There is a growing trend in the pharma sector for small biotechs to take molecules further down the development pipeline themselves, rather than partnering with a big pharma company at an early stage. They may even take the compound all the way to market on their own.

This, of course, adds to the challenges they face. A small biotech will be heavily reliant on outsourcing partners for many aspects of a drug’s development, as they are unlikely to have the necessary resources in house. Identifying and engaging effective outsourcing partners is a critical step, not least in the important area of chemistry, manufacture and controls (CMC).

CMC comprises the wealth of data that describe the manufacturing process for a drug, its quality control release testing and the product’s specification and stability. It also includes comprehensive information about the facility where the drug is made, including all the support utilities, notably their design, qualification, operation and maintenance.

Errors or omissions in CMC data required by regulatory filings pose a real problem. The expedited programmes increasingly being offered by regulatory bodies to potentially transformative therapies exacerbate the risk of these problems occurring. The regulators are asking for more data, and to keep up with aggressive timelines, these data have to be supplied more quickly.

Regulatory missteps are costly, both financially and time-wise, and this is a particularly important consideration for a small company with a product that is on some form of accelerated pathway. Working with a partner who can guide them through the regulatory maze and get everything right first time is essential. It can be the difference between failure and success.

Regulatory pitfalls

It’s worth taking a look at what can occur if a regulator decides not to file or approve a new drug application. When the US FDA receives an application, there are two possible responses other than approval: it might issue a refusal to file notice or it could send a complete response letter. Neither of these is good news for the company making the application.

If it issues a refusal to file (RTF) notice, this will be sent within 60 days and indicates that FDA believes the application is incomplete. The notice allows the company to repair the deficiency in their filing and resubmit. While this takes time, it does not cause delays as great as those that result from a complete response (CR) letter, which rejects the filing.

A CR letter pushes the entire application back to the company and is provided once FDA has carefully reviewed all the data, which, on average, takes the regulator about ten months. At a minimum, it will cause a very long delay while the filing is reworked and additional data gathered. In the worst case scenario, it could even mean the end of the line for the molecule and, maybe, even the company.

The consequences of such a delay are significant. A small biotech with a single product in its pipeline may find its very existence threatened by the delays and additional costs that result. Running further clinical studies or making changes to the manufacturing process could be enough to put them out of business, as they may struggle to raise the extra funding required to finance the additional work. It might also allow a competitor to leapfrog them and reach the market first, reducing potential revenue further.

These RTF and CR notices are only made public if the company chooses to release them, and even then they may not publish the full details of the response. There is, therefore, limited readily available information about the deficiencies that FDA identify in these filings. However, there is research in the academic literature that gives some pointers (Sources: FDA MAPP 6025.4 & 21CFR314.110).

Unsurprisingly, significant numbers of these notices include mentions of insufficient efficacy or safety data, but the single biggest deficiency FDA cited was CMC data that was either insufficient or absent. The research also highlights that the median time it took to resubmit an application after an RTF notice was about six months. As well as the direct costs of fixing the application, delaying approval by this period of time could easily equate to hundreds of millions of dollars in lost revenue, quite apart from the fact that patients are left waiting for longer to benefit from the new drug.

Regulators routinely carry out physical inspections of the facilities where a company plans to manufacture the product. This means that the facility must be available to inspect at short notice and if the facility is not ready for inspection when the regulators require it, then this is a problem. Indeed, lack of availability for inspection is a common cause of CMC deficiency. The risks here are particularly great if the facility is not owned by the company itself, as is so often the case for a small biotech. They will be reliant on their CMO or CDMO making the facility available for inspection when requested by the regulator.

The impact of receiving a CRL are illustrated very well by the example of a small US pharmaceutical company, which had filed for approval for a potential migraine treatment in the second quarter of 2021. It received a CRL in 2022, stating that the main reasons why the CRL had been issued related to CMC concerns, and that the FDA had requested additional CMC data about both the drug product and the manufacturing process.

Following a meeting with the FDA to discuss the issues, a press release from the company in September stated that FDA required further CMC information, including stability data on newly manufactured commercial scale batches, in the resubmission. It also stated that the expected resubmission would be in the third quarter of 2023 – well over two years after the company initially filed for approval.

Picking the right CMC partner

With so much risk lying in the regulatory process, it is clear that it is incredibly important to get the CMC data right first time. So, what factors should a biotech take into account when looking to select a partner to help with their CMC work?

One aspect to bear in mind is the breadth of the CDMO’s service offering. Is it able to manufacture both drug substance and drug product services? Are the two functions well- integrated? If this is the case, then not only should it facilitate faster development, it will have the added bonus of reducing the vendor management burden.

Enabling technologies are another factor to consider. With the growing complexity of small molecules entering the development pipeline – from synthetic challenges to highly potent molecules to solubility issues – what technologies do they have available to assist in overcoming the hurdles these forms of complexity introduce?

Experience of late-phase development and commercial supply are also important. If the plan at the outset is to take the molecule deep into clinical development without out-licensing or selling it to a big pharma company, it’s worth considering choosing a partner at the start who will be able to work all the way from early lab studies right through to commercialisation. This will remove the need to find and move to a large-scale supplier later on, with all the time and technology transfer implications this implies.

Companies experienced in late-stage development should also be able to provide regulatory support. Their programme management teams will have a good idea of what the regulators require and be able to efficiently manage all of that all-important CMC information. This will be invaluable when looking to avoid regulatory missteps, keep to aggressive timelines and get a molecule into the hands of patients, thus recouping its development costs more quickly.

*Lonza’s connected experts provide contract development and manufacturing services for pharma and small biotech companies. Throughout the molecule’s journey from early development to commercialisation, the company works as one with the client.