A CRADA Diary: Part I

For the past two years, a novel Cooperative Research and Development Agreement (CRADA) involving FDA and the software company Conformia has been looking at bumps on the road to science-based manufacturing. In this first of several interviews, CDER’s Office of Pharmaceutical Science director, Dr. Helen Winkle (HW), and Conformia cofounder Anjali Kataria (AK) share their views on the CRADA’s progress.

PhM – How did the idea for this program come about?

AK – Conformia had given a number of briefings to FDA about the drug development space. The Agency felt there were gaps in its understanding of the issues, but they appear to have realized that, as a third party, we had a different perspective than an operating pharma company. We offered some middle ground.

We’re trying to raise issues that are important to helping the industry understand the underpinnings of ICH Q8, Q9 and the emerging Q10, especially since drug companies will have to file applications in a new way, using the principles of Quality by Design.

PhM – Have there been any surprises so far?

AK – What surprised me is that there are bottlenecks on both sides, on industry’s and on FDA’s, as the Agency attempts to get reviewers, inspectors and policy makers alike to adopt QbD across the board. Under the pilot CMC program, three companies have announced that they’ve been approved under the new paradigm, but that’s a very limited group.

Moheb Nasr at FDA is very committed to QbD, but who else is committed on the inspection and policy side? What kind of integration is occurring between these two groups? That connection is not visible to the industry yet. The biggest challenge for FDA has been in the small molecule side of the business. The Office of Biologics has already had a team approach for years in which reviewers and PAI inspectors are joined at the hip, but that doesn’t yet exist for the larger inspections for small molecules. Unlike at CBER, there’s no guarantee that the inspector is talking with the reviewer, and that the reviewer is sharing files, or that either have bought into the new paradigm.

PhM – What are pharma’s biggest challenges right now?

AK – There is a lot of time wasted in trying to understand what validation requirements are, for systems validation and GMP documentation. Multiple systems, silos and geographically dispersed handoff points are all problems. Information is scattered, held in heads of key scientists, preventing what FDA is calling for: The systematic capture of process understanding and the ability to go back and demonstrate the rationale of why you did what you did, or what you didn’t do, or why it had failed.

In order to have that level of sophisticated support, one needs to go back to years of information, and to be able to rely on that information. FDA’s situation only mirrors the industry’s.

PhM – Dr. Winkle, what are your views?

HW – FDA now feels that we may have been a deterrent to pharma modernizing its manufacturing. We want to make corrections in our regulatory process to change this picture. Product quality has been reasonable, but at a high cost to both the agency and the industry, because of the scrutiny given manufacturing. It’s a shame that we haven’t focused more on manufacturing and the science behind it because it is 25% of the cost of the product, yet it’s not getting the kind of look or review that it should.

We have found that many companies aren’t utilizing their equipment---capacity utilization rates can be as low as 15%, while waste is also common.

PhM – What needs to change?

HW – At FDA, we had taken a “mothering” role. Now we need to hand the responsibility for process understanding and control back to the industry. We need to step out of the role we’ve played for years, as overseer, and do valid reviews but get out of the business of making all the decisions for industry.

PhM – What are you doing about the “disconnect” that Anjali mentioned, between different functional groups within FDA?

HW – We want to have much more interaction between the field and reviewers so that decisions are more collaborative, so that inspectors will know what the commitments are and whether or not they can be achieved.

PhM – How are you doing that?

HW – We are going to have more of our reviewers go on inspections, especially preapproval inspections, with field inspectors. We’re looking at more cross-training efforts, such as one in September that will bring field inspectors in to meet with reviewers. This will allow for more one-on-one interaction.

Most of our involvement will be with the PI. We’ve had them in for several training sessions….trying to figure out how best to bring them in line with daily thinking in Center.

PhM – Will you be expanding the PI?

HW – I’ve been allocating more funding each year for the program. We’ll see more money coming this year. The problem is not so much funding but focusing more on what we need to get them to understand, and to look at some of the gaps between what we do in review and what they’re doing in inspection.

PhM – How about the international inspectorate?

HW – FDA is in the process of applying and going through the audit. We’re also looking at more international inspections with sister agencies overseas. We’re having bilateral discussions to discuss where we could have dual inspections or inspect for each other.

PhM – Are government and industry collaborations the way of the future?

HW – These will be very important, especially with the Critical Path Initiative, where we need to improve manufacturing science. We already have a number of CRADAs going on with Novartis and Light Pharma.

PhM – Will there be more funding for training at FDA?

HW – With the 2008 budget, we’ll have more funds available for training and education and also for sending our people on inspections and plant visits so they have understanding of unique manufacturing processes, so they can bring that understanding back into the review process.

PhM – What progress has been made in rewriting and modernizing guidance documents?

HW – One of the things that has bothered me is that they’ve been extremely prescriptive. We have three or four revisions on the drawing board now, including a new comparability protocol that will give more flexibility for legacy products to present QbD data for regulatory flexibility.

In addition, we’re starting up another QbD pilot for biotech products. Guidance will come in the next year or two.