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Understanding Multinational Regulatory Filings: New Chemical Entity

By Jim Springer, Steve Halpin, and Megan Kuikstra, Albemarle FCS --

Every regulatory agency in the world might look at a sponsor’s filing a little differently. An adept CDMO partner can anticipate challenges based on its experiences and prepare sponsors for, or help them avoid, issues that may arise.  

Finding the right long-term CDMO partner for development and commercial launch of a new chemical entity (NCE) presents sponsors with a uniquely challenging scenario. First, “right” must be defined in quantifiable metrics, then the search begins for a  CDMO exhibiting those qualities. The challenge is magnified when a multinational launch is planned.  

For many sponsors, the search for a CDMO partner begins in earnest during Phase 2 of clinical trials:  the new chemical compound, chemical structure,  or mechanism of action (MOA) is producing positive results, and the sponsor is actively evaluating the patient population and dose. They are trying to estimate volumes for launch and predict where growth might take the product in five or 10 years. 

To navigate these steps for commercial launch,  particularly through parallel multinational filings,  most sponsors seek a CDMO partner that offers clear, direct communication, proven compliance expertise in similar projects, and the infrastructure to quickly ramp up production in response to surges in demand or entry into new markets. Not every  CDMO offers those skills and assets.  

Multinational Filings Can Introduce  Time and Cost Pitfalls 

Most sponsors and their consultants are well-versed in FDA New Drug Application (NDA) filings, but they may lack experience in European Medicine Agency  (EMA) or Japanese regulatory requirements and expectations. The expectations of regulators around the world are continuously evolving in parallel with the quality standards outlined by current good manufacturing practices (cGMP). In these instances, CDMO  experience emerges as the clearest differentiator between potential partners. Specifically, the CDMO  must be able to connect the dots between its recent endeavors and successful launch of your product.  

It is difficult to predict exactly what information regulators might request in addition to the base filing. However, Albemarle FCS has traversed the process enough times to have identified general patterns in what certain nations want to see or what they tend to focus on. Additionally, we understand certain countries are more likely to require additional feedback, and thus require more support from us on behalf of our customers.  

Once the sponsor submits its application, regulators may ask for additional information and a deadline typically is attached to the sponsor’s response. Albe marle prepares and ensures resources are in place to support our customers by understanding what could become. Parallel multinational filings may include increased analytical expectations by the regulator,  and the CDMO must have a project team ready to execute promptly to ensure these expectations are met. Our strength is built on up-front work from an analytical and process standpoint, gathering and organizing all information we anticipate a client may need to support its filings within a given timeline. 

For example, one area Albemarle has seen a clear difference in expectations between regulators is starting materials (i.e., what is considered an appropriate designated regulatory starting material). While the one regulator may accept a particular advanced molecule of a multi-step synthesis as a regulatory starting material, another may not. If the sponsor has to reassign the regulatory starting material from further back in its synthesis to file the molecule worldwide, a significant delay could result.  

Other areas of differing expectations from country to country include analytical validation and analytical method development. Based on our previous experiences and trends observed, Albemarle may advise sponsors to consider additional method validation, or at least prepare them for regulator questions they may face. The Albemarle FCS Process Development and Analytical Services groups have shepherded products approved by the FDA and intended for additional markets by understanding where analytical expectations may increase, often beyond what’s listed in guidance. Almost all projects encounter snags, but you want to eliminate avoidable major issues — saving time, work, and expense.  

Finally, a CDMO’s understanding of its process capability is vital, and must be considered during development, generating a comprehensive body of data as a  foundation for regulatory filings. This understanding of process capability allows a CDMO to respond to different regulatory authorities in the event they request a sponsor tighten a certain series of specifications. On several occasions, Albemarle has supported a sponsor through a first regulatory approval accepting a set of specific impurity specifications, only for another regulatory authority to examine both those impurities and some process history, then request some specifications be tightened.  

