ISPE Launches Enabling Global Pharma Innovation: Delivering for Patients

Program Goals

To goal of the program is to catalyze consistent and harmonized interpretation and implementation of ICH guidelines with the intention of improving global patient access to innovative medicines and technology.

Regulatory harmonization, which is fundamentally based on ICH guidelines, is imperative to improve the advancement of pharmaceutical and technological innovation and requires the following pivotal objectives:

• To contemporize manufacturing technologies currently supported by some local/regional regulatory authorities but not universally accepted by others.
• To reinforce globally harmonized implementation of ICH guidelines that are functionally necessary to advance innovative technology and approaches such as Pharma 4.0, for example a globally agreed control strategy.
• To identify the sources of regulatory challenges that serve as barriers or create limitations in applicability across multiple therapeutic modalities.
• To increase the level of clarity and consistency in harmonized approaches to encourage and provide incentives for implementation of innovative technology for new, already approved, and generic products.
• To leverage relevant regulatory harmonization activities under consideration and convergent regulatory approaches in progress regionally.
• To encourage and provide incentives for regulatory authorities to work together to accelerate adoption and implementation of ICH guidelines and other harmonization proposals, i.e., mutual recognition/reliance.
• To assess learnings from the pandemic such that the global regulatory and supply distribution experience can serve as a roadmap for improved implementation of innovative technology.

Harmonization of global regulatory requirements has been progressing for more than thirty years under the International Council for Harmonisation (ICH). ICH has the mission “to achieve greater harmonization worldwide to ensure that safe, effective, and high-quality medicines are developed and registered in the most resource-efficient manner.” Great progress has been achieved in agreement of internationally acceptable scientific guidelines, primarily, but not exclusively, applicable to commercial registration of new drug products and drug substances. However, several published assessments and a large body of anecdotal examples indicate that implementation of a globally acceptable drug product control strategy is currently not achievable (see, for example, Toward a Single Global Control Strategy: Industry Study).

Problem Statement

Scientific- and risk-based approaches in pharmaceutical development were first explicitly described in ICH Q8 and further elaborated in ICH Q9, Q10, and Q11 as well as Q12 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 that have forced companies to adopt multiple control strategies for a single product using the same manufacturing process globally, or worse, diluting the control strategy toward the most conservatively harmonized common denominator. This has not only created manufacturing and supply chain challenges but has 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 hinder innovation in product development and lifecycle management while providing no improvement in product quality, safety, or efficacy. Global regulatory divergence has served as a barrier rather than an incentive to develop innovative manufacturing technology, new medicinal modalities and continual improvement initiatives that have, in some instances, created temporary drug shortages in some markets.

Regulatory Activities

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

USA: FDA established the Emerging Technology Program in 2014 and has actively promoted the program. In his keynote presentation at the 2022 ISPE Annual Meeting, Dr. Michael Kopcha, Director, Office of Pharmaceutical Quality emphasized FDA’s commitment to promoting advanced manufacturing referencing CDER’s 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 patients.

European Union: The national competent authorities (NCAs) of the 27 EU Member States plus those of Iceland, Liechtenstein and Norway and including the European Medicines Agency (EMA) released the European medicines agencies network strategy to 2025. Two of six strategic focus areas are data analytics, digital tools and digital transformation and Innovation. In line with this strategy EMA established the Innovation Task Force (ITF), which is 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 development.

United Kingdom: The Medicines and Healthcare products Regulatory Agency (MHRA) established the Innovation Office which is open to ideas for innovative medicines, medical devices and manufacturing processes.

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 pharmaceuticals quality control

While all 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 is costly and frequently technically and commercially risky, made even more so in the absence of a regulatory landscape that does not offer or assure 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 Heads of Agencies of thirty medicines regulatory authorities, issued a policy statement in June 2021, Global Pharmaceutical Quality Knowledge Management: Enhancing Regulatory Reliance and Agility, 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.” ICMRA goes on to state: “ICMRA 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.”

ICMRA also has established a Pharmaceutical Quality Knowledge Management System (PQKMS) and as part of this strategy is commencing two pilot programs focusing on:

• i) collaborative assessment with initial focus on chemistry, manufacturing, and control (CMC) post-approval changes and
• ii) collaborative hybrid inspections. The overall aim of these pilots is to improve manufacturing capacity for production of critical medicines and facilitate collaborative assessments and inspections by multiple regulatory authorities

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 August 2022, eight countries are listed as Project Orbis Partners: Australia, Brazil, Canada, Israel, Singapore, Switzerland, United Kingdom (UK), and US. US FDA.
• The Access Consortium is a collaborative effort between Australia, Canada, Singapore, Switzerland, and UK, (like-minded, medium-sized regulatory agencies).

Learning from Covid Pandemic

In response to the magnitude and urgency of the COVID 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, effectively leveraging prior knowledge significantly accelerated 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:

• 3D printing
• Improved efficiencies in chromatographic separation technology for manufacture and purification of small and large molecules
• 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
• Development of innovative and patient-centric drug delivery and administration options
• Use of spectroscopic technologies that establish real-time release testing rather than conventional end product testing
• Continuous process manufacturing
• Deployment of machine learning and artificial intelligence technologies to optimize manufacturing operations and processes
• Introduction of automation and robotics to improve operational consistency for manufacturing and analytics
• Increased digitalization

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
• 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, using less energy and producing less waste
• Seamless and integrated digital information flow up and down the supply chain operations

The achievement of these objectives and the potential to increase innovation is largely dependent on improving the implementation of globally harmonized regulatory expectations. Industry investments in innovative technologies and modalities are incentivized by the ease with which they can be approved and implemented globally.

ISPE’s Enabling Global Pharma Innovation Program

To deliver this program, ISPE has assembled a multi-disciplinary, multi-national team of subject matter experts under the auspices of ISPE’s Regulatory Steering Council (RSC).

While the ultimate objective is to provide potential solutions to improve implementation of global regulatory expectations, this team will initially gather data to define even more the barriers and challenges to innovation. Case studies will also be developed with proposed solutions, which should support engagement with regulatory authorities globally. ISPE membership will be updated at appropriate ISPE meetings.

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

Please contact Carol Winfield, ISPE Senior Director Regulatory Operations with questions or for more information.

View the Full Series of Regulatory Digest

• Bob Tribe, ISPE Asia-Pacific Regulatory Advisor, Retires
• ISPE’s Regulatory Commenting Process
• ISPE Launches Enabling Global Pharma Innovation: Delivering for Patients
• Regulatory Panel Discussions: Annex 1 Implementation from the Regulators’ Point of View