Regulatory Relief Explored for QbD Use in Post-Approval Changes

There is little evidence that using QbD for managing post-approval changes will confer regulatory relief to pharmaceutical manufacturers. FDA and industry officials say that current FDA guidance documents on change control are not keeping up with the science.

FDA should update its guidance on change control because it does not support science- and risk-based approaches to manufacturing changes, say agency and industry officials. As a result, the promised regulatory relief for manufacturers that embrace quality by design, or QbD, has not happened.

The status of change control policies in the U.S. and the European Union and their similarities and differences, particularly with respect to change management protocols, came up at a June 25 workshop at the Drug Information Association’s annual meeting in Philadelphia on “Post Approval Change Pathways in the EU and the U.S.: Challenges and Opportunities for Harmonization.”

Christine Moore, the acting director of FDA’s Office of New Drug Quality Assessment, said that “even though we put in this great science- and risk-based structure for what you put in the initial submission, we don’t have clear rules or guidance on how to use these same principles post-approval.”

Change control is challenging

Moheb Nasr, vice president of regulatory CMC strategy for GlaxoSmithKline, and former director at FDA’s ONDQA, said that the current change control system in the U.S. is challenging to implement for both industry and regulators and does not reflect QbD principles.

Nasr left FDA in 2011 after spearheading many of the QbD initiatives in the agency. He was also an active participant in the International Conference on Harmonization quality working groups promoting QbD.

He said that the change control system “is very complex and costly and resource intensive. It discourages transparency in regulatory filings and hinders innovation and continual improvement and is responsible in some cases for drug shortages. It is mostly a checklist approach and is less reliant on product and process understanding and applies the same or similar rules to different classes of drug products.”

Yet this system does not reflect the fact that lifecycle management of chemistry, manufacturing and controls, or CMC, is becoming increasingly critical due to business, technology and regulatory realities.

“This will get me in trouble but frankly in the pharmaceutical industry we are still in the dark ages with respect to our efficiency. This is not a good way for large, small and medium size pharmaceutical companies to be in the 21^st century.”

What happened to regulatory relief?

Nasr said that the regulatory relief envisioned by ICH and FDA for manufacturers that adopt QbD has not materialized.

“If I was sitting in your place I would say, ‘change management again? That has been discussed over and over again.’ Another question I would ask is, ‘whatever happened to the promise of regulatory relief?’”

Nasr said that FDA’s Pharmaceutical Quality for the 21^st Century initiative, the evolution of process analytical technology, FDA guidance on change control, and the incorporation of QbD approaches in ICH Q8, Q9 and Q10 guidelines, have all espoused regulatory relief to manufacturers that embraced these principles.

“I would argue that many things we have made progress on, but [in] the reduction of post-approval submissions, there has been very little progress.”

He noted that “each one of these initiatives brought in a promise of simplifying change management. A key question for us today is how can we effectively have a paradigm shift to simplify expectations and simplify compliance to regulatory requirements?”

For example, he said that the ICH Q8 guideline says that the degree of regulatory flexibility is predicated on the level of relevant scientific knowledge provided and “that provided opportunities for flexible regulatory approaches.”

Yet the draft CMC guidance on postapproval changes that FDA issued in June 2010 has also done little to bring about regulatory relief. Nasr said that most of the downgrades to annually reportable were for very low-risk administrative changes (Also see "FDA Proposes to Ease Reporting Burden for Low-Risk CMC Changes" - Pink Sheet, 1 Jul, 2010.).

Nasr said that “I would argue that the outcome of the guidance was not what was expected earlier and I would urge FDA to assess its value and implementation progress.”

CMC PMP never fully implemented

Another earlier initiative to reduce supplement filings, FDA’s CMC Post-approval Management Plan (CMC-PMP), also known as the CMC Regulatory Agreement, was never fully implemented but had two important features.

It provided clarity on regulatory relief. “Without that we will never have regulatory transparency. There will always be a desire to put in as little information as possible.”

The second feature conferred a significant reduction in post-approval manufacturing supplements if manufacturers could demonstrate product and process understanding and controls.

Nasr said that “this means that the more you know the more we trust manufacturers to make changes without regulatory approval.”

The CMC-PMP was developed at an October 2005 meeting sponsored by the American Association of Pharmaceutical Scientists, the International Society for Pharmaceutical Engineering and FDA to help guide the agency in addressing the practical issues involving in implementing QbD in the quality assessment area (Also see "FDA’s QUALITY ASSESSMENT SYSTEM" - Pink Sheet, 15 Nov, 2005.).

