Many of the pharmaceutical companies we work with have questions about how to best scale-up the manufacturing process for their products. With the bright promise of ramping sales and distribution comes the immediate challenge of identifying the most optimal manufacturing strategy to maximize their product’s market acceptance. In this article, we’ll take a closer look at the most important parameters you will have to consider for a successful scale-up of your product’s manufacturing process.
Batch size is an Important Factor in Scaling up Pharmaceutical Production
To scale-up the manufacturing process, one of the first things to consider is how large a batch size you will need. The answer to that question is typically driven by your marketing plans. Your marketing plans will help you determine the optimal batch size for your product. Here are the 2 questions your marketing plans should help you answer:
- What is your product’s annual product forecast?
- What are your product’s projected launch quantities?
Answering these two crucial questions will help determine the optimal commercial batch size and equipment scale.
You want to do the same thing for the Active Pharmaceutical Ingredient (API) and raw materials. In some cases, you may not be using the same raw materials but it’s important to find the same material grades, and ideally, they’re from the same supplier. It’s easier to draw correlations that way and it rules out material interactions and material differences. We recommend starting the process by:
- Charting the development scale or the small-scale feasibility batches.
- Identifying variables that can be derived from the product documentation, including specifications, manufacturing directions and analytical test methods.
- Create a similar chart for the proposed manufacturing process train.
It’s best to look at absolutely every little nuance that can be derived from available development report documentation, validation reports, batch records and comments from the batch records – virtually anything that provides insight into bringing this product to fruition.
Next parameter to evaluate is process change. Critical process steps identified during small scale manufacturing should always be challenged, but at larger scale, there may be other process steps that should be challenged as well. For example, a blend in a one cubic foot V-blender for three minutes doesn’t always correlate with a larger blender that may have a different rotational mixing speed. So, the determining factor in this case is the number of revolutions in one blender to get the same correlation in a different size blender.
Rigorous Data Comparisons Provide Key Insights
There are many variables like that which are commonly found during scale-up – the type of variables that seems to fall out of thin air. You may come to realize that you may not have challenged one of these variables and have to draw those correlations. The more rigorous and robust manner the small-scale work was performed, the more sampling and data available, the easier the process scale up is. By comparing data from the many steps in the process, will give the ability to tell if a process or product is in fact comparable and scalable. It will also potentially identify new and critical process parameters at the larger scale.
Once this is completed, you’re ready to produce your first full-scale feasibility batch using target process parameters. Then, with each successive batch, you develop your process ranges.
Of course, the scale-up plan should be documented through an approved protocol written before you start any of this work. It’s best to plan on manufacturing about 3-5 batches at this stage.
Producing Confirmation Batches is Highly Recommended
There are many ways to approach this, of course. If it’s a high shear granulator/fluid bed drying process and it’s a 500 kg batch, for example, it may take 2, 3, 4, maybe even 5 high shear granulator/fluid bed dryer loads to produce that batch size. Each one of those sublots could be used as an experiment. So, it doesn’t mean you need to manufacture five 500 kg batches to collect the necessary data out. Once all process ranges have been identified, we recommend following it up with a confirmation batch. This batch should also be manufactured using target parameters.
If the batch data is found to be comparable to the small-scale lot, you’re now ready for validation. Provided there are no changes made and the validation is successful, then the confirmation batch may also be deemed saleable.
Once you have all the data compiled, validation reports written and approved, the batches are now considered saleable, and this is the point where the product can be considered transferred. Of course, determining whether any of these batches are saleable or not should be approved by your regulatory affairs department.
The Shift in Focus to Regulatory Considerations for the CMC Regulatory Submission
Everything up to this point has focused on the technical side of pharmaceutical product scale-up aspects, but there’s the regulatory aspect to consider as well. For example, FDA’s Scale-up and Post-Approval Changes (SUPAC) is a guidance document that the FDA has issued that helps you determine the changes you need to make in your process and how that will impact your product. For a Prescription New Drug Application (NDA) or Abbreviated New Drug Application (ANDA), there will be regulatory filing requirements you will have to make to effect changes to your approved drug product.
Following U.S. FDA’s SUPAC guidance will help evaluate the changes you’re making from a:
- Scale-up perspective
- Equipment perspective
- If you’re changing excipients
- Anything else that may impact the product performance
- What kind of regulatory filing would you require?
It’s also in your best interest as an NDA or ANDA holder to discuss those changes with the relevant regulatory agency to let them know what you’re planning to do. For example, if a change is immediate, you may have to file a Prior Approval Supplement which requires the FDA to notify you that they’ve accepted your changes. It’s important from a regulatory affairs perspective that before you change your product you need to know what impact that change is going to make to your regulatory filing and that you’ve addressed all the relevant issues.
You could delay process validation at that point, get that confirmation batch on a stability program for 6 months, generate the necessary information and submit with that data. While you’re waiting for the Prior Approval Supplement (PAS) to be approved, you can start developing the validation plans and commercial launch plans.
Ensuring your pharmaceutical product is a runaway market success and meeting increases in demand for your pharmaceutical product requires careful planning and the appropriate scale-up processes. As we have demonstrated above, there are proven ways to approach scale-up that minimize problems and control costs – both of which are critical factors in getting your product to the market at a profit.
