CDER collaborates with global regulators on pharmaceutical quality assessments and inspections

By: Theresa Mullin, Ph.D., CDER’s Associate Center Director for Strategic Initiatives, and Michael Kopcha, Ph.D., R.Ph., director of CDER’s Office of Pharmaceutical Quality

FDA and the European Medicines Agency (EMA) recently completed the first collaborative assessment of a proposed post-approval change for a critical oncology biologic with the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) serving as an observer. The work, in which FDA and EMA reviewed and approved a proposal to add new manufacturing and quality control sites, can help assure the supply of the medicine.

This collaboration is the first achievement in an international pilot program conducted as part of the International Coalition of Medicines Regulatory Authorities (ICMRA) Pharmaceutical Quality Knowledge Management System (PQKMS) effort to bring regulators together to enable better industry quality management to reliably supply critical medicines for patients in need.

This collaboration comes on the heels of global regulators joining forces to address challenges with drug availability. Drug manufacturers often make changes to their processes or facilities to keep equipment and processes up to date and address supply chain hurdles. Depending on the extent of the change, regulators may need to assess, inspect, and approve it. Because drug manufacturers often sell the same product in many countries, they must work with global regulators that have different expectations and review timelines for such changes. A single manufacturing change, even when critically important, can be complex and time-consuming to implement.

With FDA as a founding member of ICMRA, in 2019 CDER saw a unique opportunity to utilize the strategic role of ICMRA to propose a multi-year project that would lead to greater regulatory reliance (meaning regulators in one country are able to consider the assessments of regulators in another country) when making decisions about a product and enable greater manufacturing quality management and agility for industry. The ICMRA PQKMS project was launched in November 2020.

ICMRA PQKMS aims to strengthen international collaboration by building the collaborative processes and information infrastructure needed to support global development, manufacture, and supply of pharmaceutical medicinal products. As part of the PQKMS work, ICMRA introduced two pilot programs to identify differences and potential areas for collaboration in pharmaceutical quality assessment and inspection across ICMRA regions. This is an important first step to help harmonize chemistry, manufacturing, and controls (CMC) assessments and inspection-related regulatory procedures worldwide, which will lead to more efficient drug application reviews across regulators.

These pilot programs were borne out of the unprecedented stress that COVID-19 imposed on the global drug supply chain. Immediate actions were warranted to implement flexible approaches that would allow manufacturers to rapidly increase manufacturing capacity for production of COVID-19 therapeutics and vaccines and avoid or mitigate shortages for non-COVID-19-related products, without compromising patient safety or product quality.

In July 2021, ICMRA and industry representatives conducted a workshop to improve regulators’ understanding of specific challenges faced by manufacturers seeking to increase manufacturing capacity for COVID-19 therapeutics and vaccines and improve industry awareness of current regulatory approaches to enable the rapid increase of manufacturing capacity. The workshop also sought to identify opportunities for further collaboration to enable a more efficient and effective global regulatory response.

Two pilots were identified to optimize the design of future collaborative interactions leading to greater regulatory alignment and efficiencies in global CMC assessment and inspection activities: One pilot focuses on collaborative assessments for protocols that facilitate streamlined CMC post-approval changes and the other pilot deals with collaborative hybrid inspections. Together, these two pilots are working to identify best practices and standards in the quality assessments of CMC post-approval changes and the collaborative hybrid inspections that may be needed to support these assessments. The work accomplished through these pilots will also identify any differences and potential areas for future alignment or harmonization across regions.

The collaborative assessment pilot has already begun. Under the pilot, when the submission from a participating applicant is received, multiple regulatory authorities form a global assessment team and engage in a collaborative assessment of the applicant’s protocol for proposed post-approval changes. Regulators will also identify differences in how various regions assess CMC changes. The working group prepares a single list of questions or comments to the applicant. After seeing the applicant’s responses, the regulators will complete the assessment.

Meanwhile, the collaborative hybrid inspection pilot will aim to conduct a collaborative facility assessment using a combination of on-site inspection and remote assessment tools. A regulator from one country will perform an on-site inspection with regulators from one or more other countries remotely connecting at the same time. The pilot aims to identify the best virtual platforms and information technology (i.e., video) to facilitate concurrent on-site inspection and distant assessment. The pilot will also develop protocols and reports for performing hybrid inspections to share with other ICMRA regions.

These pilots ultimately will help regulators rely on the pre-approval inspections of other regulators, reduce or eliminate the need for multiple on-site inspections from various regulatory authorities and help to avoid duplicative assessments relating to CMC-related post-approval changes.

To date, ICMRA has accepted several proposals for the collaborative assessment pilot, including the recently completed FDA/EMA supplement assessment. The other proposals cover different post-approval change scenarios from across the manufacturing lifecycle, including transfer of quality control sites for a biologic, addition of a new drug active pharmaceutical ingredient manufacturing site, and addition of a new finished drug product manufacturing site. The hybrid inspection pilot has accepted two proposals that cover: 1) a pre-license inspection to support the drug substance manufacturing and quality control site transfer for a biologic, 2) and a preapproval inspection to support the addition of a drug manufacturing site. We anticipate ICRMA will complete the remaining pilots by early 2024.

For the first application reviewed under the pilot program, the FDA/EMA collaborative assessment teams had a positive and productive experience, which produced a common set of highly aligned information requests and comments to the applicant. Not only did this assessment result in an FDA approval, but there was no delay in the standard assessment timeline. In fact, it was completed under the four-month goal window for a standard manufacturing supplement assessment. The EU also approved the submission on the same day as FDA, marking a significant accomplishment in aligning FDA and EMA on the assessment process and timeline. This assessment experience also received positive feedback from industry on the coordination of efforts between the FDA and EMA.

ICMRA recently held a virtual joint workshop with industry to discuss experiences and learnings to date for the PQKMS and pilot programs. The recording will be made available on the ICMRA website.

Further regulatory collaboration in ICMRA, coupled with CDER’s on-going standards efforts in other international regulatory harmonization and information-sharing bodies, such as the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), can drive toward a single assessment outcome across regions. CDER will continue to work with our international counterparts in ICMRA and other international venues, on these and other issues, to advance pharmaceutical quality to benefit patients and consumers in the U.S. and worldwide.

07/28/2023