFORTS TO ADDRESS PARADIGM SHIFTS many critical medicines. The complexity of the global supply  chain can create logistical and regulatory challenges which While it is useful to understand and recognize the quality make it difficult  for drug manufacturers to quickly ramp up  paradigm shifts in the evolving pharmaceutical landscape, production in response to increases in demand (19). Additional AAPS J (2021) 23:112 Vol(0123456789) the question remains as to how these changes should be as the United States Pharmacopeia (USP) and British Phar- addressed. Beyond just recognizing these issues, it is much macopoeia. In several Stimuli Articles, USP has presented more challenging to determine the consequent transfor- examples of how QbD approaches could be used to support  mations that need to occur to address these rapid changes flexible  yet robust strategies for analytical procedure life- and meet the diverse needs of patients and industry. While cycle development. (25–33). Recently, in September 2020, industry and science evolve organically, subsequent changes USP also proposed a new general chapter ⟨1220⟩ Analytical to guidance, standards, and regulations require purposeful Procedure Life Cycle in the Pharmacopeial Forum (33). action and periodic evaluation to ensure they are aligned The APL approach is based on and focuses on the reality  with contemporary and future needs. If standards and regu- that an analytical procedure must be demonstrated to be fit   lations fail to evolve to meet these needs, they may become for its intended purpose and provides mechanisms to move increasing detrimental and hinder rather than support from prescriptive to more flexible  approaches. The purpose  improvements needed to ensure quality. of applying lifecycle principles to analytical procedures is Regulators, industry, academia, pharmacopeias, and other to holistically align analytical procedure variability with the stakeholders have recognized the need for this evolution and requirements of the product to be tested and to improve the are pursuing new regulatory and standards approaches that reliability of the procedure by understanding, reducing, and will help ensure quality while facilitating access to afford- controlling sources of variability. Enhanced understand- able as well as novel therapies. Organizations such as the ing of variables that affect  the performance of an analytical  National Institute for Pharmaceutical Technology and Edu- procedure provides greater assurance that the quality attrib- cation (NIPTE), the American Association of Pharmaceuti- utes of the tested product can be reliably assessed. The APL  cal Scientists (AAPS), and the Product Quality Research approach provides a framework for defining  the criteria for  Institute (PQRI) reflect  broad collaborative efforts  among  and development of an analytical procedure that meets the these stakeholders to explore and advance emerging regu- acceptance criteria. The procedure then becomes part of a  latory science topics relating to the quality and efficiency   continuous verification  cycle to demonstrate that it meets the  of pharmaceutical research, development, and manufac- predefined  criteria over the life of the procedure. turing. The US Food and Drug Administration (FDA) has  In addition to the APL approach, improved data manage- been working to find  ways to accelerate and support indus- ment and increased use of digital technologies could also try adoption of advanced manufacturing technologies, and provide many potential solutions which could allow industry recently entered a memorandum of understanding (MOU) and regulators to adapt to the current paradigm shifts. Some with the National Institute of Standards and Technology  of these advances in the digital space, such as assisted intel- (NIST) to further this work (23). ligence and machine learning, are driving paradigm shifts on As an outcome of its Pharmaceutical Quality for the their own. Currently, only the surface has been scratched of twenty-first  Century Initiative, the FDA recently introduced  the potential benefits  that digital technologies could provide  a new Quality Maturity Model (QMM) (24). The FDA’s  if fully utilized and integrated throughout the pharmaceuti- interest QMM builds on ICH Guidance Q10: Pharmaceuti- cal manufacturing process. cal Quality System, which moves beyond CGMP and tradi- Applications of improved data use could include embed- tional quality management systems to the notion of an eeff c - ding of standards content software that defines  methods and  tive pharmaceutical quality system that facilitates innovation interfaces with lab instrumentation. Likewise, establishment and continuous improvement throughout the entire product of systems to ensure data integrity and automatic transfer lifecycle. Like Q10, QMM emphasizes management’s essen- to regulatory agencies could allow for added trust between tial responsibility for establishing a company-wide commit- industry and regulators. Adoption of data integrity and data ment to quality and investing in people and resources. QMM sharing along with other quality processes could be incen- recognizes that today’s complex and dynamic pharmaceu- tivized by allowing for reduction in inspections and provid- tical environment requires a multi-faceted and proactive ing for streamlined approval of products. This could benefit   approach to quality that includes risk management, predic- manufacturers who establish mature quality management tive analytics, robust quality metrics, and a focus on continu- capabilities and allow regulatory agencies to focus their ally improving performance and outcomes. efforts  on facilities at greater risk for quality issues. A step  USP’s Quality Advisory Group has identified  two funda- in this direction is FDA’s Knowledge-aided Assessment and  mental solutions that can complement these efforts  and help  Structured Application system (KASA), which uses struc- advance the transformation of quality frameworks. These are  tured data and information capture, predefined  rules, and  the broad adoption of the Analytical Procedures Lifecycle algorithms, and computer-aided analyses improve the qual- (APL) approach and increased utilization of digital technolo- ity, efficiency,  consistency, and objectivity of FDA’s regula- gies. The APL approach, which includes Analytical Quality  tory actions by evaluating risks in a more systematic fashion. by Design (aQbD), is being developed by organizations such The FDA’s commitment to KASA represents a significant   Vol(0123456789) AAPS J (2021) 23:112 regulatory paradigm shift, leveraging digitalization and of digital technologies are just two examples of potential  structured data for improved access to historical data (e.g., broad solutions that could help achieve these goals. drug flings)  related to similar products already approved on  Further dialog and