The key publications (2, 3, 6), workshop reports (4, 5), and draft guidance (7,8,9,10,11,12) describe several best practice approaches for CMC for early patient access and pandemic supply. Furthermore, the development of these materials has documented and highlighted several examples highly relevant to the rapid development and supply of pandemic medicines: including the learnings from the development of pandemic vaccines for Ebola and COVID-19, and many biological and chemical oncology therapies. Whilst excellent progress has been made in developing core principles, challenges to practical implementation are still encountered despite the agreement between regulators and the industry. There are also additional topics (highlighted in the publications and reports) that need further advancement to enable accelerated CMC development and supply of new medicines for pandemic scenarios.

Reflecting on what has been learned and agreed to-date, the authors note the following:

1.

The substantial need to advance reliance/collaborative assessment

Work-sharing and reliance between regulatory agencies is a well-established principle in the area of GMP, for example where Mutual Recognition Agreements establish a legal basis for recognizing inspectional activities by one regulatory authority to rely on the expertise of another authority (24). This helps optimization of resources in regulatory agencies and companies, providing a considerable benefit to patients by enabling medicine availability via global supply chains. In pandemics, it would be highly beneficial to extend the concept of collaborative use of available quality expertise to address CMC regulatory aspects of submissions (including EUA/CMA) and variations and thereby facilitate the optimal use of regulator and industry human expert resources globally. The use of Reliance/collaborative assessment processes could also be extended to other supply-related aspects, such as importation testing for vaccines and medicines, and to facilitate (virtual) GMP and pre-approval inspections.

The authors acknowledge that some progress has been made through schemes such as FDA Project Orbis (25) for oncology treatments and the recent EU OPEN program (26) and recommend that further collaboration by stakeholders should be fostered to tackle the significant legislative, procedural, and cultural barriers to global collaboration.

2.

The need for defining early key decision points and streamlined engagement between industry and regulatory authorities on CMC matters

It is essential for the development and commercial supply of pandemic medicines that the strategy for CMC development and supply (in the pre-and post-approval phases) is agreed upon with regulators globally and early during development. Consistent expectations for the content of CMC development across regulatory authorities are necessary because key CMC decisions are highly inter-related and, combined with compressed timelines, may require careful consideration of trade-offs in areas of development. These trade-offs may include aspects such as optimization of the pharmaceutical dosage form, formulation, supply chain (including manufacturing, testing, batch release sites), manufacturing process, scale of manufacture, control strategy, process validation, and stability strategy. Many of these decisions need to be made early to fully exploit the opportunities to realize early patient access and facilitate supply. In addition, the industry cannot customize manufacturing and controls to satisfy individual regulatory expectations for each market whilst also meeting global demand with the required urgency. Furthermore, for complex products such as vaccines, release to the market involves the review of a manufacturer's production data and quality control test results by the relevant national regulatory authorities (NRA) and national control laboratories (NCL). This may be supplemented by confirmatory laboratory testing by the NCL, all of which add additional requirements to the timeline of CMC development and supply.

For these reasons, a fundamental principle of accelerated CMC development is that early and frequent dialogue between industry and regulators is essential to agree on the Applicant’s planned, product-specific approaches to CMC development. But parallel dialogues—between a company and multiple regulatory agencies, and an agency and multiple companies—where regulatory expectations are not clear or aligned strains expert resources in both companies and agencies. There are currently approximately 600 therapies and vaccines approved or under development for the treatment or prevention of COVID-19 (27). As such, companies and regulators cannot allocate the resource or time required to discuss every critical decision on CMC development and supply individually. Hence, it is vital that CMC approaches, which may differ from those in ICH and regional guidelines but which have been discussed and agreed (based on science and risk) as broadly applicable to CMC development and supply for unmet medical needs, can be implemented as efficiently as possible. Globally harmonized agreement on the general principles of CMC acceleration for pandemic situations should streamline product development by reducing the number of interactions and prior agreements needed between industry and regulatory agencies. This would facilitate an efficient and collaborative response to pandemics.

