| Comment Record |
|
Commentor |
Dr. Arthur Fabian |
Date/Time |
2003-04-14 16:12:20 |
|
Organization |
SST Corporation |
|
Category |
Company |
| Comments for FDA General |
| Questions |
|
1. General Comments
|
The three general Goals of this Initiative, as announced on August 21, 2002 are indeed admirable and, frankly, long overdue. I applaud the Agency for moving ahead on it.
Based upon my many years of experience implementing/interpreting past Agency Guidance/Initiatives, I appreciate the opportunity to add the following thoughts/advice/ideas to the present effort:
· Keep the mindset for the Initiative not simply the Drug Product (DP) but the Drug Substance (DS) as well. In 1978, CFR 210/211 was written (updated) for DP but, in the preamble, it was proposed that specific regulation would soon emerge for DS and, in the interim, CFR 210/211 was to be used as a guide. That proposal clearly demonstrated the Agency’s lack of understanding of the difference between the DS and DP worlds. This generated the key inspectional problem that is still with us today: Inspectors auditing a DS Facility as if it were a DP facility. A terrible waste of resources for all, and a source of business for lawyers when the law suits started. Not only did it take the Agency about 20 years to get around to writing GMPs for DS, or APIs, but the 20 years were filled with GMP interpretation and Filing problems. One would think the lesson was learned. However, I see the same thing happening again. The language, mindset, examples, draft guidelines already issued, have the exclusive mindset of the DP. And when it’s all over, the DS world will be relegated to another unfullfilled preamble promise. Let’s not let that happen for the second time! There are many opportunities for change in the DS world which are very innovative and sometimes parallel that of the DP world and sometimes, not; especially in the area of process change. Further, the entire DMF system needs overhauling since it simply does not work in the Generic World, or, works with such inefficiency, it crys out for fixing ! Already I see statements like, “ This initiative is intended to step back and evaluate the currency of FDA drug product quality regulatory system (CMC review and cGMP inspections ) to ensure…..”. Note, “drug product” rather than drug substance and drug product. So please be certain that whatever guidance/regulation emanates from this Initiative, DS gets its share of the hype and, more importantly, its share of the mindset of those crafting the guidances coming from the Initiative. We all understand that it is the dosage form that requires the Filing, but there needs to be a new, broader view than that. We don’t want to repeat the History of CFR 210/211, but I see it starting already!!?!! Let’s stop it now!
·Given that one of the major objectives of the Initiative is to make the Center consistent with the Field, please consider the following threat to that highly desireable objective: FDA-approved, inspectionally-oriented Q7A, contains a definition for an API Starting Material. It is critical that any future definitions emanating from the Filing side of the Agency (ie the Center) are consistent with this definition. For example, if the definition to be found in the upcoming revision of the ’87 Guideline for Format and Content of an ANDA/NDA, conflicts with the Q7A definition, we will have total confusion on the part of Industry. There is no reason why there should be any conflicts in this critically important definition between the Center and the Field. The molecule a DMF Holder enters as the Starting Material of the first synthetic step reported in the synthesis, should be the same molecule as seen in the CMC section of the filing. Chaos, especially between Inspectors and Reviewers, will result if this is not the case, since the API Starting Material is the point at which GMPs begin. The definitions do not need to be identical, but do need to result in Companies coming to the same conclusion as to what molecule is the API Starting Material whether for filing or inspectional purposes. Having different points for GMP to begin, is a situation that needs to be avoided and is not necessary.
·In concert with the Initiative’s objective to promote Innovation: Presently there is a Guideline (Changes to an Approved NDA/ANDA, Nov ’99) that contains a statement that completely preempts the yet-to-be-published BACPAC II. It states that all changes after the Final Intermediate need to be filed via a Preapproval Supplement (PAS). It was this type of broad-brush guidance/regulation on the same issue that caused CFR 314.70 to be terminated by FDAMA and replaced by one that allows the filing mechanism to be proportional to the potential impact of the change on the Drug Substance/Drug Product. If one is going to have science-based guidance/regulations/GMPs, this makes perfect sense, ie, “Let the punishment fit the crime.” Until BACPAC II is published, this Changes Guidance, is a major barrier to Innovation for the last step of a synthesis, in the same way that 314.70 was a major barrier to Innovation to every step in the synthesis. Given the absence of BACPAC II, it should not have appeared in the broad brush way it did, but hopefully the strength of this Initiative will quickly end its reign of terror over Innovation, much like FDAMA ended that of CFR 314.70.
I look forward to the April 22-24, 2003 Workshop on the Initiative to further discuss the above and many other aspects of DS guidance/regulation. Thank you for the opportunity to input.
|
|