How to Run a Successful Clinical Study the First Time - Part Two

Manufacturing_API.jpgAdam Kujath, Site Director at Alcami’s API manufacturing and development facility in Germantown, Wisconsin, recently spoke about the business challenges clients face, and the circumstances that led to the successful resolution of this customer’s issues. In this second part of the series, Kujath addresses supply chain management and strategies involving the API process.

To recap, when an innovative New England-based biotech company needed a fresh batch of Active Pharmaceutical Ingredients (API) for a quickly approaching clinical trial, they turned to Alcami. The neuroscience pioneer company previously partnered with Alcami and the proposed work would help secure their next round of financing. The biotech company utilized other vendors for formulation, solid-state and analytical services, believing they had their process under control. They later realized a fragmented supply chain and non-integrated control strategy led to a six month delay, requiring a repeat of their clinical study. The company relied on Alcami next for rapid and robust API manufacturing support.

Q. How did you address the supply chain issues?

A. The investigation and additional development work of the customer’s formulation supplier had taken months, so things were time critical for an impending clinical study. Knowing we had expertise in not only drug substance and drug product, but also solid state chemistry, the customer requested Alcami take control of the program.

Q. What actions did you take next?

A. We quickly identified four different crystal habits present in a single polymorph which had been seen consistently in the manufacturing process. Additionally, in the screening for possible polymorphs it was determined there were several possible, depending on crystallization conditions. Ultimately both the polymorph and the crystal habit was identified critical quality attributes (CQAs) of the API for the client’s desired formulation. It had not been previously identified as a CQA from the drug product formulation team, so there was no feedback into the API process accounting for a desired crystal habit or preferred orientation.

Unfortunately, the previously fragmented supply chain design resulted in a failure of the non-integrated control strategy, creating a six month delay and a repeat of the clinical study.

Q. How did Alcami tackle this delay?

A. We employed our ProForm Select™ methodology – an integrated approach to solid-state chemistry and formulation development – to promptly come up with a resolution to the setback. With ProForm Select, we proactively addressed both the API process and formulation in parallel to ensure our client faster time through the clinic, improving process stability and reduced both filing and supply chain risk.

ProForm Select icon 2.png

Q. How did you proceed without changing the overall formulation strategy?

A. Rather than changing the formulation, we pinpointed the CQAs needed to achieve the desired formulation. To get the compressibility needed to improve friability, we had to target the less stable polymorph and get a consistent columnar crystal habit.

Once we understood the constraints of the CQAs, we reexamined the crystallization controls of the API process itself, looking for potential issues.

Q. What strategies did you use to implement the critical quality attributes back into the API process?

AWe did a Design Failure Mode and Effects Analysis (DFMEA) to consider all potential process input parameters that could impact the output – in this case, the polymorph or the crystal habit of the product. We were then able to identify parameters to vary in the solubility screening and the crystallization Design of Experiments (DOE) performed.

Next, we ran a high resolution DOE using automated platforms in our Weert, Netherlands API facility to establish prescriptive API crystallization controls. Cooling rate, specific grade of ethanol and water control were critical factors that allowed us to get the desired polymorph and columnar habit.

Implementing these back into the API process allowed us to successfully control a very complex morphological landscape.  

Q. What key notes should readers take away from this experience?

A. The interplay between drug substance and drug product are critical in the development life cycle of a new product. We can’t stress enough the incredible value of an integrated technical team and control strategy. Having a cyclical feedback loop in place allows for real-time experimental analysis and design solutions that take into account all process stages. An integrated team can significantly shorten your development time and prevent a potential repeat of a clinical study.

To learn more about our client’s story and how Alcami’s unique ProForm Select™ offering can help reduce timelines and prevent the repeat of a clinical study, be sure to download our on-demand webinar, “Critical Drug Substance Considerations for Formulation Success in Drug Product Development.”

On-Demand Webinar: Critical Drug Substance Considerations for Formulation Success in Drug Product Development

Topics: Thought Leadership