Enabling Global Pharma Innovation: Delivering for Patients

It is incumbent for industry to modernize manufacturing processes to improve efficiency and increase confidence in quality assurance for the benefit of patients while introducing novel technology and modalities as the science advances. However, significant barriers exist for the global implementation of new, innovative technology for chemistry, manufacturing, and controls (CMC). Most important, the lack of global regulatory harmonization reduces incentives for industry to invest in these innovations, which, in many ways, limits access of safe, effective, and quality drug products to patients globally.

The Initiative

This initiative is consistent with ISPE’s mission and vision and is aligned with the advancement of the Pharma 4.0™ program. The scope includes innovations in modalities, modes of delivery and administration of medicines, pharmaceutical manufacturing and analytical technology, and digital transformation.

A team of industry leaders with expertise in advancing innovative technology and products and with experience addressing regulatory divergence was assembled in late 2022. This ISPE team developed a comprehensive survey, with the objective of gathering data on the specific origins, extent, and magnitude of the challenges and barriers that limit or reduce the development and implementation of innovative technologies. The survey launched in April 2023 and is still open! 

The survey consists of three parts, with the option to respond to all or any of the parts. The first is a list of questions requiring multiple-choice answers; the second requests brief answers to specific questions; and the third requests more detailed information and, where appropriate, examples of innovation challenges.

In addition, the team members intend to solicit responses from industry manufacturers, contract development and manufacturing organizations (CDOs and CMOs), material suppliers, equipment and facility engineers, and designers. Representatives from regulatory authorities are also encouraged to complete the survey. Results will be presented at meetings, summarized in blogs, and eventually issued in a report.

Data and information from the survey will be used to develop case studies and potential solutions that could serve as substrate for engagement with regulatory assessors and inspectors globally. A focus on the specific sources of challenges to innovation will encourage advancement of globally acceptable and enabling regulatory approaches and will reveal pragmatic opportunities and potential incentives to capitalize on stakeholders’ commitment to innovation.

This article describes the goal of the initiative, characterizes the anticipated challenges to innovation, summarizes the industry’s need to innovate, and discusses regulatory initiatives that are currently in progress, including learnings from the recent pandemic. In addition, this article provides an explanation of the purpose and expected outcomes from the survey, subsequent plans for communicating the results from the survey across ISPE, and development of concrete proposals to address the sources of challenges and barriers to innovation.

Program Goal

The program’s goal is to catalyze consistent and harmonized interpretation and implementation of International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, with the intention of improving global patient access to innovative medicines and technology. Addressing divergence in global regulatory expectations is imperative to improve the advancement of pharmaceutical and technological innovation. Regulatory harmonization, which is fundamentally based on criteria described in ICH guidelines, depends on several pivotal objectives, such as:

• Leveraging relevant regulatory harmonization activities under consideration and convergent regulatory approaches in progress regionally
• Increasing the level of clarity and consistency in harmonized approaches that encourage and provide incentives for implementation of innovative technology for new, approved, and generic products
• Reinforcing globally harmonized implementation of science- and risk-based ICH guidelines that are functionally necessary to advance innovative technology and approaches like Pharma 4.0™, which requires a globally agreed-upon control strategy
• Contemporizing manufacturing technologies, especially those innovations currently supported by some local or regional regulatory authorities but not universally accepted by others
• Identifying sources of business as well as regulatory challenges that serve as barriers or create limitations in development and applicability of innovations across multiple therapeutic modalities; developing and implementing solutions to reduce or eliminate these challenges
• Encouraging and providing incentives for regulatory authorities to work together to accelerate adoption and implementation of ICH guidelines and other harmonization proposals, e.g., mutual recognition and reliance and collaboration and resource-sharing
• Assessing learnings from the pandemic with respect to the global regulatory and supply distribution experience, which can serve as a roadmap for improved implementation of innovative technology and can expedite increased patient access to medicines globally

Harmonization of global regulatory requirements has formally and informally progressed for more than 30 years under the ICH. ICH is committed “to achieve greater harmonisation worldwide to ensure that safe, effective, and high-quality medicines are developed and registered in the most resource-efficient manner”1.

