Do’s and Don’ts of API Technology Transfer in Phases 1, 2 and 3 Clinical Trials

Our recent article discussed various technology transfer problems that can arise. We provided a checklist of required information to assure a smooth transition when moving an Active Pharmaceutical Ingredient (API) from the R&D stage to full scale production of the New Chemical Entity (NCE).

Although in the lab, process research has been carefully completed and analytical methods developed, the handover to manufacturing—the technology transfer—remains tricky. There’s still much to be learned about the chemistry and plenty that can go wrong when scaling up new chemistry for Phase 1, Phase 2 clinical trials.

While a CMO’s experience is valuable, no one can ever predict with certainty how the molecule will behave in later stages of development and scale-up.

This article will elaborate on early stage technology transfer vs. later stage transfer and provide some do’s and don’ts to help minimize technology transfer problems as the drug candidate progresses through clinical trials en route to commercialization.

Considerations for Phase 1 Technology Transfers

The big question when transferring technology from the lab to a CMO is whether the product can be successfully manufactured, turned from a seemingly robust laboratory scale process to a pilot or semi-commercial scale process.

A Phase 1 program still entails determining whether the process will work when somewhat larger quantities – for a 5 to 20 healthy volunteer Phase 1 trial – are needed.

Here are some do’s and don’ts for transfer of an API to manufacturing for Phase I trials:

Do’s:

• Know that additional investment may be required to achieve the end goal – a Phase I supply.
• Understand that it’s nearly impossible to determine what that cost will be.
• Choose a CMO you trust – your only other alternative is to build out the manufacturing infrastructure in-house.
• Pick a competent company with the capabilities, experience, equipment and flexible business model that allows you to start and stop, make changes, and do what the project requires.
• View and treat the CMO as an extension of your company.
• Realize that it’s a business relationship.
• Beware of fixed-price programs: if the CMO is losing money on your project, you may not get the best people working on your behalf.
• Make the Process Transfer Protocol (PTP) as comprehensive as possible for an efficient transfer that minimizes rework and repeated calls for more information.

Don’ts:

• Don’t convince yourself that everything will work as developed in the lab – it may, but it may not when scaled up.
• Don’t tell the CMO something works when you know it doesn’t.

Sponsors sometimes come to us while searching for an API manufacturer with another proposal that is as much as $200,000 less than our estimate. We say, “Good, would you share the name? We’ll hire them for our other projects and make a big profit.” They usually get the point. To get the top people who will focus on working efficiently on your project, our approach is to charge a set fee for each week of lab work required, and a set fee for each week in the manufacturing plant. Our fees are straightforward: $7,500 and $75,000 per week, respectively.

Phase 1 technology transfer from lab and manufacturer

Early-stage technology transfer from the lab to the CMO for Phase 1 requires more extensive interaction between scientists than later transfers, even though the latter has far more stringent requirements for compliance and process validation. Why? Because for Phase 1 to proceed, the CMO needs a great deal of starting information, including the following:

• Process information.
• Latest chemistry experiments.
• Latest technology developed.
• Parameters used in developing the latest chemistry.
• Conditions under which experiments were run.
• Everything that was tried – what worked and just as importantly, what didn’t work.
• Analytical methods.
• The number of times the procedures have been performed.
• The largest batch size produced.
• Samples of intermediate steps.
• Qualified reference standards.
• Assay qualification reports.
• In-process controls.
• Guidance on process ranges.
• Markers for impurities and process intermediaries.
• Bill of materials

No doubt budget and time are important to you. Being fully prepared and providing the above information in the package you prepare for your CMO helps the project move along far more efficiently.

Technology transfer for Phase 2

All of the above apply to preparing for Phase 2 clinical trials, where product manufacturing is scaled up for a larger number of trial participants – up to several hundred.

There are three major add-ons for preparing product for a Phase 2 trial:

• Optimizing the chemistry, which usually requires an additional investment to solve problems encountered in Phase 1.
• Fully validating analytical methods.
• Thorough review of specifications.

Technology transfer for Phase 3 trials: last chance for change

Despite more stringent regulatory requirements for pivotal Phase 3 clinical trials, much of the scientific work on the API is done, although process improvement for greatest manufacturing efficiency may continue.

Whether embarking on full cGMP production or commercialization, the critical task is to review processes ahead of Phase 3 trials. Can the processes be further optimized to run faster? See impurities better? Calculate purity?

If methods or processes didn’t work as well as could be expected in Phase 2, now is the time to make changes, particularly if there is need to:

• Improve yield.
• Change out raw materials.
• Take additional steps for process optimization.

These changes must be made before starting Phase 3. It’s the last opportunity.  Once Phase 3 trials begin additional changes invite additional regulatory complications.

There is less interaction between scientists in Phase 3 because the science is essentially set. At this point, everyone understands that Molecule A and Molecule B will make C.

As the scientists step aside, the engineering and manufacturing staff take control.  The chemists created the chemistry and the process. Now the engineers modify processes for bigger equipment and larger scale product production..

They create master batch records, determine how processes will run, and make multiple batches to assure the same level of quality in each batch for agency review. The subsequent Analytic Package submitted to the regulatory agency contains methods and standard operating procedures that any analyst should be able to run.

Details, details

They key to successful technology transfer for Phase 1, 2 or 3 trials is to be as specific as possible, including all technical information, materials, processes, analytic methods, reference standards and samples.

To sum up, whether preparing for Phase 1, 2 or 3 trials, the process of technology transfer is an arduous one at each phase. An efficient process requires teamwork, forethought and good communication between teams every step of the way.

We have significant experience in successfully transferring API technology and managing the API through Phase 1, 2 and 3 trials. We have more than 17 API and other advanced materials products in our commercial pipeline. We’d be happy to answer questions you may have. Please call us at (978) 462-5555.