Getting a pharmaceutical product to perform beautifully in the lab is one thing. Getting that same result to scale-up seamlessly in the production stage is entirely different.
There are myriad issues that could affect the outcome, including varying batch sizes, different process conditions, and altered material properties. All or any of these could trigger an unanticipated issue that negatively impacts performance.
Still, the pilot scale up process can help scientists understand a product’s ultimate potential. While there might not be a golden ticket that guarantees success, it helps to know which pitfalls to avoid and best practices to follow along the way.
Today, we’re sharing a road map to follow when undergoing this process, including steps to take to encourage as successful an outcome as possible.
Ready to learn more? Let’s get started.
What is Pilot Scale Up and Process Validation?
In short, pilot scale up process describes the steps taken to develop a product before preparing the first pilot-production batch. There are four main development activities to follow, including:
- Designing, selecting and optimizing the formula
- Creating the laboratory pilot batch of the drug product
- Performing initial stability testing
- If stable, performing more pilot lab batches for expanded use (non-clinical and clinical)
Step 1: Selecting the Formula
The first step in the pilot scale up process is to choose a suitable preliminary formula. You’ll complete this process in the development laboratory.
The formula you select should be one that you want to test and learn more about based on a range of factors, such as initial design requirements and specifications. You’ll refer to this selected formula as your (1x) laboratory batch.
In most cases, the size of this initial (1x) laboratory batch will be:
- Three to 10 kg of a solid/semisolid
- Three to 10 liquid liters
- 3,000 to 10,000 tablet or capsule units
Before you can create tablet or capsule units, a process called milling must occur. In short, this is the most common procedure used to reduce particle sizes before they’re made into tablet or capsule form. During milling, the material breaks down into smaller, more uniform particles. Later, developers can blend, compress, and coat the particles into a final dosage unit.
An improvement over traditional basket mills, immersion mills combine both milling and mixing functions. This results in particles that are better size-distributed and higher quality. They also improve production efficiency and profitability. You can learn about immersion mills to determine if this system could benefit your processes.
Step 2: Create the Laboratory Pilot Batch
Did you determine your initial laboratory batch to be chemically and physically stable? One way to test its features is to perform initial temperature-based stability testing. For instance, you might expose the batch (in standard packaging) to a temperature of 40 degrees Celsius for three to four months and note any changes.
If so, the next step is to create a laboratory pilot batch. While the initial batch was (1x), this one will be (10x).
In short, the pilot lab batch is the first replicated scale-up that you’ll create from the chosen formula.
Because you’re essentially multiplying your initial batch by 10 to get this larger scale, the size of your pilot (10x) laboratory batch will be:
- 30 to 100 kg of a solid/semisolid
- 30 to 100 liquid liters
- 30,000 to 100,000 tablet or capsule units
Keep in mind that while these numbers are standard, they are not a concrete rule. In fact, there are a few factors that might control or alter the size of your laboratory pilot batch. These include, but are not limited to:
- The availability of your necessary equipment
- The cost of your raw materials
- The Active Pharmaceutical Ingredient (API) in your formula
- The inventory you require to perform later testing (clinical and non-clinical)
Like your initial batch, you’ll create the pilot batch within your development laboratory. In most cases, these steps will need to take place in a CGMP-approved space.
Note that while there will be a more formal validation process that takes place later in the piloting sequence, process capability studies often occur during this second step of the pilot program. During this time, scientists can begin to study the initial performance of a given batch, analyzing the following:
- Process characterization
- Process ranging
- Process optimization
Step 3: Perform Stability Testing
After preparing pilot laboratory batches and establishing process demonstration, the next step is to perform advanced stability testing.
At this time, the product will now be in its approved packaging, rather than standard packaging. As before, this testing phase normally lasts around three to four months.
Step 4: Ongoing Pilot Production
Once stability testing is complete, it’s time for the pilot production phase.
This stage can be completed as a joint effort between the development laboratories and manufacturing entities. Or, it can be performed as a process demonstration by a separate pilot plant or individual process development unit. Today, the latter is often preferred, as these facilities are best-suited to carry out scale-up projects in a time-efficient manner.
However, an argument can be made in favor of the joint process, as well. This allows the development lab to work in tandem and close partnership with the pharmaceutical production process.
During the pilot production phase, the batch scales up again, this time to 100x. As such, the size of this batch is now:
- 300 to 1,000 kg of a solid/semisolid
- 300 to 1,000 liquid liters
- 300,000 to 1 million tablet or capsule units
While this batch size is normally sufficient for most drug products, there are instances in which pharmaceutical production must scale to even higher in size. If these numbers become vastly different, however, it will necessitate additional validation studies. Moreover, the actual size of this largest batch will still hinge on raw material availability, inventory and more.
Upon successful completion of pilot production batches, the product will undergo additional stability testing in approved packaging. Most validation studies require three pilot-production batches before a product can be considered valid.
Planning Ahead in Pharmaceuticals
It might be unrealistic to assume that the scale-up process will work seamlessly and that products will perform as well in production as they did in the lab.
However, your chances of replicated success are greatest when you follow a defined set of steps, such as the ones described above. You’ll begin the pilot scale up program in development laboratories and fine-tune it throughout, eventually validating the process in the pilot plant or pharmaceutical production.
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