Internationally, acceptable scientific guidelines—primarily applicable to commercial registration of new and generic drug products and drug substances—have dramatically improved regulatory alignment for many technical approaches focused on safety, efficacy, and quality of drug products. However, several published assessments and a large body of anecdotal examples indicate that implementation of many concepts described in ICH guidelines (i.e., a single global product control strategy) is not currently achievable2.

Diverse regulatory expectations create additional burdens and challenges in carrying out continual improvement initiatives.

Problem Statement

Science- and risk-based approaches in pharmaceutical development were first explicitly described in ICH Q83and further elaborated in ICH Q9, Q10, and Q11 4^, 5^,6 as well as in Q127 for post approval changes. Conceptually, quality by design (QbD) is a prospective approach that increases process understanding, manufacturing robustness, and product knowledge to improve confidence in quality of pharmaceutical products.

However, during the last decade, industry has experienced a proliferation of regulatory divergence with respect to the interpretation and implementation of ICH guidelines (and control strategies) across geographic regions. Rather than the adoption of globally harmonized regulatory criteria, localized interpretations of ICH guidelines have resulted in widely different regulatory expectations, which have forced companies to adopt multiple control strategies for a single product using the same manufacturing process globally, or worse, diluted the control strategy toward the most conservatively harmonized common denominator.

This has created manufacturing and supply chain challenges and discouraged technical innovations that might otherwise provide increased quality assurance and expedite patient access to medicines globally, both at initial regulatory approval and for subsequent changes. These diverse regulatory expectations create additional burdens and challenges in carrying out continual improvement initiatives and, even the perception of divergence hinders innovation in product development and life cycle management while providing no improvement in product quality, safety, or efficacy. Global regulatory divergence has served as both a real and perceived barrier to develop innovative manufacturing technology, new medicinal modalities, and continual improvement initiatives that have, in some instances, created temporary drug shortages in some markets.

To date, there remains no effective mechanism to obtain consistent, globally aligned regulatory assessment for innovative pharmaceutical technologies or modalities.

Regulatory Activities

Over recent years, several regulatory agencies have established initiatives to promote pharmaceutical manufacturing innovation.

USA

The FDA established the Emerging Technology Program (ETP) in 2014 and has actively promoted the program8. In his keynote presentation at the 2022 ISPE Annual Meeting & Expo in Orlando, FL, Dr. Michael Kopcha, Director of the Office of Pharmaceutical Quality, emphasized the FDA’s commitment to promoting advanced manufacturing. The Center for Drug Evaluation and Research (CDER) established the Framework for Regulatory Advanced Manufacturing Evaluation (FRAME) initiative to prepare a regulatory framework to support the adoption of advanced manufacturing technologies that could bring benefits to patients9.

The EU

The national competent authorities of the 27 EU member states, plus those of Iceland, Liechtenstein, and Norway, and the European Medicines Agency (EMA) released the “European Medicines Agencies Network Strategy to 2025” in 202010. Three of the six strategic focus areas are data analytics, digital tools and digital transformation, and innovation. In line with this strategy, the EMA established the Innovation Task Force (ITF), a multidisciplinary group that includes scientific, regulatory, and legal competences. It was set up to ensure coordination across the agency and to provide a forum for early dialogue with applicants on innovative aspects in medicines development11.

The UK

The Medicines and Healthcare Products Regulatory Agency (MHRA) established the Innovation Office, which is open to ideas for innovative medicines, medical devices, and manufacturing processes12.

Japan

The Pharmaceuticals and Medical Devices Agency (PMDA) has established the Innovative Manufacturing Technology Working Group (IMT–WG) with objectives to propose a new regulatory framework for the pharmaceutical quality control by the new technologies and to establish PMDA’s perspective on the latest technologies of pharmaceutical quality control13.

