FDA, EMA Address Quality & Manufacturing Issues for Breakthrough Therapies with Expedited Approval

On July 31, 2019, the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) published a joint report on their efforts to support the development of and expedite access to breakthrough therapies that address unmet medical needs.  In addition to outlining the tools currently available to manufacturers seeking expedited approval of breakthrough therapies, the report recognizes the need for further regulatory innovation to advance emerging scientific knowledge and support timely access to new medicines without compromising established quality and manufacturing standards.

To obtain marketing approval for breakthrough therapies, sponsors face challenges to obtain clinical, non-clinical, and manufacturing information that meets the standards for regulatory approval on compressed timelines.  FDA/EMA recognize this, and on November 26, 2018 held a workshop on FDA’s Breakthrough Therapy Designation (BTD) and EMA’s Priority Medicines (PRIME) programs.  The aim of the workshop was to facilitate discussion with industry stakeholders on challenges associated with quality, manufacturing, and data requirements during early development, and possible scientific and regulatory approaches to address them.

With regard to challenges related to quality and manufacturing data, the report provides FDA/EMA’s perspectives and outlines follow-up initiatives being considered for process validation and control strategy, current good manufacturing practices (cGMP) compliance, comparability and stability data, and regulatory tools to support early access.  The key takeaways relating to quality and manufacturing data are provided below:

Process Validation

  • The regulators agree that clinical drug substance material may be used for drug product process validation, which decouples drug substance and drug product process validation activities.
  • Addressing an unmet patient need may justify allowing commercial launch of a product manufactured in a clinical manufacturing site/process, but consideration must be given to the technical requirements to establish comparability for product manufactured at a commercial manufacturing site.
  • For products addressing a high unmet medical need, applicants may be able to defer submission of certain process validation data until after approval.  The regulators also express willingness to consider concurrent validation.
  • For biological products, approval specifications wider than available batch data may be considered if there is a plan to develop such data post-approval.  Statistical process controls may also be used to provide assurance that specifications are appropriate.

Control Strategies

  • CMC development plans (or “quality lifecycle plans”) are discussed as a tool to describe quality development and product lifecycle planning.  More flexible control strategies may be acceptable, but the consistent quality of the products would need to be demonstrated.
  • Relevant prior knowledge can be used to justify the acceptance criteria for certain product attributes and attributes to monitor control strategies.  Depending on risk-benefit analysis, controls with wider limits than those used for clinical trials may be acceptable.
  • Novel methods and strategies may delay approval if they are introduced in expedited developments, because the product knowledge is limited and justification of their use could be challenging.
  • FDA/EMA will consider issuing guidance harmonizing regulatory approaches to performance-based control strategies, with the goal of enhancing companies’ ability to develop custom controls.

cGMP Compliance

  • Recognizing the importance of cGMP compliance, the agencies stress the benefits of early discussions on the relevant topics, which include the issues identified above.  Industry highlighted a series of cGMP considerations that could facilitate accelerated access, including greater clarity on how clinical cGMP considerations can be applied, the benefit of enabling commercial supply from clinical manufacturing sites, and harmonizing cGMP considerations in inspections among different regulatory agencies.
  • FDA/EMA are working on increased harmonization (e.g., EU-US MRA agreement for recognition of cGMP inspections, which we previously covered here).


  • Where ethical considerations or limited availability preclude using patient (or patient-specific) material to demonstrate comparability, it may be possible to use surrogate non-patient material (e.g., healthy donor material) at scale and follow up with concurrent validation using patient material.
  • It may be acceptable to rely on a risk-based approach for identifying critical quality attributes affected by manufacturing changes and then conducting a comparability exercise.  Regulatory guidance may be developed on this approach.
  • When products manufactured in clinical sites/processes are launched commercially, transfer to the commercial site/process requires appropriate (often extensive) comparability data to ensure product efficacy and safety.

Stability Data

  • Demonstrating compliance with standard stability requirements according to ICH Q5C guidelines may not be feasible for breakthrough therapies subject to accelerated assessment for marketing approval.  Predictive stability models to extrapolate shelf-life may be an appropriate model to establish an acceptable shelf-life for a product, even if full-time, product specific data have not been submitted.
  • Relying on accelerated and stress stability data may be acceptable, possibly including extrapolation from stability data trends for biological products using mathematical models based on prior knowledge of structurally similar molecules.  Stressed data may also help in understanding if the product will follow the predictive stability model.

Regulatory Tools

  • It is important for applicants to discuss their overall development plans, including their quality programs, in advance with regulators, in order to be prepared to handle uncertainties, avoid delays, and to enable accelerated assessment (where applicable) and obtain regulatory approval.
  • Sponsors and manufacturing sites need to closely coordinate manufacturing and cGMP readiness to facilitate (and avoid delays in) development, approval, and distribution of breakthrough or PRIME products.  It is recommended that industry establish a strict coordination between the sponsors and the CMOs, as cGMP issues can delay regulatory approval.

Although the devil is in the details and there remain many details to work out, this report represents an important step forward in the regulatory agencies’ helping sponsors and manufacturers take advantage of the BTD and PRIME programs.  We will continue to closely follow FDA/EMA’s efforts in this area.


Authored by Jim Johnson, Philip Katz, Elisabethann Wright, Christopher Fanelli, Scott Kaplan and Lowell Zeta


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