Technology Transfer to a CMO
Anyone that has been in the contract business has stories of extremely successful transfers, as well as nightmare project transfers. The key for a successful transfer sounds easy in theory: the transfer of all technical information to a new set of people or group of people. In practice, however, many technical packages provided to the contract manufacturer do not provide enough detail, such as number of times the procedures have been performed, the largest batch size produced, analytical methods or the level to which the analytical methods have been developed.
The quality of the information provided in the technical package is very important. Does the technical package contain detailed information on experiments that where not successful, as well as, the one that were successful? Has the purity information been collected by a single validated HPLC method or has the purity information been collected with several different methods where the HPLC method does not determine some of the major impurity peaks? The quality of the information will change depending on where the drug is in the development process. High quality information from a pre-clinical study may not be viewed as high quality information for a product nearing commercialization. As the drug development process gets closer to the new drug application (NDA), methods and procedures should be validated; where earlier stage activities may not require validation.
Technology transfers differ in many ways. For example, during Phase 1 or Phase 2 development, the transfer may be undertaken to determine whether the product can be successfully manufactured from a laboratory-scale process to a pilot scale producing cGMP material for the first time. Such an early-stage transfer requires extensive interaction between the scientists compared to a transfer in Phase 3 for full-scale cGMP production and commercialization, which has far more stringent requirements for compliance and process validation. In either case, however, a comprehensive Process Transfer Protocol can make all the difference between an efficient transfer and a process bogged down in rework, inadequate protocols, and repeated calls from the recipient for more information.
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, this description includes the sequence of operations for the process, the rationale for each process unit operation, initial operating ranges for process parameters, in-process controls, and initial acceptance criteria for the product. As the receiver conducts experiments and manufactures test batches, the 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.
Bill of Materials (BOM): The BOM typically lists all 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, amounts that are needed for the specific manufacturing campaign, and special tests, if any, that need to be performed for acceptance.
Analytical Package: The analytical transfer is a separate exercise that occurs either in parallel or before the process being transferred. This is much more important for a Phase 3 project as opposed to 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); stability-indicating assays are qualified and subsequently validated at a later stage (before process validation).
The Process transfer protocol should also be accompanied by other relevant documentation from the client. This list should include development batch records, process and analytical development reports, assay qualification reports, and test methods. Guidance from the client on process ranges and operating parameters as well as initial specifications are very helpful in compiling the development of transfer protocols and batch records at the receiving site. Any information that is inadvertently not included in the initial documentation may be obtained by interaction of appropriate personnel and 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.
One of the most important areas that need to be addressed in the transfer is clearly defined milestones and the deliverables of each of the milestones. Both the contract manufacturer and the pharmaceutical company should require clear deliverables this will keep the project focused and allow for much easier manageability. Another issue results from the fact that many procedures, know-how or techniques are taken for granted with each site and not communicated. This issue can be managed by having the transfer of personnel from either the contract manufacture visiting the pharmaceutical companies or vice versa.
The real test of the technology transfer will be how well both teams interact during a technical issues that 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 of program progress will allow for quick development of action plans to resolve the technical issues. The contract manufacturer must be viewed and must perform like an extension of the pharmaceutical company.