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IPQ Inside the global regulatory dialogue

Separate Review Track Proposed for Design Space to Avoid Marketing Application Approval Delays

A separate review track for design spaces could allow more room for industry/regulator dialogue on the issues involved without delaying the clearance process for the marketing application, Health Canada Center for the Evaluation of Radiopharmaceuticals and Biotherapeutics Senior Regulatory Scientist Anthony Ridgway suggested at a CMC Strategy Forum on implementing quality by design (QbD) cosponsored by the biotech science society CASSS and FDA in mid-July.

Ridgway made the suggestion in the context of the discussions at the July forum of the outstanding nexus of issues around defining the design space and its relationship to the control strategy and the quality system, what needs to be filed in applications, and the regulatory implications as the design space knowledge base expands.

July’s meeting was the third of the CMC strategy forums focused on implementing QbD in the biotech context. [Editor’s Note: The dialogue at the first two QbD forums is analyzed in the Sept./Oct 2007 and Sept./Oct 2008 IPQ Reports, respectively.] The forums are held semiannually in the US and once a year in Europe.

The July forum was focused in particular on the key learnings from FDA/industry collaboration in the A-Mab Case Study and in the CDER Office of Biotechnology’s QbD pilot program (IPQ May 2010 Report).

The A-Mab case study, which addresses the application of QbD principles in the development of a hypothetical monoclonal antibody, was the result of a two-year effort by a consortium of seven leading biotechnology companies, known collectively as the “CMC-Biotech Working Group.” A-Mab represents an important reference point for the industry/regulator discussions on how to implement QbD.

CDER’s QbD pilot is ongoing with OBP still accepting volunteers for working with the review office on QbD-oriented applications and supplements.

Ridgway threw out the idea of an independent regulatory pathway for design space as a possible solution to the resource challenges that agencies already face in QbD implementation, particularly smaller ones such as Health Canada, and the need to avoid having the potentially more involved design space discussions jeopardize clearance timelines.

Acknowledging that Health Canada is “struggling to deal with applications around quality by design,” Ridgway explained that his agency has solicited companies involved with the FDA biotech pilot to share some of the “backcourt” discussions, which they have been willing to do.

“We recognize the challenges as a small regulatory agency dealing with the same types of products that bigger agencies are dealing with,” he said. “It is a real resource challenge. It is a training challenge.”

Citing projections that almost three-quarters of the biotech products under development are from “very small biotech” companies, Ridgway added that these companies will be pushing to get their products on the market as quickly as possible to satisfy investors before resources are exhausted. “So they won’t be putting the effort into at least developing design space,” although “hopefully they will be putting it into quality by design.”

With the full QbD packages only likely to come from big pharma, “there is a real resource dilemma as to what to do where and how much. We are still trying to deal with that,” he said.

Design Space Adds Another Layer of Complexity to QbD Reviews

Ridgway views the general influence of QbD on the review process as part of the evolution of science, which is “a good thing,” providing “advantages to the industry.”

He echoed CDER Office of Biotechnology Products (OBP) Director Steven Kozlowski’s observation at the forum that in terms of QbD “the cat is out of the bag,” and there will be “a trickle down effect for companies that were never intending to file a quality-by-design submission.” They are going to be subjected to the same kinds of questions about process and product parameter criticality, for instance.

In turn, Ridgway noted, the biotech industry has been doing “quality by design lite from its inception” – having to control “black box” processes to have confidence in what “you get out compared to what you put in…. So there is experience with the industry for that.”

He pointed out, however, that the issue of design space “is a whole other measure of complexity on top of that. It has the potential to slow down reviews – cause a lot of more discussions back with the companies. I think if the reviewers are looking at a QbD submission that is not necessarily looking for design space, there may be fewer questions.”

The Canadian regulator recognized that, as the science develops, there will be more QbD-type questions and the bar will be raised to satisfy reviewers that “there is enough information there” to approve the product for the market.

If the company is at the same time asking for design space, with its implications for product quality and regulatory relief, and “that reviewer then has to make decisions on whether the design space is adequate, I think they are going to be looking at it with far more scrutiny, asking more questions. And there is the potential [for] a lot more back and forth – questions about design space.” That potential, in turn, would impact on the ability to get the review done in the allotted 180-day time frame for “Priority Review” or the 300-day time frame for regular submissions prescribed in Canada.

As such, Ridgway proposed that there “could be some advantages” to breaking the two apart – “having the design space discussion run in parallel, under a different track perhaps, then the evaluation for marketing approval.”

This could “allow a bit more time” to evaluate design space issues such as their size and number, and potentially allow for a broader input – for instance, from the inspectorate, “because it could be very important that the inspectorate is fully aware of the ramifications that are wrapped in the design space.”

Harmonized Global Approach At Issue

Having the separation for the design space considerations could also allow for a more harmonized international approach, Ridgway suggested.

“There is not much good in having your design space in one jurisdiction if you are a global company and you have design spaces of different size.  It would be good if there would be some kind of harmonization on managing the size of the design spaces.”

The regulatory issues around quality by design applications in general become particularly challenging for small agencies, the Canadian official pointed out.  Even with the resources of the European Union or the FDA, it is a challenge to train the reviewers and get the understanding, uniformity and continuity across different parts of the regulatory agency needed to implement the QbD paradigm.

Ridgway sees these challenges as a potential driver for harmonization, where the small agencies would need to piggyback on the ICH region reviews.

“The big agencies are going to have those kinds of problems. And absolutely smaller agencies and smaller jurisdictions are going to have a much bigger problem and may have to lean on the experience and the decisions made in the big jurisdictions,” he said.

The regulatory flexibility component of the design space paradigm has extra implications for different jurisdictions “in terms of releasing control,” Ridgway pointed out. Canada does not have comparability protocols, and the EU is only now moving toward their use.

The complicating factor of the impact of different regulations could give additional weight to the idea of separating out design space consideration from the marketing application clearance process.

“That is another issue that we have to deal with,” he maintained, “because granting design spaces is highly analogous to comparability protocols – advance approval of things which you don’t know the details of.”

CDER OBP Director Kozlowski views the ICH process and the openness about QbD implementation in the US and EU as an important factor in helping the rest of the world deal with QbD.

“I think the more transparent QbD is and the more available, the more likely that it will be accepted across different regulatory agencies,” Kozlowski said.

The challenge in the biotech context is to get started. “And I think that as people get started and discuss openly, then that knowledge can be shared.” Certainly for some companies, for example, with platform products, “it may be worth it to be pushing that envelope, because you will see some benefits, even if the [related filings] aren’t global at the beginning.”

The FDA biotech regulator added that currently firms also face “different specifications in different parts of the world. It is not that the global issue is only for QbD. It is a challenge.”

Genentech Senior Director Wassim Nashabeh commented that the discussion has been primarily focused on the ICH regions at this point.

“Some companies who are trying to go global with this,” he noted, “are experimenting with two documents – one that can go into some areas and another one that is more streamlined that can go in other areas.” Once the expectations and the wording in the guidances are more harmonized within ICH, the momentum for global harmonization will increase, Nashabeh stressed.

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