Reproduced with permission from DIA North America.  You can see the original here.

By Sarah DeMare, Facet Life Sciences

Quality by Design (QbD) was introduced nearly ten years ago as part of FDA’s 21st century quality initiative. The ultimate goal is to reach the desired state of quality defined by Janet Woodcock as “a maximally efficient, agile, flexible pharmaceutical manufacturing section that reliably produces high quality drug products without extensive regulatory oversight.” Over the past decade, the QbD concepts have become more broadly accepted and used by many sponsors, particularly in the area of process understanding. As a result, four ICH guidances have been implemented; FDA and EMA have partnered in a joint QbD pilot; and even the recent reorganization of CDER’s Office of Pharmaceutical Quality (OPQ) was done with an eye toward the desired state.

Christine Moore, Acting Director of Office of Process and Facilities at FDA, speaking recently at the 2075 DIA CMC Workshop, indicated that although QbD concepts are commonly used, the main focus has been on process understanding, rather than control strategy.

“Regulatory flexibility,” originally touted as one of the key benefits of QbD, has yet to be fully realized, and there has been minimal advancement towards achieving “true continual improvement.”

Moore emphasized that to achieve “true continual improvement,” sponsors need to look beyond drug development, which is where many of the QbD initiatives and ICH guidelines Q8-Q11 have focused; it is just as important to understand and advance these concepts over the entire life cycle of the product, particularly in postapproval change management.

A new ICH guideline is currently under development: ICH Q12: Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management; while still in its very early stages, the scope of this new guideline is defined as covering pharmaceutical products, including currently marketed chemical, biotechnological and biological products. A concept paper endorsed n September 2014 identifies the desired state as “an enabling system to facilitate managing quality, innovation, and continual improvement throughout the entire product life cycle” and delineates three important issues to be addressed with the new guideline on page 2:

  • Regulatory Dossier
    • Explore the development of a harmonized approach to “regulatory commitments” for inclusion in the guideline. Such approaches could enable post approval changes that facilitate continual improvement and encourage the adoption of innovative technologies.
    • Delineate the appropriate level of detail and information necessary for regulatory assessment and inspection in the dossier, in order to create a more enabling postapproval change management system.
    • Pharmaceutical Quality System (PQS) aspects
  • Establish criteria for a harmonized and risk-based change management system based on product, process and/or clinical knowledge that effectively evaluates the impact of change on quality, and, as applicable to safety and efficacy.
  • Clarify expectations and those changes on product quality.” He suggested that such a plan could include:
    • The proposed filing category, with data to support the changes;
    • A justification for the proposed filing category using risk assessments and science based arguments, and
    • A description of the differentiation between changes made that require a regulatory submission versus those that can be handled within the PQS.

If adopted globally, this particular aspect of ICH 012 may help to ease the burden of postapproval changes by reducing the amount of prior approval supplements. Additionally, it may expedite approval of changes by potentially reducing the reporting category of changes made under a PACMP.

An industry perspective on life cycle management today, provided by Ganapathy Mohan from Merck revolves around challenges relating to diverse regulatory requirements from agencies around the world, the time it takes to implement changes, and the logistical problems that occur in sourcing product with many different dossier versions. Currently, it can take three to five years to get one postapproval change implemented in one drug product that is marketed globally. Many of the non-lCH regions have their own requirements which sponsors argue are simply a box-checking exercise that is not necessarily relevant to the safety of the product, an example of which is the requirement for drug product stability data for a drug substance change.

Perhaps, more importantly, having a well thought out plan that is approved along with the initial application will accelerate the preparation and approval of postapproval changes. Nosal indicated the PACMP completes the QbD story by establishing a mechanism to extend the QbD principles of scientifically justified and risk-based approaches to a products life cycle maintenance. ICH Q12 is expected to reach Step 2 in June 2016. This will be a particularly interesting and important space to watch, as development of this guidance document progresses.


1 R. Iser, Global Drug Development and its Impact on CDER’s Drug Review Process Symposium. 24 June 2014.

2 Final Concept Paper Q12: Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management. 28 July 2014.