Nasr said that an earlier initiative to simplify change control, draft guidance on comparability protocols issued in 2003, also failed to provide much regulatory relief. It was called “Comparability Protocols: Chemistry, Manufacturing and Controls Information.”

Nasr said that “there was a lack of understanding from industry about the industry’s expectations.”

FDA officials acknowledged even back in 2008 that the guidance was hard to figure out and needed to be revised (Also see "FDA to Encourage Continual Quality Improvement With 'Special Reports'" - Pink Sheet, 1 Sep, 2008.).

A comparability protocol differs from a prior approval supplement in that much of the supporting data is submitted later, after the protocol has been approved. It prospectively specifies the tests and studies that will be performed to support the change. The idea of using these protocols is to allow manufacturers to make changes faster.

The guidance emphasized the importance of identifying the analytical methods to be used to assess the effects of a manufacturing change on the drug product (Also see "DRUG GMP WARNING LETTERS" - Pink Sheet, 15 Apr, 2003.).

‘Tremendous changes’ in the EU

The EU has made “great efforts” to simplify post approval changes under its new variations legislation, which went into effect in 2010, as well as its accompanying guidance on post-approval change management protocols (PACMPs), said Nasr.

“The EU has made tremendous changes in the variations regulation. … One is that continuous improvement should be supported. That was new. It encourages innovation.”

Nasr said that of the four comparability protocols submitted to the European Medicines Agency, three have come from GSK.

A PACMP describes changes that a company would like to implement during the lifecycle of the product and how these would be prepared and verified. It is a step-wise approach to assessing changes including early and later evaluation of the data to support the change.

In one case the company got a PACMP protocol to register an alternative manufacturing site for a drug provided as a lyophilized powder for intravenous infusion in sterile single-use vials. The approval was for an alternative site for the manufacture and primary packaging of the drug product. The PACMP protocol was considered as an appropriate mechanism for managing the change.

In the second case, GSK needed an alternative site of manufacturing and primary packaging to expand drug product manufacturing capacity to mitigate supply continuity risk. Overall, the manufacturing process remained the same. Yet several changes were driven by the requirement of the new site and process improvements such as a doubling of the scale-up in the batch size, the use of disposable technologies and changes to non-critical process parameters.

FDA’s need to update guidance

Moore agreed with Nasr that FDA needs to update its change control guidance to reflect the science- and risk-based approaches that are taking place in manufacturing and to encourage lifecycle improvements.

She said, “What is the issue with our current state of guidances? To start with they are old. They are before the QbD paradigm. While SUPAC uses the risk-based approach, they categorize everything within the same dosage form using the same risk … this is not necessarily a good assumption for all products. Often you wind up with overly conservative change reporting categories and evaluation methods. Sometimes you get too liberal categories in evaluation methods.”

The SUPAC immediate release guidance was issued in 1995, SUPAC modified release guidance in 1997, SUPAC semisolid dosage forms in 1998 and SUPAC for postapproval changes for analytical testing laboratory sites in 1998. SUPAC stands for Scale-Up and Post-Approval Changes.

Moore further noted that “we have evolved the science- and risk-based approaches under QbD but we have not provided additional flexibility beyond design space and real time release testing and related them to post-approval changes.”

A better understanding of the risks

Moore said that under the current science- and risk-based paradigm, the risks posed by manufacturing changes are different – even for drugs in the same dosage form and class.

She further noted that it is important to understand product- and process-specific “failure modes” in managing changes.

She gave an example of how one product – a film-coated immediate release solid dosage form – can have different risks from different failure modes. The risks are posed by blending, compression and coating.

“In the first case you have a low dose drug but a highly stable API. In the second case you have a high drug loading so content uniformity should not be as much of a problem. But this has a moisture sensitive API. Even though at the outset this is the same drug and the same dosage form, the risks from these two products are different because the failure modes are different.”

She further noted that risk assessments done in development are not limited to QbD applications but can be used for older products as well.

The next step for FDA’s Center for Drug Evaluation and Research in evolving a new approach for post-approval changes is reforming its Council on Pharmaceutical Quality to include new members within FDA.

Moore said that the CPQ currently includes only the Office of Pharmaceutical Science and the Office of Compliance but “we are branching out soon to other offices” including the Office of Regulatory Affairs and the Center for Biologics Evaluation and Research to shape the future direction of CMC quality, including change management and supplements, which also “have a stake in these matters.”

Additionally, CDER will soon be asking for public comment on how to modernize change management, which is expected to be linked to a rework of the draft SUPAC manufacturing equipment addenda.

