What’s the Best Way to Scale up the Manufacturing Process for my Pharmaceutical Product?

Posted by Wellspring Pharma Services

Many of the pharmaceutical companies we work with initially contact us with questions about scaling up the manufacturing process for their products.  With the bright promise of ramping sales and distribution up comes the immediate challenge of identifying the best place to begin.  We’ll take a close look at the most important considerations of the scaling process in this article.

Batch Size is an Important Factor in Scaling up Pharmaceutical Production

One of the first things to define in scaling the manufacturing process is how large of a batch size you want to produce. The answer to that question is typically driven by your marketing plans, the annual product forecast and your projected launch quantities, all of which need to be factored into the equipment scale.

MMU_Counter_Rotating_Mixer_for_Pharmaceutical_Cream_Manufacturing

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 really important that you 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 and then 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.

So now you’re only looking at 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. An example of that would be a blend in a one cubit foot V-blender for three minutes doesn’t always correlate with a larger blender that may have a different rotational mixing speed. You have to know all of your equipment, inside and out. 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 Insight

There are many variables like that which are commonly found during scale up – the type that seems to fall out of thin air. You may come to realize that you may not have challenged one of these variables.    You’ve got 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, you’ll be able 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 you’ve done all of that, you’re getting ready to produce your first full scale feasibility batch.  You make your first 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. Unless you’re incredibly lucky, you should plan on manufacturing about 3-5 batches at this stage.

Using Confirmation Batches is Highly Recommended

Determining-Best-Manufacturing-Processes-Guide-For-Pharmaceutical-Products There are many different 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. You could use each one of those sub lots as an experiment.  So it doesn’t necessarily mean you have to manufacture five 500 kg batches to pull the necessary data out of it. Once you have all of your process ranges identified, we recommend following it up with what’s known as a confirmation batch. This batch should also be manufactured using target parameters.

If everything goes well and the batch data is found to be comparable to the small scale lot, then 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

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 you evaluate the changes you’re making from a:

  • Scale-up perspective
  • Equipment perspective
  • If you’re changing excipient ingredients
  • Anything else that may impact the product performance
  • What kind of regulatory filing that would 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.

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Topics: Manufacturing Scale-Up

WellSpring Pharma Services is a full-service provider of pharmaceutical contract manufacturing and packaging outsourcing solutions for solids, semi-solids, and non-sterile liquids. WellSpring offers full-service contract cGMP manufacturing, packaging and analytical testing services from a single FDA inspected and Health Canada licensed facility.

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