Transferring API Technology to a CMO? Use This Checklist

Technology transfer has various connotations in academia, law and business. In the pharmaceutical industry, the concept applies to the transfer of process technology from the R&D stage to a Contract Manufacturing Organization (CMO) for either clinical or full scale production of the Active Pharmaceutical Ingredient (API) or New Chemical Entity (NCE).

You might think it would be an easy handover. The R&D has been done, analytical methods developed and off goes the process to the manufacturing suite. But as it turns out, the process of technology transfer from the lab to manufacturing is far more arduous.

This article will discuss technology transfer problems encountered by CMOs – and what you can do to minimize them.

Phase 1 and 2 vs. Phase 3 technology transfers

To make matters more complicated, technology transfers differ in several ways. During Phase 1 or Phase 2 of drug development, for example, the transfer may be undertaken to determine whether the product can be successfully manufactured from a laboratory-scale process to pilot a development scale process.

Such an early-stage transfer requires extensive interaction between scientists. By comparison, a transfer in Phase 3 for full-scale cGMP production and commercialization, which has far more stringent requirements for compliance and process validation, may involve less technical interaction but more regulatory and analytical interaction.

In either case a comprehensive Process Transfer Protocol (PTP) can make all the difference between an efficient transfer and a process that gets bogged down with rework, inadequate protocols, and repeated calls for more information.

Issues from the CMO perspective

Here are the main technology transfer issues from a CMO perspective.

• Although some sponsors provide sophisticated packages that can be transferred to the lab, what we often receive requires extensive reworking.
• That’s because many people don’t know all that a CMO needs to be successful. Just because a sponsor spent $100,000 on R&D, it doesn’t mean the API is ready for manufacture. As we have detailed in our API manufacturing blog many technical packages provided to us are lacking in sufficient detail. Often the technical packages we receive lack such important information as:
  – The number of times the procedures have been performed
  – The largest batch size produced.
  – Analytical methods used
  – The level to which the analytical methods have been developed
  – Samples of intermediate steps, not just process information

People not familiar with the CMO side of things don’t think about some of these things but they are critical to moving forward efficiently.

If your budget is important to you (and it always is), keep in mind that the more efficiently your CMO operates, the easier it is to control the budget.  Do all that you can to help your CMO operate as efficiently as possible. Here’s how.

Putting a package together for the CMO

The key to successful technology transfer is to be as specific as possible by including all the technical information, processes, analytics, reference standards and samples available. The  CMO can then compare to what was done previously and won’t have to reinvent the wheel.

Another important factor to keep in mind: don’t hide anything from your CMO. The CMO also needs to know what was tried and didn’t work so efforts won’t be duplicated.

Providing these pieces of critical information to the CMO will help keep costs down. After all, manufacturing facility costs at $75,000 per week are 10 times higher than lab costs (at $7,500 per week), so solid information will save considerable time and money.

What the CMO needs prior to initiating technology transfer

The quality of the information provided in the technical package is very important. Here are questions to ask and prior to the handover:

• We are repeating this because it’s so important: Does the technical package contain detailed information on experiments that were not successful, as well as all the experiments that were successful?

• Has analytical information been collected by a single validated HPLC method or with several different methods where the specific method does not resolve some of the major impurity peaks?

Note that the quality of the information required will change depending on where the drug is in the development process. What is considered high quality information from a pre-clinical study may not be considered high quality information for a product nearing commercialization.

When  the drug development process gets closer to the new drug application (NDA), methods and procedures should be validated, whereas earlier stage activities may not require validation.

Final Process Transfer Protocol Checklist

Regardless of which party writes the final Process Transfer Protocol or whether both parties create it together, it should include the following components:

• Process Description – Based on molecule and process knowledge accumulated during research and development, the process description includes the following:
  – Sequence of operations for the process.
  – Rationale for each process unit operation.
  – Initial operating ranges for process parameters.
  – In-process controls.
  – Initial acceptance criteria for the product.
  – Development batch records.
  – Process and analytical development reports.
  – Assay qualification reports.
  – Test methods.
  – Guidance on process ranges.
  – Operating parameters as well as initial specifications.
  – Qualified reference standards.
  – Markers for impurities and process intermediates.

As the CMO conducts experiments and manufactures test batches, the process description will be revised to characterize the process in light of new knowledge.

• Equipment List: This includes details of the equipment that will be used at the receiver site to manufacture the product. Such a list is always important, but it is even more important if the receiver’s equipment differs from that of the donor and if scale-up is desired. Changes in the equipment can be addressed during the execution of transfer protocols to ensure that product quality is not affected by equipment change?

The technology transfer package should include:

• Bill of Materials (BOM): The BOM typically lists all the raw materials and process consumables that will be used to manufacture the product. This helps in identifying key attributes such as long lead-times for procuring the materials and consumables that are needed for the manufacturing campaign, and special tests, if any, that need to be performed for acceptance.
• Analytical Package: The analytical transfer package is a separate document that is presented either in parallel or before the process is being transferred. This is much more important for a Phase 3 project than for Phase I or Phase 2 projects. The state of analytical method development at the donor site can severely impact the transfer and successful execution at the receiving site. Typically in early development, release assays (used to monitor product safety, identity, strength, purity, and quality) are simply qualified but for latermstage programs stability-indicating assays need to be validated before process validation can begin.
• Danger Points: A review of the potential for unsafe or hazardous conditions that could arise during the process is a must. During technology transfer a meeting with the Research and Development team, Engineering team, and the Health and Safety team must occur in order to determine possible danger points during manufacturing. Some chemicals can be hazardous to the operators who are managing the reactor vessels, so during these additions extra care must be taken to protect them. Another example would be a reaction with an upper temperature limit above which a dangerous impurity could form.

Didn’t include something? No worries

Any information that is inadvertently left out of the initial documentation in the checklist above may be obtained by interaction of appropriate personnel and by adding appropriate information to the transfer documentation.

Further, throughout the transfer process, both sides should not only communicate fully and often, but also meet face to face. The personnel from the receiving site should become process experts by visiting the donor site and, conversely, donor personnel should be present for initial runs at the recipient site.

Communicate!

The real test of the technology transfer is how well both teams interact when technical issues arise during the execution of the project. Immediate communication by the contract manufacture when technical issues occur is a must. Relationships built during regular communication allow for quick development of action plans to resolve any technical issues as they arise.

Projects move more swiftly and smoothly when the contract manufacturer is viewed as, and performs as, an extension of the pharmaceutical company.

To sum up, the process of technology transfer is an arduous one that takes teamwork, communication, and, most importantly, the ability to foresee potential obstacles that could arise.

Finally, keep this overarching principle in mind: do your best to set up the project and CMO for success.

The technology transfer stage is a critical one to get correct. Aside from the science itself and manufacturing capabilities and scientific expertise, tech transfer, like documentation in the API manufacturing process, is an important-but-often-overlooked component to the success of any project.  If you have questions, please call us at (978) 462-5555.

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.