On August 20, 2013, FDA and the EMA (European Medicines Agency) published a document entitled, “EMA-FDA pilot program for parallel assessment of Quality-by-Design applications: Lessons learnt and Q&A resulting from the first parallel assessment.”   The Q&A document provides information regarding agreements that were made between the agencies as a result of the first FDA-EMA parallel assessment that was conducted in a three year pilot program that began in March 2011.  The document fulfills an objective of the program to share program results with the public.  The pilot parallel assessment program provides a mechanism for NDA and MAA reviewers to exchange and discuss their findings regarding the implementation of ICH concepts and regulatory requirements for certain Quality/CMC sections that are relevant to QbD (quality by design) such as drug development, design space, and real time release testing.  A main purpose of this pilot program is to ensure consistent implementation between the EU and the US of ICH Q8 (Pharmaceutical Development), Q9 (Quality Risk Management), and Q10 (Pharmaceutical Quality System) guidelines.

The full Q&A document can be found here.

Some highlights from the document are:

  • Critical quality attributes (CQAs) should be listed for the drug substance(s), finished product and excipients, when relevant, in a tabular format.  A discussion should be provided regarding how the drug substance and excipient CQAs relate to the finished product CQAs.
  • The Agencies did not accept a three-tier classification of critical process parameters (parameters whose variability has an impact on a CQA).  The applicant proposed that parameters be assessed as critical, key, and non-critical.  The Agencies will accept such an approach in a Pharmaceutical Development Report as a way to communicate development findings; however, the description of all parameters that have an impact on CQA should be classified as “critical” in Sections 3.2.P.3.3 (Description of the Manufacturing Process and Process Controls) and 3.2.P.3.4 (Control of Critical Steps and Intermediates).
  • With regard to the level of detail for the manufacturing process description, process descriptions must be comprehensive.  The Q&A document provides guidance regarding how much information should be provided.
  • There is currently no international consensus on the definition of ATP (Analytical Target Profiles) and MODR (Method Operational Design Ranges) for analytical methods.  Until consensus is achieved, any application that includes these QbD concepts will be evaluated on a case-by-case basis.
  • An ATP can potentially be used as a qualifier of the expected method performance by analogy to the QTPP (Quality Target Product Profile) as defined in ICH Q8(R2).  However, the Agencies will not consider analytical methods that have different principles to be equivalent solely on the basis of conformance with the ATP.
  • Similar principles and data requirements described in the ICH Quality Working Group Points to Consider (R2), Section 6 “Design Space”, could apply for MODRs. For example, data to support an MODR could include: (a) appropriately chosen experimental protocols to support the proposed operating ranges / conditions; and (b) demonstration of statistical confidence throughout the MODR. Issues that will require further consideration include the assessment of validation requirements as identified in ICH Q2(R1) throughout the MODR and confirmation of system suitability across all areas of the MODR.

The pilot program appears to be making strides in its goal to ensure consistent reviews between the EU and the US regulatory agencies.  As more parallel reviews are completed, we hope to gain further understanding from the two agencies with regard to their unified expectations for NDAs and MAAs utilizing QbD principles.

For additional information on quality by design concepts in new drug applications, please contact Joan Janulis at j.janulis@LachmanConsultants.com .