29/30 September 2021
Biopharmaceutical firms are calling for a global effort to decrease their heavy post-approval change filing burdens that would clarify and harmonize change classification and submission requirements on a risk-based foundation.
High on the priority list are a common definition of what information in marketing applications is a regulatory commitment and a broader adoption of "do and tell" mechanisms for notification of minor, low-risk changes.
The regulatory quagmire global companies face in trying to make post-approval adjustments to their manufacturing and control processes received front-burner attention at the CASSS/FDA WCBP Symposium in late January in Washington, D.C.
A plenary session was held at the conclusion of the conference to focus specifically on the post-approval change problem and pathways to address it. Highlighted were the amount of valuable resources that the problem consumes, the extended and varying clearance timelines, and the product distribution complexities that ensue.
The result, the participants noted, is that manufacturing and control improvements are not being made that should be and the supply of products to patients is being jeopardized.
Bristol-Myers Squibb (BMS) Global Regulatory Sciences CMC Executive Director Annie Sturgess set the stage by providing background and context regarding why post-approval changes need to be made for biopharmaceuticals, and how the regulatory complexities play out in long approval timelines and inventory issues.
Following Sturgess to the podium, Roche's Head of Marketed Biologics in the EU Ralf Gleixner delved further into the consequences of the divergent expectations among regulators for CMC submissions and post-approval changes. He provided a handful of case studies revealing the hurdles and extended approval timelines that firms encounter in pursuing even minor changes.
The session also included a presentation by Merck Biologics VP and Biologics/Vaccines Regulatory CMC Executive Director David Robinson. Speaking for the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA), Robinson offered insights on the impact that the global quality regulatory maze is having in the vaccine arena, in particular - including complicating vaccine approval, discouraging innovation, and jeopardizing patient supplies (IPQ, February 23, 2014).
The discussions that followed the three presentations revolved around how the current CMC paradigm discourages transparency and putting information in applications that is not strictly necessary for approval, since the additional information can decrease the room for making needed post-approval adjustments.
However, participants noted that the applications are getting more detailed, particularly on the biotech side, reflecting the increasing complexity of the products and processes, further exacerbating the problem. In turn, the learning curve is getting steeper, and technology moving faster, enhancing the need for regulatory flexibility around changes.
At issue was how the paradigm could be adjusted on the international level such that more transparent, information-rich applications were rewarded with lessened post-approval burdens.
The closing session extended discussions that had begun in the opening session of the WCBP symposium three days earlier (IPQ February 24, 2014).
The opening session brought together a panel of regulators from the U.S., Europe, Brazil, Canada, and Japan to review the regulatory CMC obstacles that need to be addressed to facilitate getting new medicines that fill critical healthcare gaps more rapidly to patients and the pathways being explored among the various regulatory agencies, such as FDA's breakthrough therapy initiative. The discussion encompassed the problems in the post-approval change arena, which come into play in making the needed regulatory adjustments.
Post-approval change concerns also drew front-burner attention at CASSS' CMC Strategy Forum Japan, held in Tokyo in December (IPQ February 6, 2014). Presentations were given there by a Japanese review official, who explained Japan's system, as well as by a Japan Pharmaceutical Manufacturers Association (JPMA) representative and an Amgen expert that focused on the post-approval change constrictions in Japan and how they compare and interface with those confronting firms across the global regulatory landscape.
Differing Change Expectations Pose Challenges
After providing some background and context, Sturgess discussed: - the challenges in interpreting regulations and timelines - the concept of a "living license" or "living dossier" - the implications of implementing global changes - the inventory problems that the current system fosters, and - mitigation strategies (Sturgess' complete remarks are provided below).
She concluded that managing post-approval changes is complex and time-consuming, with long approval times that cause inventory issues, delay implementation of changes, and hinder innovation and continuous improvement.
The BMS exec emphasized that "post-approval changes are essential. We want to stay current. We want to innovate. We want to improve. We learn new things. We are learning them every day. We don't want to hold back change."
Her recommendations on how to improve the current system include better guidelines that are harmonized globally. "I think we all recognize that each country has its own legislation," Sturgess said. However, harmonized guidelines could "help to bring clarity and consistency in interpretation for better risk-based decisions."
She explained that a change that may be the right one to make may not be made by manufacturing if the regulatory burden is judged to be excessive. "I never want my manufacturing colleagues to make a decision" based on the change category assessment, she commented. "That is not where we should be going."
Gleixner illustrated the post-approval change problems using case studies that focused on three different low-risk changes. These involved a laboratory method and drug substance and drug product technical transfers (Gleixner's complete remarks are provided below).
In his first example, Gleixner detailed how a change in preparing a laboratory reagent used in an upstream in-process test that had no impact on the associated method took a total of over two years for approval in all of the countries where the product was registered. The drug substance and drug product change cases took even longer.
"What results in the end is a very complex supply situation which is very difficult to plan for, including needing high bridging stocks, which you have to have in case something goes wrong," he emphasized. "That then leads…to drug shortages. And you hinder innovation and continued improvements of the process and product because you think very, very carefully before you submit one of these changes. And that, of course, has an impact on quality and safety to the patient."
Gleixner echoed Sturgess in recommending the harmonization of change classifications, submission requirements, review timelines and the development of common guidelines to help remedy the situation - potentially through regulator collaborations involving PIC/S, WHO or ICH. Mutual recognition of decisions by reference countries would also benefit both regulators and industry, he said.
Another approach that would "greatly reduce" the number of change filings, the Roche official maintained, would be harmonizing the documentation requirements and removing the GMP elements, such as analytical SOPs and batch records, from the scientific documentation, and verifying these elements, instead, on inspections.
"Changes that innovate or improve the quality of the product could be fast tracked to drive progress," he proposed, and "their categorization should be driven by their potential to influence patient safety and efficacy."
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