Quality by Design Part 1

In the past, Coda’s blog has covered many initiatives undertaken by the Food and Drug Administration that were developed in order to improve regulatory strategies, and agency systems and tools.  These improvements were developed and implemented in the hopes of contributing to industries’ efforts to develop new and safe therapies as quickly as possible and for as many portions of the population as possible, and as inexpensively as possible.
Some of those initiatives included:
·         The BioSimiliarsGuidance intended to incentivize production of lower cost biologics
·         The Fast Track Initiative intended to provide a pathway to accelerated review and approval of novel drugs
·         The Priority Review program prioritized the resources FDA has to review applications, giving higher priority to either pending applications that promise major advances in available treatments, or a new treatment for a space where no adequate therapy currently exists
·         The Accelerated Approval process applied to fast-tracked treatments, allowed the approval process to sustain the accelerated pace that the Fast Track review process set
·         The Innovation Pathway intended to provide a pathway to accelerated approval of novel medical devices
·         The Critical Path/Orphan Drug Initiatives intended to incentivize production of treatments for illnesses and diseases that affect small portions of the American population
·         The 21st Century Initiative intended to modernize Title 21’s current Good Manufacturing Practices, in the hopes of allowing advances in technology to  promote more efficient manufacturing and regulatory schemes. As the new programs were rolled out, the response from industry was generally straightforward, allowing the impact of the programs to be well-measured and easily monitored.  The good news was that monitoring data seemed to support the effectiveness of the new programs that were designed to spur development as the pace of innovation rose steadily.
However, the monitoring data that reflected the impact of the initiatives that were designed to enable manufacturers to lower the cost of the treatments did not seem to be indicating the same level of success.
For instance, one of the most dramatic initiatives that FDA launched offered incentives to industry to adopt enhanced approaches to pharmaceutical development that involved sophisticated understanding and use of statistical, analytical, and risk assessment methods.  This collection of methods had not been systematically used by regulators or the pharmaceutical industry in the past and was referred to as “Quality by Design” (QbD).  FDA, through QbD, hoped to incentivize manufacturers to strengthen their control systems in design space, by offering them the ability to propose regulatory and approval schemes as long as the approach they suggested was data driven and was developed to manage consumer-centric risk.
When presenting this option to industry, FDA described Quality by Design as:
“A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management.”
The QbD systems approach hoped to allow manufacturers to produce high quality product as efficiently as possible by allowing them to develop not only their product, but a suggested regulatory approach to demonstrating that their processes were sound and in control.  The concepts that were critical to the QbD program represented a significant paradigm shift, and as such, FDA collaborated with the International Conference on Harmonization and co-published the following Guidance Documents:
The guidance documents were created to work together and to underscore that QbD was a systems-based approach.  Taken together with the public statements issued by FDA, it was clear that in order to implement QbD successfully (i.e., participate more directly in the way in which FDA would review and approve a new application, and plan and execute subsequent approval and routine inspections), manufacturers’ systems would need to be developed with the following in mind:
–          Understanding of how components affect each other; will never be a function of only knowing the components
–          Some issues and assets that effect all stages of manufacturing, including talent, knowledge, and tools
–          Almost all quality improvement comes via simplification of design, manufacturing layout, processes, and procedures (~Tom Peters)
–          The quality of the decision making process will always be a function of the quality of the information evaluated.
The Guidance Documents made it clear that any manufacturers wishing to take advantage of the offer of regulatory flexibility would first need to develop and implement systems that sought to:
–          Develop an understanding of the impact of processes and the effects of actions
–          Address and utilize universal issues and assets consistently
–          Identify trends and highlight relationships between upstream activities and downstream  results
–          Provide the most current, relevant and objective information possible, allowing decision makers to make data-driven decisions, geared toward the general goal of improvement
–          Recognize that the supply chain is made up by multiple and equally critical perspectives, and facilitate consensus between them by introducing each to the system at the appropriate point in time

Who could refuse such an offer when the Holy Grail of Pharmaceutical Manufacturing – the ability to collaborate with FDA and have input into the data that was required to apply for a license, and into the manner in which facilities would be inspected – seemed to be in reach.

All manufacturers would need to do is re-develop a few development systems, change the way they make and document decisions, and develop and implement more sophisticated process control and system surveillance tools.

However enticing the offer was designed to be – QbD based applications did not come rolling in, and therefore the cost cutting benefits of allowing manufacturers more control were not realized.

Many practical issues arose as companies attempted to implement QbD.  Issues that ranged from determining the nature and number of systems that required development, and knowing which existing systems would need to be replaced by the new systems, to shifting design, communication, and change management paradigms across entire organizations.

Additionally relevant, and perhaps even more daunting, would be deciding how to collect and present data generated by the new systems within the chemistry, manufacturing, and control (CMC) sections of New Drug Applications (NDAs).  NDAs were designed to expect the type of data that was generated under the old systems, and utilized formats that were not famous for their flexibility.

Industry also wondered what impact adoption of the QbD approach for submission to American regulators would have on applications to foreign regulatory bodies.  Would they need to preserve both systems in order to participate in different application processes?  If parallel systems were required, and QbD was optional, then taking the new approach would seem to raise over head instead of lowering it.

The topical guidance documents noted earlier in the blog were released in response to the system and concept questions, each accompanied by a string of public workshops.  In order to respond to the questions regarding alignment with foreign licensing processes, the FDA and the European Medicines Agency (EMA) introduced a pilot program that would allow manufacturers to submit a single CMC package to a review panel that represented both agencies prior to preparing an entire NDA.

The program would allow manufacturers whose choose to submit a QbD application to the pilot program, an opportunity to have the quality and CMC data reviewed in parallel by both agencies.  The companies involved in the pilot program were also promised direct communication with the regulators, allowing any issues to be addressed prior to final preparation of the entire licensing packages.

This pilot program was limited in duration; it began in 2011 and was targeted for closure in 2014.  The number of applications processed within this time frame was hoped to be enough to:

1.      Ensure that common ground would be reached by FDA and EMA, ensuring that any organization adopting QbD would be able to use that single approach when applying for American and European licenses, and
2.      Allow a representative number of manufacturers direct access to the process, and hopefully address all applicant questions along the way, while
3.      Ensuring interactive parallel review, allowing industry to ask direct questions, provide direct feedback, and watch the process unfold, instead of being notified of the output of the review process after it had completed.
Those companies that participated in the program saw the roll out first hand, but the rest of us have been waiting for a progress report.
Recently, the FDA and EMA released a joint question and answer document, summarizing the events and outcome of the first parallel reviews.
Coda has chosen to use the October installment of the blog to review the events that led to the pilot program, and we will use the November installment to present our review of the newly released Q and A document and our interpretation of the progress to date.
We will review the document in detail, and provide our opinion as to whether or not the pilot program’s early output suggests that the very valuable objectives stated above are being met.  We will also weigh in on whether or not we feel that the experience gained since 2011 will result in changes to any agency program, related guidance document, and/or the application process itself.
We hope that you will visit the blog next month, consider our opinion, and leave one of your own!

Post a comment or leave a trackback: Trackback URL.

Post a Comment

Your email is never published nor shared. Required fields are marked *


You may use these HTML tags and attributes: <a href="" title=""> <abbr title=""> <acronym title=""> <b> <blockquote cite=""> <cite> <code> <del datetime=""> <em> <i> <q cite=""> <s> <strike> <strong>