Understanding Multinational Regulatory Filings: New Chemical Entity

By Jim Springer, Steve Halpin, and Megan Kuikstra, Grace FCMS - 

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 two 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 ten 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 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, Grace Fine Chemical Manufacturing Services (FCMS) 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. Grace FCMS prepares and ensures resources are in place to support our customers by understanding what could be coming. 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 Grace FCMS has seen a clear difference in expectations between regulators is starting materials (i.e., what is considered an appropriate designated regulatory starting material). While one regulator may accept a particular, advanced molecule of a multi-step synthesis as a regulatory starting material, another may not. If the sponsor must 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, Grace FCMS may advise sponsors to consider additional method validation, or at least prepare them for regulator questions they may face. The Grace FCMS 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 is 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,

Grace FCMS has supported a sponsor though 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 Grace FCMS Supports Multinational Filings

Grace FCMS’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 that the average program, from phase one 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, Grace FCMS 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, Grace FCMS 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 Grace FCMS involves our commercial assets — can we support these larger commercial volumes?

Another common sponsor need is moving manufacturing to a domestic supplier. Grace FCMS 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.


Grace FCMS 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 Grace FCMS will let them know what to expect and when. To learn more, contact the authors or visit

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