Practical Considerations in Pharmaceutical Production Scale-Up

Posted by Norm Fong

Scale-Up Blog Series, Part 1 

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From first-in-human and through each of the clinical trial stages and into commercialization, scale-up of formulation design is a natural part of pharmaceutical development. At each stage of process development, the batch size increases, from laboratory-scale batches that may be quite small to support preclinical and early clinical stages, to pilot batches that are used in process development, and finally to the production-scale batches needed to support commercialization.

Not surprisingly, the size, speed and power of the equipment involved in production has a significant impact on the entire process and must be matched to the batch-size requirements for production efficiency. Regardless of the size of the batch and its application — for use in clinical trials and stability testing, to service a smaller patient population with an orphan drug, or to provide for a larger population with a commercial product — the object is always the same: the finished product must be identical to the original formulation design regardless of the volume under which it is was produced.

Challenging the Parameters

Although some scale-ups are easier than others by virtue of their manufacturing process, scale-up is always a meticulous process of trial and error. For each stage of the scale-up process, the product must be physically and analytically tested against approved physical and analytical specifications and the critical process parameters must be challenged in order to ensure the process can be validated.

For example, with a wet granulation in the high-shear granulator, we may begin the rate at which the granulation solution is applied to the blend at 1000 grams per minute and then compare that to a batch in which the same amount of granulation solution is added at 3000 grams per minute. If there’s no change in the net result, a range is established for validation batches and we could improve process efficiency by adding granulation solution at three times the original rate.

This type of process is carried out for every stage of production regardless of whether formula is being scaled up from two-kilo laboratory batches to 10-kilo study batches or 1000-kilo production batches. The process is also repeated for any scale-up of more than 10 times the original size. To scale up a 10-kilo batch to 1000 kilos, the entire scale-up process would have to be repeated first when we scale from 10 to 100 kilos and again when we scale from 100 to 1000 kilos according FDA Scale-Up and Post-Approval Changes (SUPAC) guidelines.

Gaining Regulatory Approval

As with all stages of pharmaceutical production, scale-up requires careful planning and meticulous documentation of data. Working with the client, the technical transfer team develops a process development protocol and prepares batch manufacturing instructions. As the final step, a process development report is prepared as part of the submission package. Comparing data from each step in the process helps determine scalability requirements and identify critical process parameters at full scale. When successful physical and analytical testing at each stage is complete, the first full-scale feasibility batch can be produced and fine-tuned to maximize process efficiencies.

When the technical transfer team is satisfied with the process development or feasibility batches, registration batches are produced for submission to regulatory agencies. If approved, validation batches are produced in order to establish that the process is valid, stable and able to reliably reproduce the product formulation performance, efficacy and safety as originally devised.

Next Time: Part 2 — Introduction to Scale-Up and Post-Approval Changes (SUPAC)

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Topics: Pilot Batch, Feasibility Batch, Registration Batch, Validation Batch, Process Development, SUPAC, scale-up

Norm is the technical transfer manager, business development, for WellSpring. He has over 21 years in the pharmaceutical manufacturing industry and has held development, transfer and commercial manufacturing positions over the course of his career with Patheon, Global Pharm (formally Pharmacia Upjohn) and Genpharm (owned by Merck). Norm is responsible for overseeing technology transfer and all validation activities in the organization.

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