This series of blog posts on CMO risk mitigation has been focused on the challenge of building an effective working relationship with the contractor a pharmaceutical company chooses to manufacture a drug. So far, we have concerned ourselves with the risks associated with CMO selection and technology transfer.
Ultimately, however, this discussion is moot unless the partners can produce a stable, consistent product for clinical or commercial purposes. This third and final post in this series addresses the problem of bridging the gap from the laboratory to the manufacturing floor.
Manufacturing-scale production is qualitatively different from lab-scale production. There will be new risks. So when scaling up a new process for GMP manufacture, be sure to learn as much as possible about that process before it goes to the plant – experimenting at plant scale is risky and expensive.
Preparing for GMP
Start by ensuring that the CMO familiarizes you with its standard procedures for critical GMP-scale processes (e.g., compounding, filtration, filling, etc.). Seek to verify that CMO laboratory development personnel understand their own manufacturing facilities (surprisingly, this is not always the case). As we noted in our earlier discussion of critical process parameters (CPPs), it is impractical to cover every conceivable risk factor. Focus on determining what parameters are most likely to impact the quality of your finished product. If you don’t know, then allow time in the lab to explore.
Consider a design of experiments (DOE) approach to scale-up, documenting:
- The anticipated variables;
- Which combinations can be modeled; and
- The outer boundaries – What happens in case of unexpected events (e.g., if the API takes longer to dissolve than expected, what will be the impact on impurities and other quality attributes?)
Establish a written protocol and gather data that methodically documents what happens to each process variable when you scale it up. Once a process is established, run one or more lab batches at the largest scale possible prior to transferring production to the plant. In these test runs, model as closely as possible the conditions on the manufacturing floor, using equipment that mimics plant-scale equipment. In planning for these lab batch runs, consider:
- Are any CPPs candidates for in process control (IPC) methods?
- Should you involve Operations/Production personnel during lab batch execution?
Document each lab batch according to a developmental batch record to set the stage for GMP batch record preparation. Be sure to note any unexpected results and brief Operations, in order to avoid surprises. As the project sponsor, you should consider having your own people on site during this critical step to observe and advise. Capture lessons learned and overall experience in a written report and disseminate it to all parties who need this information especially Operations Department personnel.
Remember: You chose your CMO for its expertise. The CMO may have experience with similar molecules – learn from that experience. However, if the molecule is truly unique, the onus will be on you to help the CMO understand what is critical.
One feature of your CMO’s approach that is worth exploring in detail is its commitment to automation, at each stage of the process. Automation is not a frill, and is not principally a labor-saving expedient. Humans are the number one source of errors in manufacturing. Increasing automation greatly reduces opportunities for mistakes. Ensure that you and your CMO are on the same page about this.
Give yourself the time you need to succeed. Manufacturing is hard enough without the added pressure of tight timelines. Yes – this is easier said than done. But deliberately build in a time buffer to account for the unforeseen. And build in ample time for technology transfer to ensure it is completed well in advance of manufacture, to allow for preparation and review of high-quality batch record, and training for key personnel.
If you are contracting out manufacturing of a drug for which you already have a well-established process in house, your focus should be on figuring out what is different in your new CMO’s facility compared to where the process was previously run. Some of the differences will be obvious:
- Scale (not just vessel size, but other factors like process duration);
- Equipment type (e.g., type of filter/dryer, type of dispensing pumps); and
- Raw material sources and grades.
More subtle differences may include:
- Isolators vs. clean room; or
- Means of sanitization (e.g., vaporized hydrogen peroxide vs. other sterilants).
There are too many variables to be considered in detail in this blog post, but the planning process can be summarized in the following graphic:
Prepare for the Next Campaign
Almost invariably, you and your CMO will learn something in the course of manufacturing your first GMP batch. Using the performance metrics you established during tech transfer activities, evaluate whether further exploration of CPPs may be necessary. For example:
- Process – Did impurities match expectations? Were yield losses as expected?
- If further scale-up is necessary – Do you anticipate that time to produce a larger batch will pose issues? Will there be other process variables impact product quality, such as:
- Reaction rates;
- Dispensing rates; or
- Other process-specific factors for more complex formulations (e.g., suspensions or emulsions)?
Don’t think of your first manufacturing campaign as an experiment. But treat it as a dress rehearsal for your next campaign – don’t repeat past mistakes!
You and your CMO are partners. Give each other honest feedback as to what worked well and what could be improved, in the process, facility/equipment, or personnel. By adopting a collaborative approach and taking advantage of each organization’s strengths and knowledge, you can help minimize risks to your strategically critical drug manufacturing project.