Well, it’s January 2015 and the Office of Pharmaceutical Quality (OPQ) is about to be stood up (“FDA speak” for official) and will be addressing quality issues across the New Drugs and Generic Drugs arenas. The concept is of one quality voice and one standard, but more about this in a bit. The new leaders of OPQ are outlined in a CDER posting relative to the new organization:
Office of Pharmaceutical Quality Offices and Leadership
The following individuals will begin serving in January, 2015:
Acting Director: Janet Woodcock, M.D.
Deputy Director: Lawrence Yu, Ph.D.
- Office of Program and Regulatory Operations (OPRO): Giuseppe Randazzo (Acting)
- Office of Policy for Pharmaceutical Quality (OPPQ): Ashley Boam (Acting)
- Office of Biotechnology Products (OBP): Director: Steve Kozlowski
- Office of New Drug Products (ONDP): Sarah Pope Miksinski (Acting)
- Office of Lifecycle Drug Products (OLDP): Susan Rosencrance (Acting)
- Office of Testing and Research (OTR): Lucinda (Cindy) Buhse (Acting)
- Office of Process and Facilities (OPF): Christine Moore (Acting)
- Office of Surveillance (OS): Theresa Mullin (Acting)
As you can see, the new organization will initially be reporting to Dr. Woodcock who is also the Director for the Center for Drug Evaluation and Research (CDER) and Lawrence Yu will serve as Deputy Director. Changes made in the new organization include:
- Realignment of functions and personnel from the Office of Pharmaceutical Science (OPS) to OPQ
- Realignment of preapproval and surveillance inspection activities from the Office of Compliance (OC) to OPQ
- Realignment of inspection-related activities for bioequivalence/bioavailability and non-clinical studies from OC’s Office of Scientific Investigations (OSI) to the Office of Translational Sciences (OTS)
The concept of a single quality voice will be a welcome tune, should the new components actually sing in unison. However, if past history is any guide, a review or Complete Response Letter
(CRL) from the previous New Drugs chemists and a review or CRL from an Office of Generic Drugs (OGD) reviewer were much different. The New Drug application review appeared to concentrate more on the safety and efficacy (S&E) of the NDA product, while the detail and depth of review from the quality side seemed to be secondary to the S&E review. Questions were more straightforward than those seen in OGD reviews, and questions identified early in the NDA review were handled as informational requests and issues were hammered out during the NDA review so there was not a continual back and forth. We understand that is the direction that OGD is moving, but based on some CRLs seen lately, there is a long way to go before there is parity among the reviews for New Drugs and Generic Drugs. This is a monumental philosophical change in the way that quality issues are approached and, thus, one would imagine that there will be some bumps along the way. One of the goals of the new program as explained in the CDER posting (here) is to:
Establish consistent quality standards and clear expectations for industry. Safeguarding the clinical performance of a drug requires establishing consistent, scientifically sound, and clinically relevant quality standards. Product standards should be captured in critical quality attributes and clinically relevant specifications. Identifying quality problems, requiring corrective actions where standards are not met, and making enforcement decisions will require close interaction among OPQ, the Office of Compliance, and the Office of Regulatory Affairs.
And herein lies the problem, as I see it. The FDA expectations are very dynamic in nature and are often times decided on a case-by-case basis. There are lots of chemistry management leaders and many more individual chemists. Getting them all to agree on the same quality standards, or even defining what those standards are, is very difficult as the FDA staff faces the same challenges that industry does- they have to interpret what the FDA Guidance really means. Thus, when the Guidance documents used to establish standards are not crystal clear, then that opens the document to interpretation and oftentimes the FDA interpretation is not consistent with that of industry.
To elaborate, when you get a different answer or question from different FDA reviewers on the same issue in multiple applications, this creates a problem for the firm in responding, as multiple applications may have to provide slightly different quality solutions to the same problem. This also makes it difficult for firms to get it right for each product, as the perception of the industry is that in many instances, they have to hit a moving target. FDA regulatory expectations also may change without advance industry warning with adverse impact on or resulting in a change in filing type of a particular type of supplemental application (i.e., CBE-30 vs. PAS). For instance, in the Changes to and Approved NDA or ANDA Guidance, a site change may be submitted as a CBE-30 for “a move to a different manufacturing site for the manufacture or processing of any drug product, in-process material, or drug substance that is not otherwise provided for in this guidance” (see Section IV.C.1), unless the new site does not have a current cGMP inspection for the same or similar operation. Recently, we have learned that OGD has expanded its interpretation of this section of the Guidance to exclude newly purchased ANDAs where a site transfer is required unless the new site has specific experience with the drug substance or drug product. Maybe there is good reason for this change, but I can tell you it surprised me and many of my colleagues. When OGD was questioned about the change, they pointed to a presentation that was made at a GPhA/FDA CMC conference and said nothing else.
Having FDA put forth clear expectations also means having FDA announce (without ambiguity) changes it may make in policy or interpretation of policy in a uniform manner so that the entire industry can be made aware of the change. It will not be until FDA expectations are clear and standards are fixed that industry can be expected to meet FDA expectations in a consistent and reproducible manner. Podium policy only reaches those that happen to be in front of the podium at the time. If FDA expects all to comply with FDA policy and/or standards, then there needs to be a uniform and public mechanism for dissemination of those policies and standards, especially when FDA makes a change.
I would ask that if you have experienced a change in an FDA policy or standard where the first you have seen of it was in a Complete Response Letter to an original ANDA or a supplement that you send a description of that experience on to me at email@example.com. It may be useful to bring these issues to OGD’s attention in a blinded manner to help standardize the standards. I can also recall one issue that the chemistry division directors disagreed on relative to an interpretation of a guidance on CBE changes for different package sizes. So if you made a CBE supplement in one division it sailed through, but if it went to different division, you were told that it was being made a prior approval supplement. This was brought to the OGD Director’s attention and it took one month to come to resolution and put the three Division Directors on the same page. So as OPQ stands up, let’s hope that industry can clearly see where it is standing.