Global Industry Bodies Urge Wider Use Of COVID-19-Related Regulatory Flexibilities
Harmonized Inspection Practices Are One Way Forward
Executive Summary
A range of steps have been taken to allow the scale-up of manufacturing of COVID-19 products during the pandemic. Now industry says the use of these flexibilities needs to be expanded to enhance the current pandemic response and rapidly increase product supply.
A group of national and international bodies representing R&D-based and generic/biosimilar companies has proposed a range of regulatory flexibilities that it says should be applied more broadly by global regulators in order to expand manufacturing capacity for COVID-19 medicines and vaccines.
The flexibilities include more streamlined stability testing requirements and greater use of harmonized approaches to alternative inspection procedures such as collaborative “hybrid” inspections.
In a joint statement, the industry bodies said they were ready to work with the International Coalition of Medicines Regulatory Authorities (ICMRA) and individual national regulatory authorities (NRAs) to “advance and implement science- and risk-based regulatory agilities to enable the rapid increase of manufacturing capacity for COVID-19 therapeutics and vaccines and facilitate timely access to these critical products for patients around the globe.”
The statement was issued together with a report on a 7 July workshop organized by ICMRA that focused on enabling manufacturing capacity during the COVID-19 pandemic. It came shortly after ICMRA produced its own statement calling for regulators and industry stakeholders to “interact with each other to further understand and exchange lessons learned from both sides and continue ensuring uninterrupted supply of medicines to patients.”
The signatories to the statement are the international industry federation IFPMA, the UK’s ABPI, Europe’s EFPIA, PhRMA and the BioIndustry Organization in the US, Japan’s JPMA, and Medicines Australia, as well as the international generics and biosimilar industry body, the IGBA, and the Developing Countries Vaccine Manufacturers Network.
Addressing The Challenges
The aim of the ICMRA workshop was to look at the challenges facing manufacturers wanting to increase manufacturing capacity for COVID-19 therapeutics and vaccines, and to examine regulatory flexibilities implemented by ICMRA member regulators during the pandemic.
Also on the agenda were opportunities for further collaboration, harmonization or alignment with a view to mounting a more effective global response to the pandemic and future health emergencies.
According to the workshop report, the “unprecedented stress” imposed by COVID-19 on the global drug supply chain warranted “immediate actions” to implement flexible approaches to allow regulators and manufacturers to “rapidly increase manufacturing capacity for production of COVID-19 therapeutics and vaccines to meet global demand, as well as avoid or mitigate drug shortages for non-COVID-19-related products, without compromising patient safety or product quality.”
Discussions at the workshop among industry and NRAs showed a consensus on the need to go further. Participants identified a number of key “enablers” (or prerequisites) that could maximize the use of regulatory flexibilities introduced in response to the pandemic, according to the report.
The enablers specifically identified included remote inspections, review of and reliance on inspection reports by other agencies (for example under a mutual recognition agreement), risk-based approaches to chemistry, manufacturing and control (CMC) regulatory packages, use of “global” regulatory processes such as the World Health Organization’s emergency use listing, and flexibility on importation testing.
Regulatory Recommendations
In their statement, the industry bodies said that the “workshop dialogue highlighted the challenges experienced by biopharmaceutical companies surrounding data generation, dossier preparation and submission, and pre-approval site inspections that result from inconsistent regulatory requirements and processes globally.”
Other barriers were identified that “impede the rapid increase of manufacturing capacity, such as raw materials, supply constraints and workforce readiness,” they said.
While the enablers identified at the workshop “provide the foundation for improved implementation of regulatory flexibilities, building upon these is critical to enhance the current pandemic response and rapidly increase supply of COVID-19 therapeutics and vaccines,” according to the statement.
Industry has therefore come up with a set of specific priority recommendations that, “if implemented more broadly by ICMRA members, would help to reach the objectives of the workshop.”