The Need for Global Focus

Although these regulator-sponsored initiatives represent opportunities to encourage and accommodate innovative technology, each is regionally focused. To date, there remains no effective mechanism to obtain consistent, globally aligned regulatory assessment for innovative pharmaceutical technologies or modalities. Investments in the development of these innovations are costly and frequently are technically and commercially risky. This is made even more true in the absence of a regulatory landscape that does not provide for the prospect of a single globally harmonized approval for the implementation of that innovative technology or modality.

Many leaders from regulatory authorities across the globe are beginning to appreciate these challenges and the lack of a globally harmonized regulatory incentive to motivate pharmaceutical innovation. The International Coalition of Medicines Regulatory Authorities (ICMRA), consisting of the heads of 30 medicine regulatory authorities, issued a policy statement in June 2021 recognizing “that pharmaceutical manufacturers seek agility to maintain robust supply chains and continually update manufacturing processes to incorporate changes and improvements as equipment ages, suppliers change, innovations are developed, and knowledge is gained 14.”

ICMRA goes on to state that it “recognizes that regulatory authorities can gain efficiencies by developing common procedures, guidelines, requirements, and interoperable infrastructure that would facilitate the timely sharing of information among regulators on changes occurring within the supply chain”6.

ICMRA has established a pharmaceutical quality knowledge management system and, as part of this strategy, is commencing two pilot programs focusing on a) collaborative assessment, with initial focus on CMC postapproval changes and b) collaborative hybrid inspections. The overall aim of these pilots is to improve manufacturing capacity for production of critical medicines and to facilitate collaborative assessments and inspections by multiple regulatory authorities15.

In addition, regulatory work-sharing programs have introduced opportunities for regulatory alignment across multiple regulatory authorities that could serve as models for implementation of global regulatory harmonization. Project Orbis was started in May 2019 by the FDA’s Oncology Center of Excellence (OCE) to enable faster global access to cancer treatments. As of April 2023, there are eight countries involved: Australia, Brazil, Canada, Israel, Singapore, Switzerland, the UK, and the US16. The Access Consortium is a collaborative effort between Australia, Canada, Singapore, Switzerland, and the UK, all like-minded, medium-sized regulatory agencies17.

Learnings from the COVID-19 Pandemic

In response to the magnitude and urgency of the COVID-19 pandemic, several opportunities emerged that could be adapted to improve global convergence of regulatory alignment for the implementation of innovative technologies and modalities, including the following learnings:

• The implementation of parallel, rather than sequential, development in accordance with science- and risk-based approaches and effectively leveraging prior knowledge significantly accelerated the development of innovative products
• Increased collaboration between industry sponsors and regulatory authorities as well as collaboration among regulatory authorities enabled rapid approval of new applications, and applications for new manufacturing sites and manufacturing changes/optimizations that expedited global access to products
• The effective embrace of mutual reliance and mutual acceptance for both regulatory application reviews and inspections improved global access to products

Industry Push for Innovation

The pharmaceutical industry has continued to introduce innovative technologies and modalities despite the divergence in regulatory expectations. These include a) improved capability and efficiency in chromatographic separation technology for manufacture and purification of small and large molecules, b) the use of spectroscopic technologies that establish real-time release testing rather than conventional end product testing, and c) the adoption of agile manufacturing methodologies that increase flexibility through portability and modularization, and allow manufacturers to respond to patient needs on demand, offering a potential solution to enable timely access to critical medicines regionally.

Artificial intelligence (AI) and automation have also seen strong interest. This is evident from the deployment of AI and machine learning technologies to optimize manufacturing operations and processes, as well as the introduction of automation and robotics to improve operational consistency for manufacturing and analytics. Other examples include 3D printing of drug products, novel and improved devices and diagnostic tools, continuous process manufacturing, increased digitalization toward adaptive controls, and the development of innovative and patient-centric drug delivery and administration options.