3.

The need to further facilitate ‘post-approval’ changes

Accelerated CMC development for early patient access means that work is continued into the post-approval/authorisation phase generally leading to more frequent and more significant post-approval activities. During the period of emergency use, the process for providing updates, confirmatory data, and optimizations/changes may not use conventional administrative approaches designed for making variations to Marketing Authorisations. In the context of this publication, the term ‘post-approval’ is used to encompass changes reported to regulatory authorities after authorization for emergency use (by whatever mechanism is defined in the regulatory framework) and approval of a full marketing authorization.

In a global pandemic situation, this ongoing work is amplified by the need to rapidly expand supply to billions of patients, leading to increased challenges for lifecycle management and PACs. Examples of these post-approval CMC challenges include the following:

Scaling-up of manufacturing, including expanding supplies of raw materials and manufacturing capacity of raw materials and components, to meet patient demand.

Evolving and aligning the control strategy across markets to incorporate increasing knowledge and experience of the product and process.

Demonstrating comparability pre- and post-changes when there is limited batch history.

The ongoing acceptability (e.g., in the context of PACs and inspections) of approaches accepted in the original application (e.g., use of extensive modelling in establishing a shelf-life/retest period).

Modifying or implementing approved Post-Approval Change Management Protocols (PACMPs).

In the future, defining and revising the established conditions for a product, due to evolving process knowledge.

It is important to recognize that for many accelerated pandemic medicines, the generation of confirmatory data, and data to fulfil regulatory commitments associated with approval for emergency use, will be a continuous activity during assessment and into the initial phase of commercial product supply. It is acknowledged that recommendations already made for COVID-19 by regulators such as EMA (14) and FDA (9, 11), (including rapid scientific advice, rolling review, and proposals for compassionate use) are positive steps forward. The authors believe there are also opportunities to consider adapting such regulatory tools for review and approval of CMC PACs, including for products for unmet medical need. Although ICH Q12 Product Lifecycle Management reached step 4 consensus in November 2019, implementation of Q12 by ICH members had just started with the transition of the Expert Working Group to an Implementation Working Group when the COVID-19 pandemic emerged. Consequently, full understanding and experience of the regulatory tools described in the Q12 guideline that are intended to facilitate PACs and product lifecycle management have not yet been achieved across industry and regulatory agencies globally.

Reflecting on the above, the authors recommend:

Improved planning and alignment among regulatory authorities to establish a harmonized and consistent approach for regulatory applications and inspection criteria for pandemic situations, as well as for acceleration of medicines for unmet medical needs.

Continued efforts aimed at harmonization of requirements for post-approval changes (variations) globally, with a focus on science- and risk-based regulations and guidance.

Optimization of the avenues for provision of data post-authorization in addition to the established procedures (i.e., via implementation of commitments agreed in marketing authorizations, use of PACMPs, and science- and risk-based variations regulations and guidance)

Exploiting the full functionality of PACMPs (e.g., via greater flexibility in timelines, modifications and details, and broader scope), established conditions, and other tools described in ICH Q12 to facilitate product lifecycle management

Ensuring that emergency use/conditional marketing authorizations allow specifications to evolve as product and process knowledge is developed. For example, allowing initial, interim acceptance limits that are wider than the available batch data, which may then be tightened as justified by the development of additional data that consider clinical relevance (28). In certain cases, impurities may be included in the specification while data are accrued to demonstrate their clearance (7). As outlined in Table I, Topic 8 (Commercial Product Specification), it is not considered viable to implement tight specification ranges that would incur an elevated risk of batch failure and unnecessary discard of an otherwise good product. Continuation of close collaboration between regulators and industry into the post-authorisation phase, including consideration of innovative approaches to meet GMDP requirements.

Agreement with regulatory agencies on CMC development plans (or quality lifecycle plans’) specific to accelerated products as a tool to describe the quality development and product lifecycle planning.

