Innovative Drug European Associates


In drug development, it’s often the area you least expect that causes the most problems. In my experience, one of the biggest hold-ups to completing regulatory submission dossiers relates to manufacturing, not the safety and efficacy data. The information needed for the Investigational Medicinal Product Dossier (IMPD) or CTD Module 3 (M3) — stability testing, validation methods, impurity detection, DMF/ASMF’s, and the product specifications and certificates of analysis, or distribution and supply chains – these are where the most time-consuming problems typically lie.

To avoid these setbacks, companies need to have those conversations with manufacturers from the outset. Ensure you have the information you need, the right stability data, and other key data that the regulators will expect to see. This is what most often holds up clinical trial or marketing authorisation submissions and creates cost headaches for companies as they come across unexpected delays to their milestone payments.

Often not having all the data needed for an IMPD/M3 leads to questions from the regulators, rejections, and panic, but that’s not necessary. Instead, companies need to consider the type of product they’re developing and where they are in the process, and then build a plan, based around the principles of Quality by Design (QbD) for acquiring the necessary data, and offer sound justifications where it is not available. Some data will be needed upfront, such as the stability data to support the claimed shelf-life, but in the early phases it’s okay to tell the regulators you’re still working to gather data on method analysis and validations. That’s normal when we’re talking about a new product, because no one understands fully how it works until development progresses.

The other problem that often arises with manufacturing is whether novel manufacturing methods can be scaled up later. Some methods may be fine in the laboratory when you only need 500ml of a product, but will you still be able to carry out extraction methods when you need 5l or 500l? These are complex considerations for young biopharma companies, especially those developing a first-in-class compound.

To avoid problems – and disappointment – later, new companies should get expert regulatory CMC advice, and for more complex issues or gaps in the data for quality and manufacturing aspects of their product they should seek formal scientific advice. After all, the FDA warning letters that are frequently sent out are mostly due to good manufacturing practice (GMP) problems – something unwanted got into the formula, a manufacturing plant isn’t up to GMP standards, and so on.

These are a vital part of the process, because if your manufacturing has problems, isn’t GMP compliant, can’t be carried out in a consistent, cost-effective way, or the batch works but can’t be replicated, then no matter how good your clinical data is, you won’t have a product to bring to market.

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