These innovative technologies provide improvement to meet several important objectives:

• Increased product quality assurance
• Reliability and adaptability of supply chains and inventory management to accommodate global access to medicines
• Manufacturing and analytical efficiencies
• Continual improvement opportunities
• Product access by facilitating speed to market
• Introduction of process optimizations and new patient-centric dosage forms
• Introduction of new drug substance manufacturing technologies that are environmentally sustainable, use less energy, and produce less waste
• Seamless and integrated digital information flow up and down the supply chain operations

Industry investments in innovative technologies and modalities are incentivized by the ease with which they can be approved and implemented globally. Improving global regulatory alignment, harmonization, and collaboration are therefore critically important to motivating pharmaceutical innovation.

ISPE Actions

To deliver this initiative, ISPE has assembled a multidisciplinary, multinational team of subject matter experts under the leadership of Roger Nosal, Principal Consultant with Roger Nosal PharmaCMC Regulatory Consultants. The team is sponsored by Tom Hartman, President and CEO of ISPE, reports to the Regulatory Steering Council, and currently consists of Roger Nosal as the project lead; Carol Winfield, Senior Director, Regulatory Operations, ISPE, as the Operational Project Manager; and Christopher Potter, PhD, CMC Pharmaceutical Consultant, as the Project Advisor. The team members are:

• Nina Cauchon, PhD, Director, Regulatory Affairs–CMC, Amgen Inc.
• David Churchward, Global Head Sterility Assurance, Cell and Gene Technologies, Lonza Biologics
• Jean François Duliere, Regulatory Advisor, ISPE
• John Lepore, PhD, Principal, JVL Phama Consulting LLC
• Maurice Parlane, Principal/Director, New Wayz Consulting Ltd./CBE Pty. Ltd.
• Alice Redmond, PhD, Chief Strategy Officer, CAI
• Greg Rullo, Senior Director, Regulatory Affairs–CMC, AstraZeneca
• Hirofumi Suzuki, PhD, Product Supply Japan, Head of Project Supply Coordination, Bayer Yakuhin Ltd.
• Tim J.N. Watson, PhD, Vice President–Head of CMC Regulatory Affairs, Gilead Sciences

Although the ultimate objective is to provide potential solutions to improve implementation of global regulatory expectations, this team will initially gather data to identify specific sources of industry and regulatory challenges to innovation. A survey has been designed to determine the extent and magnitude of challenges and barriers globally in developing and implementing innovative technologies. The survey was launched in late April 2023 and is open to both ISPE members and non-members.

Survey Design

The survey is divided into three parts and all sections focus on the development and implementation of innovative technologies and modalities. Part 1 is a 10-question, multiple-choice inquiry that is intended to develop an understanding of the demographics and an overview of respondents’ experience with the subject. Part 2 has short-answer questions that focus on eliciting increased granularity regarding respondents’ experience. Part 3 offers the respondents the chance to provide anecdotal examples describing successful introduction of innovative technologies and/or challenges associated with developing and implementing innovative technologies and modalities.

There is an opportunity to provide contact details so that the team may follow up. Each part of the survey will be distributed through ISPE to members and other stakeholders throughout 2023. While responses to all three parts of the survey would be welcome, completion of part 1 will allow assessment of the magnitude of the concerns associated with barriers to innovation.

Case studies will be developed from the survey feedback with proposed solutions, which should support engagement with regulatory authorities globally. Results from each part will be presented periodically at ISPE meetings throughout 2023 and 2024. A final report will be provided as the basis for an ISPE workshop, with recommendations subsequently published in Pharmaceutical Engineering and other trade publications.

Conclusion

In response to the desire of both regulators and industry to introduce new and innovative technology and modalities and improve product quality assurance and access to medicines for patients globally, ISPE has launched the “Enabling Global Pharma Innovation: Delivering for Patients” initiative. A multidisciplinary, multinational project team has been assembled and early objectives have been identified.

The survey was launched in April 2023 to determine the extent and magnitude of the global challenges and barriers in developing and implementing innovative technologies. Data and information from the survey will be used to promote efforts to establish durable, globally harmonized regulatory approaches to effectively enable implementation, support continual improvement, and provide consistent guidance for innovative technologies.

Please send any questions regarding this initiative to Carol Winfield.