Things You Should Know About Phase 1 API Manufacturing

Phase 1 clinical trials represent the first phase in a long and complex drug development process. It is during this stage that a specific drug product’s safety, efficacy and effects are benchmarked and determined. 

Trying to accomplish this, however, is no easy task. During this stage, toxicity data from animal and human studies are conducted to make sure the compound’s safety is in line with what has been proven or previously understood.

A key challenge of manufacturing Investigational New Drugs (INDs) for Phase 1 pre-clinical trials is that no one knows what they don’t know. It’s impossible to predict what could occur – anything from the chemistry simply not scaling up, to impurities getting formed or the need to go back to the drawing board with analytical methods. Phases of manufacturing that proceed Phase 1 are simply a refining of what already has been developed during this complex technical phase.

Choosing the Right CDMO

To ensure successful manufacturing of Active Pharmaceutical Ingredients (APIs) during critical Phase 1, it pays to work with a Contract Development & Manufacturing Organization (CDMO) with deep expertise and experience with Phase 1 molecules. It should be one that knows how to successfully navigate FDA requirements and upholds the highest current Good Manufacturing Practices (cGMP) to avoid, for example, cross-contamination or other factors that could impact the quality of the clinical batch.

Potential hazards at the CDMO site that could impact product quality, include:

1. Sites that are not properly equipped for Phase 1 investigational drugs
2. Equipment that is not adequate for scaleup
3. Processes that are not repeatable for scale-up
4. Scientists and project managers without enough experience with INDs
5. Insufficient supply chains for quality raw materials
6. Poor FDA track records and understanding of the regulatory process

Once these potential hazards have been cleared, it’s important to ask about the CDMO’s technologies and resources that could streamline product development. An effective CDMO would utilize the following:

• Disposable equipment, which can reduce cleaning burdens and chances of contamination
• Commercial or prepackaged materials such as Water For Injection (WFI), pre-sterilized containers and closures to eliminate the need for additional equipment
• Process equipment that does not expose the investigational drug to the environment during processing

In addition to the above considerations, below are six tips to ensure successful Phase I cGMP supply

1. Make sure you have ample supply.  It’s always better to have too much product than too little, since accidents can happen and formulated batches can be lost, throwing off project timelines. At Seqens NA CDMO, where 70-to-80 percent of our projects are for Phase 1 manufacturing, we recommend making 50 percent more product.
2. Use a single CDMO for the entire project.  Everyone wants to keep costs down and sometimes it’s tempting to off-shore some manufacturing. However, the additional transition costs, as well as possibilities for transfer error can make projects costlier in the long-term.
3. Balance swiftness with thoroughness. While it’s good to have fast batch development for clinical trials, this must be tempered with a focus on process improvements, continuous refining of the manufacturing process to streamline production and improve yield while assuring pharmaceutical grade quality. Ultimately, the more efficient the process becomes, the lower the cost.
4. Trust your project manager. Trust between the CDMO and sponsor is based on a relationship built on open and frequent communication between the sponsor’s team and a project manager who can skillfully manages risk, timeline and budget. Once you have this trust, maintain ongoing contact to make sure there are no surprises that can impact the cadence of the project. 
5. Don’t leave it up to a consultant. While a consultant can be a valuable addition to your team, lending an objective perspective and valuable industry experience, it’s important with Phase 1 manufacturing to have ongoing direct communication with your CDMO.  Often, only you can provide inside knowledge about the business goals and the perspective of your key stakeholders to bear on the project.
6. Beware of low estimates. Every NCE is different and unforeseen technical challenges are bound to come up, but anticipating and quickly addressing problems are key. Some CDMOs err on the side of under-estimating development times to keep costs down, but then they must issue change orders when technical challenges arise. Understand, however that this kind of gamble, and hoping for the best can cost more than money – it can cost the project valuable time in starting the clinical trial.

A Phase 1 clinical trial introduces an investigational new drug into human subjects for the first time. For this reason, this phase is perhaps the most vital and challenging one for sponsors and their CDMOs alike. Picking the right partner to see you through it safely and effectively can go a long way to helping you reach your end-goal – successful commercialization. 

For more on working with a CDMO check out our blog for topics such as Who’s Manufacturing Your Prized API; When Does it Make sense to Use a CDMO; or Addressing Quality From All Angles in API Manufacturing.  

About the Author

Ed is President & CEO of SEQENS North America (formerly PCI Synthesis). He serves as a co-chair of the New England CRO/CMO Council and sits on the Industrial Advisory Board for the Department of Chemical Engineering at UMass, Amherst. Ed is also a long standing member of the American Chemical Society and advises the Bulk Pharmaceutical Task Force of the Society of Chemical Manufacturer’s and Affiliates (SOCMA)...

Do you have questions? Talk to Ed.