"The use of advanced modeling approaches... makes stability modeling a robust approach for vaccine stability assessment" – Janis Bernat, IFPMA
Janis Bernat, director of scientific & regulatory affairs at the IFPMA, explained some of the thinking behind the recommendations to the Pink Sheet.
Streamlining stability testing requirements. Bernat said that it was currently not clear to what extent vaccine manufacturers were allowed to leverage prior knowledge and scientific approaches to model or set the vaccine expiry date for the initial authorization and to submit confirmatory stability data generated on commercial batches as post approval commitments.
“The use of advanced modeling approaches, along with the increased use of platform knowledge, makes stability modeling a robust approach for vaccine stability assessment,” Bernat said.
Using alternative process validation approaches. The use of science and risk-based approaches, convergence on data requirements, and flexibility on the provision and type of data packages in initial regulatory filings for process validation “would clearly be beneficial to accelerating access to vaccines,” according to Bernat.
While the International Council for Harmonisaton (ICH) Q9 guideline provided for risk-based approaches to validation, different NRAs had developed their own requirements for the types of data required and timing for availability of that data.
“If all relevant NRAs could accept a level of risk (based on ICH Q9) for defining the appropriate levels of validation for equipment, process and analytical methods at time of submission, it would allow vaccine manufacturers to manage some aspects within their pharmaceutical quality system (PQS),” Bernat said. It would also allow the NRAs to receive data as post-approval commitments, she noted, adding that a risk-based validation approach should also take prior knowledge into account.
“Last but not least, drug substance and drug product validation may be decoupled: under certain circumstances, the drug product validation may be conducted using drug substance lots manufactured prior to drug substance validation.”
Increasing the use of harmonized approaches to inspection alternatives. Possibilities discussed at the workshop included a hybrid approach among regulatory agencies that uses desk-based inspection supported by technology from one agency, together with inspectors from the regulatory agency of the host country where the facility is located carrying out an on-site visit.
Bernat noted that regulatory convergence was already a reality when it came to good manufacturing practice standards for the pharmaceutical industry, and that initiatives such as the international Pharmaceutical Inspection Co-operation Scheme (PIC/S) played a “decisive role” in ensuring business continuity when inspectors had limited ability to travel and conduct on-site inspections.
To sustain the supply of high-quality medicines to patients, NRAs were able to leverage existing tools which they should continue to implement in a consistent manner as more hybrid (onsite/virtual) inspection models are implemented, Bernat said. This would be done, for example, by allowing risk-based inspection planning through implementation of PIC/S guidance, aligning best practice for optimum use of digital tool, and expanding the use of reliance for inspections.
Enhancing collaborative review and reliance practices for initial registration and post approval submissions. In the EU, the European Medicines Agency is involved in a collaborative venture called the OPEN pilot, which allows a group of national regulatory bodies to take part in the EMA’s evaluation of COVID-19 vaccines and therapeutics to speed up the availability of new products. OPEN has already produced results, with four vaccines and five therapeutics collaboratively assessed between 1 January and 26 July this year. (Also see "EU Joint Regulatory Assessment Project Bears Fruit In COVID-19" - Pink Sheet, 27 Sep, 2021.)
Bernat said that OPEN and other initiatives such as the ACCESS Consortium were “good inspirations for different kinds of collaborative assessments.” Their focus on work-sharing and the use of the “best possible expertise” were “invaluable and can be applied more regionally as well as being centralized around specific elements of a medical product’s lifecycle, eg, registration or post approval changes,” the IFPMA executive declared. The Access Consortium comprises drug regulators from Australia, Canada, Singapore, Switzerland and the UK.
“Collaborative assessments can and should include elements of regulatory reliance, and this practice should be encouraged,” she added.
In their statement, the industry bodies said that they looked forward to collaborating with ICMRA on the upcoming pilots outlined in the workshop report “to support collaborative assessments for post approval changes and foster innovative approaches for inspections while encouraging greater use of regulatory reliance.”