How Albemarle Supports Multinational Filings 

Albemarle FCS’s company culture is built upon collaboration and flexibility. Our quality and regulatory systems are designed to accommodate different filing strategies from different clients, and we embrace the ever-advancing standards of cGMP, allowing us to quickly solve new challenges and meet new expectations. We acknowledge that, while we are collaborating with the sponsor, our sponsors are working with regulatory agencies. We strive to enable our sponsors to respond quickly to agency requests by committing a full internal team: not only program managers and technical personnel, but our quality team and an experienced regulatory affairs group.  

We seek outstanding talent for those teams and have been fortunate to retain many of our experts for long periods of time. So, as programs progress from development and validation through commercialization, we have the same people working through each phase, applying a wealth of historical context, regulatory understanding, and process knowledge while building the sponsor partnership and relationship. Such knowledge continuity is critical when one considers the average program, from  Phase 1 to initial regulatory approval, based on our experience, takes about seven years.  

Often, a regulator may ask for information gathered years before a product was filed. Having a tenured product team ensures such information can be quickly retrieved and submitted. The team already knows why a particular decision was made, say, five years ago, and can work through it with greater familiarity, both from a technical standpoint and in terms of the people collaborating on a day-to-day basis.  

Additionally, Albemarle FCS has a long-standing generic drug portfolio, where we have our own drug master file (DMF) filings and support European commercialization. Few other CDMOs share the firsthand experience of owning, maintaining, and continually updating their own portfolios as part of the expectations associated with maintaining a DMF.  

Furthermore, Albemarle FCS controls significant commercial manufacturing assets. A sponsor may be manufacturing 15 metric tons a year at launch but,  within just three years, they might reach 75 metric tons a year. Thus, it is important for your CDMO partner to have the resources — technical knowledge and equipment — to scale up successfully in near-exponential fashion. In fact, the most common inquiry from sponsors to Albemarle involves our commercial assets  — can we support these larger commercial volumes?  

Another common sponsor need is moving manufacturing to a domestic supplier. Albemarle FCS has resources to move a program from kilo-lab scale up to full commercial scale, without the need for site transfers, ensuring such a risk is nullified before entering an important late phase trial. 

Conclusions 

Albemarle FCS is set apart by our talented personnel and our considerable production capacity, with the ability to increase scale quickly. None of this is possible, however, without a company culture built on transparency in our collaborations that fosters trust, leading to long-lasting, productive partnerships, fundamentally enabling support from early phase development to successful multinational regulatory approvals. 

That transparency starts with clear, reliable lines of communication between collaborators. Sponsor decision makers and experts have a direct line to their CDMO subject matter experts; decisions can be hashed out by individuals, versus crowded teleconference calls. Direct lines of contact also give sponsors confidence: they know, and have available, the people from whom they need answers. They also can be confident of project organization, that Albemarle FCS will let them know what to expect and when.  

To learn more, contact the authors or visit http://www.albcustom.com 

About the Authors 

Dr. Jim Springer is an R&D Manager for Albemarle Fine Chemistry Services. He works out of the Albemarle  South Haven GMP manufacturing site, where he manages process development for new APIs. Jim has more than 20 years of experience in process development for API synthesis and process validation. He holds a  Ph.D. in organic chemistry from Wayne State University. Jim began his career with Wyckoff Chemical in  South Haven, MI, where the primary focus was process development for generic APIs and has held positions with DSM Pharma and Vertellus Specialties. He can be reached at James.Springer@albemarle.com.  

Dr. Steve Halpin is an Analytical Services Manager for Albemarle Fine Chemistry Services, serving the Analytical Services Department at Albemarle’s South Haven GMP manufacturing site. His group is responsible for analytical method development, transfer, and validation, as well as research and development activities. Steve has been with Albemarle for eight years. He holds a bachelor’s degree in chemistry from Northern Michigan University and a Ph.D. in analytical chemistry from Michigan State  University. He can be reached at Steve.Halpin@albemarle.com

Megan Kuikstra is a Program Manager for Albemarle Fine Chemistry Services. She has been with Albe marle since February 2010 and currently leads custom programs at the South Haven, MI, facility. She has both process development engineering and program management experience in pharmaceutical and custom manufacturing. Megan holds a BS in chemical engineering from Penn State University.