Experience with protocols

Moore also described the criteria for submitting a comparability protocol and some of the shortcomings ONDQA is seeing in submissions.

She said that protocols are appropriate when an applicant understands the potential risks of the change and how to evaluate them. They are not needed for movement within a design space but could be useful for expanding or modifying the design space. They are also not appropriate for safety or pharmacokinetic evaluations.

“What have we seen with protocols? Many coming in recently have a wide variety of topics, changes in manufacturing sites, alternative manufacturing processes or analytical methods, expansion of the design space or for real-time release testing. Some of these are much broader in scope than what is in our current draft in our comparability protocols.”

Some of the deficiencies observed in protocols:

• They don’t have all the information laid out and on the studies that will measure the effect of the change;
• Claims for regulatory flexibility are in the body of the application and should instead be specified as a protocol because you are talking about making changes in the application and the reporting category;
• There are no details of the studies to be performed to evaluate the effect of the change;
• There is no acceptance criteria for how the change will be accepted; and
• There is no reporting category proposed.

EU more aligned with U.S. system

Emer Cooke, head of the international and European cooperation sector for EMA, said that one area where the EU and the U.S. are getting more closely aligned in the post-approval area is through the use of protocols to request changes.

“The EU post-approval change management protocol is very similar to the change management protocol that Christine described and asks you to describe up front what you intend to do and how you would like to do it. How you intend to do it will be verified at a later stage.”

Cooke said that the PACMP can either be submitted in the original marketing approval application or as a stand-alone variation.

“Previously you had to do everything together. You had to explain what you wanted to do and introduce the results at the same time so you couldn’t do it in advance. You had to wait until you got the results. Now in the change management protocol opportunity you can already describe your strategy up front. …This allows you to have much faster approval step at the later stage.”

She said that the types of changes that could be included in a protocol depend on the complexity of the product and its manufacturing process as well as the scientific knowledge and understanding the company has gained about them.

She said that PACMPs are not feasible for biological products where non-clinical and clinical data are needed.

A PACMP can cover multiple changes provided that they are directly related and interdependent. It is also possible to apply a PACMP on more than one occasion such as a supplier of active substance starting material.

PACMPs are also applicable to all types of applications irrespective of the development approach that has been followed, either through the traditional or QbD approaches.

“However, it is expected that if the applicant has applied QbD principles during product development, then an increased product and process understanding is achieved, thus making it easier to predict the impact of a change on finished product quality.”

The PACMP must include the following:

• Justification for the need of a specific change;
• A detailed description of the proposed change;
• Risk assessment of the impact of the change on product quality;
• Demonstrate the adequacy of the approved control strategy to identify and manage these risks;
• Describe additional controls which might be needed;
• Describe how this change will be reported to the relevant competent authority using the existing variation procedures as a Type IA or IB variation; and
• Provide data from development or pilot studies providing assurance that it is feasible to implement the change and that the proposed tests are relevant and adequate to evaluate the effect of the change on product performance.

Cooke noted that EMA has not received as many PACMPs as they had hoped and that they need more experience with EU post-approval change management protocols “but it is industry that needs to take the plunge.”

Other areas of alignment noted

Cooke further noted that besides the comparability protocols, the variations regulation also aligns the EU’s change control system more closely to the U.S. and even the Japanese systems.

“Even though the names are different, there are very similar categories between the U.S., the EU and Japan.”

For example a major change in the EU is called a Type II change, in the U.S. it is called a prior approval supplement and in Japan it is called a partial change approval application.

A moderate change in the EU is called a Type IB change, in the U.S. it is called a CBE-30 and there is no name for this type of change in Japan.

For minor changes, in the EU this is called a Type IA CBE and a Type IA IN and a Type IA AR while in the U.S. this is called a CBE or an annual report. In Japan this is called a minor partial change notification.

Other similarities between the U.S. and the EU approaches are:

• Classification based on risk;
• Possibilities to use annual reporting for minor changes (“Prior to the variations regulation we did not have this possibility. This has been a move in the right direction,” she said.);
• Expectations of effective quality management systems; and
• Use of ICH foundations for dossier content and approaches to QbD, risk management and quality systems.

Yet there are some challenges to harmonization, including:

• Granularity of approaches (Cooke said that “we have in the EU a very granular approach to the level and types of changes, and very specific details and very specific documentation requirements.”);
• Different regulatory procedures; and
• Different level of details required.

As a result of these differences, she said that “it is still difficult to manage changes in an international context.”