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.
There are three main concepts to highlight in this definition:
1. A logical procedure: Every transfer requires a well thought through analysis, which is planned and defined in advance.
2. Documentation: Any evidence of a successful transfer should be properly documented.
3. Professional expertise: As far as possible, all previous experience with the product and/or manufacturing process should be transferred.
A further implied aspect which is not as evident in the definition, is the possibility that the transfer also includes a scale-up to a larger batch size. This is very common during the different stages of the development of a pharmaceutical product and particularly as the drug development moves through to the manufacture of the first commercial-scale batches.
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.
Drug intermediates are available in various forms such as moderate quality intermediates, high quality intermediates, and premium quality intermediates. The high and premium quality drug intermediates are used mainly for research purposes. There has been an ever increasing global demand for quality drug intermediates due to the fast growing biotechnology and life sciences sectors, along with rising adoption and increasing application in research fields. Pharmaceutical companies and biotechnology companies, along with research companies are growing focus toward R&D in drug discovery and development.
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.
Key Insight
• Objectives, scope, personnel, and responsibilities
• Raw material specifications, including supplier and manufacturer details
• Equipment and facility requirements
• Detailed manufacturing process
• Health, safety, and environmental issues
• Sampling points
• Acceptance criteria
• Change control and retention samples
Using Confirmation Batches is Highly Recommended
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.
4-Bromofluorobenzene CAS No: 460-00-4
2-Acetyl Thiophene CAS No: 88-15-3
There are three main concepts to highlight in this definition:
1. A logical procedure: Every transfer requires a well thought through analysis, which is planned and defined in advance.
2. Documentation: Any evidence of a successful transfer should be properly documented.
3. Professional expertise: As far as possible, all previous experience with the product and/or manufacturing process should be transferred.
A further implied aspect which is not as evident in the definition, is the possibility that the transfer also includes a scale-up to a larger batch size. This is very common during the different stages of the development of a pharmaceutical product and particularly as the drug development moves through to the manufacture of the first commercial-scale batches.
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.
Drug intermediates are available in various forms such as moderate quality intermediates, high quality intermediates, and premium quality intermediates. The high and premium quality drug intermediates are used mainly for research purposes. There has been an ever increasing global demand for quality drug intermediates due to the fast growing biotechnology and life sciences sectors, along with rising adoption and increasing application in research fields. Pharmaceutical companies and biotechnology companies, along with research companies are growing focus toward R&D in drug discovery and development.
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.
Key Insight
• Objectives, scope, personnel, and responsibilities
• Raw material specifications, including supplier and manufacturer details
• Equipment and facility requirements
• Detailed manufacturing process
• Health, safety, and environmental issues
• Sampling points
• Acceptance criteria
• Change control and retention samples
Using Confirmation Batches is Highly Recommended
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.
4-Bromofluorobenzene CAS No: 460-00-4
2-Acetyl Thiophene CAS No: 88-15-3
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