There will be many cases where the product and process understanding, control strategy and supply chain maturity at the time of filing for a pandemic medicine may be evolving rapidly, necessitating significant PAC to achieve a “business as usual” steady state. Transparent, ongoing communications for lifecycle management of accelerated development of pandemic products (note that plans may be revised frequently due to the dynamic situation during pandemics) could help to facilitate changes that are anticipated, such as those for scale-up and scale-out of production, as well as the delivery of commitments made as part of EUA or CMA approval.

Evolution of the tools to facilitate PACs will expedite upfront agreement to CMC requirements, rolling review of marketing authorisations, and the changes needed post approval to ensure ongoing supply. Addressing these needs could help to ensure rapid patient access to pandemic medicines and help mitigate any potential supply outages without increasing the risk to patients. Overall, further collaboration and dialogue between industry and regulators would be beneficial to explore new tools and harmonised ways of working for product lifecycle management to facilitate the security of global supply of pandemic medicines.

4.

Fully exploiting prior and platform knowledge

Prior knowledge is an indispensable tool for accelerated development of medicines because it provides extensive additional information and assurance beyond product-specific information.

It was explicitly recognized at the 2017 EMA Joint QWP/BWP stakeholder workshop on prior knowledge (4) and at the 2018 EMA/FDA workshop on quality considerations related to PRIME/Breakthrough Therapy (5) that prior and platform knowledge is a vital and underused scientific tool available to accelerate many CMC deliverables for development and supply, including informing risk assessments; identification of Critical Quality Attributes (CQAs); development of control strategy elements such as identification of Critical Process Parameters (CPPs); informing specification limits, informing comparability; selection of container-closure and device; process validation; and shelf life. Table I also includes additional examples of the use of prior and platform knowledge.

In the context of pandemic-driven CMC development and supply and under extremely shortened timelines, these tools become even more relevant, often simply due to the lack of alternatives. Consequently, it is of crucial importance for regulatory decision-making in a pandemic setting to strike a balance between the need for product-specific data and the use of prior knowledge, wherever appropriate.

Regarding the efficient use of prior knowledge, the following are suggested:

The relevance and application of prior knowledge should be confirmed as soon as possible (e.g., through agency kick-off meetings or scientific advice).

It should be agreed which aspects of prior knowledge are used to complement, or substitute for, product-specific data. A risk assessment should discuss any remaining uncertainties arising from the use of prior knowledge that will be addressed post-approval. In this manner, transferable prior and platform knowledge can significantly help to justify greater flexibility in the compilation of quality data, allowing certain quality data supported by prior knowledge, to be accepted or deferred into the post-initial authorization phase.

An important regulatory question is how to enable the use of prior knowledge in an efficient way, avoiding the need for extensive ‘re-justification’ of the knowledge. Aspects for further discussion between regulators and industry could include cross-referencing the prior knowledge data and/or re-using data from previous assessments to further facilitate development and specific regulatory processes such as platform technology master files.

Overall, to maximally facilitate global development and supply of pandemic medicines, diligent implementation of prior and platform knowledge will be essential.

5.

Review and potential revision of legal frameworks

Considerable progress has been made to date with international harmonization activities under the umbrella of ICH, WHO, or Pharmaceutical Inspection Co-operation Scheme (PIC/S). Equally, harmonization work arising from the COVID-19 pandemic (e.g., via ICMRA) will remain a priority in the industry recommendations. Optimal agency review, approval, and product launch require a common structure to the submitted documentation, alignment on the type of required information, and mutual acceptance of internationally recognized standards, including pharmacopoeias. The use of well-proven harmonization mechanisms such as ICH can address the technical aspects, but perhaps other mechanisms to enable regulatory agencies to rely on the scientific assessments of experts in other agencies could also be important (24). It is acknowledged that the CMC early access approaches that are proposed in this publication, including the use of reliance practices, could necessitate some revision of the current legal frameworks of several agencies. It is therefore vital that any incompatibilities with the legal framework are identified, and the consequences for patients and pandemic preparedness can be discussed with legislators.