engagement with industry, regulators, the market, more objective risk assessment, and greater con- and other stakeholders are needed to explore these avenues  sistency in decision-making by regulators who are reviewing and identify additional approaches that could be utilized to an ever-increasing number of filings  (34). meet the challenges of the current paradigm shifts. USP and Moreover, increased use of applications such as artifi- its Quality Advisory Group are committed to collaborat- cial intelligence and predictive analytics can provide tools ing with stakeholders to develop the best solutions to these that could allow for identification  of potential quality risks  pressing issues. before they even occur. For example, predictive analytics  Acknowledgements  The authors would like to thank additional par- could alert a formulator to the potential presence of a pre- ticipants and contributors to the work including Vincent Antonucci viously unexpected impurity, preventing potential product  and Dan Snider who both participated in discussions as independent recalls that could have a negative impact on the global drug experts. Your contributions are gratefully acknowledged. supply and public health. To realize the full potential of digital solutions, standards  Author Contribution • Jane Weitzel – Drafting the work or revising it critically for important intellectual content, substantial contributions will be needed to establish parameters that would allow for to the conception or design of the work, approval of final  content data sharing and interoperability among various digital plat- • Horacio Pappa – Substantial contributions to the conception or forms, including analytical equipment, software platforms design of the work, approval of final  content, drafting the work or  that analyze process/instrumentation data, and risk manage- revising it critically for important intellectual content, approval of final   content. Corresponding author. ment platforms used by regulators that would rely on these • Gregory M. Banik – Substantial contributions to the conception data. Given the global nature of the pharmaceutical market, or design of the work, approval of final  content even greater benefits  could be gained if this interoperabil- • Amy Barker – Substantial contributions to the conception or ity can be facilitated among regulatory agencies around the design of the work, approval of final  content • Elizabeth Bladen – Substantial contributions to the conception globe. or design of the work, drafting the work or revising it critically for important intellectual content • Narendra Chirmule – Substantial contributions to the conception  or design of the work, approval of final  content • Joseph DeFeo – Substantial contributions to the conception or CONCLUSION design of the work, approval of final  content • Jennifer Devine – Substantial contributions to the conception or Changes in the pharmaceutical industry are causing fun- design of the work, approval of final  content, drafting the work or  revising it critically for important intellectual content, approval of final   damental shifts in traditional quality paradigms. Success- content fully navigating through these shifts will require new and • Steven Emrick – Substantial contributions to the conception or innovative thinking, as well as greater collaboration across design of the work, approval of final  content. an increasingly global and diverse set of stakeholders. This  • Taha Kass-Hout – Substantial contributions to the conception or  design of the work, approval of final  content includes not just regulators, industry, and pharmacopeias, • Michael S. Levy – Approval of final  content but also new stakeholders such as data technology com- • Gugu N. Mahlangu – Substantial contributions to the conception  panies, who can help harness data and analytics to better or design of the work, approval of final  content understand and drive quality. • Jaap Venema – Approval of final  content • Wes Workman – Substantial contributions to the conception or The adoption of more flexible, agile, and iterative  design of the work, approval of final  content approaches to public standard development and delivery will also be required. Historically, standards-setting has been a static and reactive process. Given the rapid rate Funding Development of this paper was funded by the United States of change in products and technologies, standards-setting Pharmacopeia. bodies and regulators will need to employ more proactive Declarations and nimble ways of introducing, evolving, and adopting standards. Conflict of Interest  The authors declare no competing interests. Working together, with a shared recognition of both the opportunities and challenges created by this rapidly evolving environment, we can develop approaches that help ensure a continued focus on quality and continuous improvement while supporting and facilitating important advances in Please submit any input on the perspectives presented in this paper therapies and technologies. Increased adoption of an Ana- to Horacio Pappa, Director, General Chapters, United States Pharma- lytical Procedures Lifecycle Approach and an increased use copeia, email hp@usp.org. AAPS J (2021) 23:112 Vol(0123456789) Open Access  This article is licensed under a Creative Commons  13. Zhang L, Mao S. Application of quality by design in the current Attribution 4.0 International License, which permits use, sharing, drug development. Asian J Pharm Sci 2017;12(1):1–8. https:// adaptation, distribution and reproduction in any medium or format, www. scien cedir ect. com/ scien ce/ artic le/ pii/ S1818 08761 63005 75 as long as you give appropriate credit to the original author(s) and the  14.  Zacché M, Andersson M. The advantages of a ‘quality by design’  source, provide a link to the Creative Commons licence, and indicate approach in pharma drug development. Pharma Manufacturing. if changes were made. The images or other third party material in this  2020. https:// www. pharm amanu factu ring. com/ artic les/ 2019/ the- article are included in the article’s Creative Commons licence, unless  advan tages- of-a- quali ty- by- design- appro ach- in- clini cal- and- indicated otherwise in a credit line to the material. If material is not comme rcial- pharma- devel opment/. Acessed April 2021. included in the article’s Creative Commons licence and your intended   15.  International Conference on Harmonisation of Technical Require- use is not permitted by statutory regulation or exceeds the permitted  ments for Registration of Pharmaceuticals for Human Use. 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Journal

"The AAPS Journal"Springer Journals

Published: Oct 15, 2021

Keywords: Advanced manufacturing; Analytical procedures lifecycle; Digital technologies and performance-based standards; Risk-based quality management systems; Supply chain

References