Quality APIs for Competitive Advantage

The quality of an Active Pharmaceutical Ingredient (API) has a significant effect on the efficacy and safety of the eventual medication. That’s a given. A high quality API can also help a sponsor execute on a preferred business model. It can provide a sponsor with a significant competitive advantage, whether by paving the way to bringing a product to market sooner, enticing a licensing agreement, or encouraging higher bids for the product.

The months-long road to developing an API anticipates intense screenings by regulatory bodies concerned with preventing defects and ensuring medication quality. Time and money can be saved when each step of the way is performed to high standards. This blog article will outline some best practices.

Poorly manufactured or compromised APIs, on the other hand, can be costly in a number of ways. Steps need to be repeated. Documentation needs to be updated. And the cost is not just monetary. Faulty APIs have been connected to serious illnesses and some deaths. They can result not only in legal action, but also in damage to a sponsor’s reputation, which is not easily overcome. With speed to market critical to achieving business goals, such unnecessary setbacks are painful. There are enough challenges in these projects without causing self-inflicted wounds.

There’s much at stake. According to Pharmaceutical Technology, APIs have become “a dynamic focal point for mergers and acquisitions, investments in innovation, lab and plant expansions…and the development of new chemistry platforms.” APIs represent a $121 billion market in 2016 and is expected to reach nearly $200 billion by 2022. Delays in API production could mean lost market opportunities. As a result, quality concerns now supersede the cost concerns that were paramount until recently.

In-housing vs. Outsourcing API Development: Which is Best?

To develop quality APIs, there are a number of considerations. Among the first thing sponsors decide is whether to in-house or to outsource the process to contract development and manufacturing partners.

There are advantages and disadvantages to in-housing.

In-house advantages include:

• Ownership
• IP protected
• Detailed knowledge

In-house disadvantages include:

• Significant internal overhead – management and technical personnel
• Capital investment
• Need extensive internal experience to meet the invariable challenges, solve problems

A rapidly changing pharmaceutical industry is leaning strongly away from in-housing.  Where once companies handled every step of the drug-making process, from conceiving the API to scaling and manufacturing it, they have turned to outsourcing. And where once they turned to Asia, concerns about the quality of APIs produced overseas have led them to contract with partners in the U.S.

It takes two to three months of solid work, after a brief period of familiarization and optimization, to create a process robust enough to develop the first batch of clinical material. This entails:

• Optimizing the chemistry
• Developing and documenting the analytic methods in a form and format consistent with Quality Assurance (QA) requirements
• Outlining steps toward a regulatory pathway

Unlike building a standard house or car, there is nothing standard about developing APIs. Every project is different. Each brings its own challenges. Additionally, much depends on a myriad of factors:

• What is the sponsor’s business model? An API intended to be out-licensed to a partner follows a different course than taking a product through to commercialization.
• Does the sponsor expect to go quickly from Phase I to Phase II on the basis of strong data?
• Has there been a change of personnel within the sponsor’s organization or an FDA guidance change? These often result in additional work that can take the project cost from $800,000 to $1.5 million and extend the project timeline.
• And for certain disease indications, the size and type of clinical trial would dictate some of the things to be done during API development.

A word about API consultants

Although knowledgeable, consultants sometimes add unneeded complexity to a project. It’s easy for consultants to point out the necessity of certain tasks to mitigate regulatory risks. They are often absolutely correct. However, their timing may be off. Their recommendation may not be a high priority right now, as it could slow down the program without adversely impacting risk. Yes, it will need to be done, but could just as well be done at a later time so the project can keep moving along.

That’s why it’s critically important to have an experienced project manager, one who makes sure everyone is on the same page – the sponsor, consultant, CRO, CMO. Constant communication to reach agreement throughout the project is key. Every person on the team is managing a budget. Everyone is managing timelines, and everyone is managing risk. But each team member comes at it from a different perspective. To reach consensus, it is important for the team to ask these questions:

• Is there risk in postponing this step?
• Do we have the resources to do this now?
• Will it add value?
• Can we plan to take this step but can it be completed just before or just after manufacturing?

To answer these questions productively, it helps to know what the FDA is looking for in the submission. Often there is no need to delay a program, prolong the timeline, scrub the manufacturing plant schedule and raise costs.

With frequent meetings, open discussion and an understanding of where each of the team members is coming from, hopefully no one will be digging in their heels and insisting on anything. The API development and manufacturing process will be smoother, faster and more pleasant for all concerned.

Take advantage of an integrated contractor’s expertise

A final consideration for an optimal API project is whether to choose an integrated contractor or to get the individual steps done piecemeal by different contractors. Some sponsors ask us if they can do process research elsewhere at lower cost and bring the product to PCI Synthesis for scale-up or manufacturing. What they don’t realize is the cost of transferring a project from one contractor to another is substantial and ultimately makes the project more expensive while also extending the timeline. It can take two to three months to transfer a program – as much time as it typically takes PCI Synthesis to develop an API from scratch.

In addition to time-saving, the advantages of having an experienced, integrated contractor develop and scale up an API are many. They include:

• Strong technical competence
• Solid problem-solving skills born of extensive experience
• Skilled project management to manage budget, timelines and risk
• Commitment to frequent and open communication
• Robust equipment – PCI has 2,000 gallon reactors to take projects to commercialization
• Excellent analytic support with a deep understanding of how to manage towards regulatory approval
• Ability to scale from pre-clinical to commercial manufacturing under one roof

Developing a high quality API, and scaling it costs less in the long run when the entire process rests with a high quality, integrated, communications-oriented manufacturing organization.

At PCI Synthesis, we’re committed to sharing insights and lessons learned. You can check out other articles on key steps, such as “Process Research Best Practices: 8 Ways to Lower Drug Development Costs and Keep Projects on Track” and “How to Keep CMO Costs Down During the Process Optimization Stage of Drug Development.”

About the Author

Ed is the President and CEO of PCI Synthesis (PCI), 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.