What is an engineering run, and do you need one?

In the fast-paced and high-stakes world of pharmaceutical manufacturing, every step of the process must be meticulously planned and executed to ensure product safety and efficacy. One aspect that often goes under the radar but is critical to preparing a new and effective drug production process is the engineering run. In this blog, we describe the purpose of an engineering run, the work that is typically included in one, and identify the pros and cons of performing a run. Finally, we describe which project do and do not need an engineering run.

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What is an Engineering Run?

An engineering run is the practice GMP (Good Manufacturing Practice) run that plays a pivotal role in refining the fill finish process. Its purpose is to identify potential risks, optimize the process, and resolve any issues before moving on to a full-scale GMP run.

Your CDMO will perform any necessary formulation, filter, fill, and/or lyophilization studies to fill any knowledge gaps, understand your drug product, and determine the optimal processes to include in your drug manufacture. Once the CDMO has collected sufficient information regarding your process, they will write a batch record that details the step-by-step instructions for all GMP activities to complete a batch production. Even though each step of the process was tested, it is critical to perform a practice run of the full process, following the batch record to test the process under real-world conditions. This is done in an engineering run, and it provides invaluable insights and assurance for the upcoming GMP run.

What to Expect During an Engineering Run

Before the engineering run, the CMO prepares a complete batch record that undergoes review by both the CMO and the client. The engineering run follows this record, using the same materials, chemicals, and equipment that will be used in the GMP run.

The CMO will formulate the full volume of the drug product solution then sterilize it via sterile filtration. Performing a full-scale formulation and filtration is critical to testing the equipment, assessing the process, and understanding the time needed in formulation to schedule the GMP run.

Once filtration is complete, the drug product will be filled on the appropriate filling line and equipment to assess the filling process efficiency. The number of filled units can vary. Filling only needs to run for as long as is sufficient to test the process. For larger scale fills only a tenth of the drug product may be filled. For very small volumes, likely all drug product will be filled. If filling occurs in isolators, the filling lines will likely not undergo a VHP cycle prior to filling for the engineering run. However, the client may be able to request VHP at their CMO and a full-scale fill if they would like.

For lyophilized products, the full drug product formulation will be filled and undergo lyophilization in the engineering run. It is important to evaluate the lyo cycle with the full quantity of drug product because the amount of product loaded into the lyophilizer may affect results.  

After filling, visual inspection is performed on a sample of the lot, typically around 10-25%, to confirm the manufacturing process’s control. Some quality testing, such as pH and concentration analysis, may also be conducted in the analytical lab.

Advantages of Engineering Runs:

There are several advantages of performing engineering runs:

  1. Verifying Equipment Fit: Engineering runs ensure that all equipment used in the manufacturing process works effectively and is compatible with the specific drug product.
  2. Determining Optimal Acceptance Criteria Parameters: Testing acceptance criteria parameters during the engineering run helps ensure consistent quality standards are met during the GMP run.
  3. Fine-Tuning Filtration and Filling Assemblies: Adjustments to filtration and filling assemblies are essential for optimal product filling and reducing the likelihood of rejects. An engineering run can help identify any additional adjustments that may be needed.
  4. Confirming Formulation and Filling Times: Engineering runs provide critical data for accurate time estimates, helping in resource planning and scheduling.
  5. Reviewing the Batch Record: Batch records are rigorously reviewed during the engineering run, identifying potential errors before they become problematic during the GMP run.
  6. Providing Training to Operators: Engineering runs offer an opportunity for operators to train on the new process, ensuring a well-prepared team for the GMP run.

Disadvantages of Engineering Runs:

Of course, engineering runs also come with a few common concerns:

  1. Time: Engineering runs take time. At Berkshire Sterile, for example, engineering runs are scheduled one month in advance of the GMP fill. If a drug production is on an expedited schedule, a sponsor may feel inclined to skip the engineering run and go straight into a GMP run.
  2. Cost: Engineering runs are not free. They require significant time, resources, and work to be performed. However, since the included work is not as extensive as a GMP run, you can expect the engineering run to cost less than a GMP run. For example, if a GMP run costs $160,000, then an engineering run may be offered at $140,000.
  3. Resources: Sometime a drug substance is exceptionally expensive or difficult to procure where performing an engineering run is prohibitive. This may deter a sponsor from performing an engineering run.

Engineering runs are often perceived to be a drain on time, money, and resources. When an engineering run goes smoothly, as both the CMO and sponsor desire, it may seem unnecessary. However, the majority of engineering runs typically identify places of improvement in the process and have often led to significant time and cost savings than if the process progressed immediately to GMP production.

When is an Engineering Run Necessary?

So, when should you consider performing an engineering run? The answer is simple: every new process deserves an engineering run. It is a valuable step in identifying potential issues or opportunities for optimization before moving into the GMP phase. While an engineering run is highly advised for most processes, the level of assurance in the process varies. For simpler and straightforward processes, the CMO may feel confident proceeding directly to GMP production. Below, we outline which processes necessitate an engineering run which processes may be able to bypass it.

Engineering runs are necessary for:

  • Complex formulations
  • Unique container closures and/or combinations
  • Suspensions
  • Temperature sensitive drug substances
  • Highly viscous solutions
  • For projects that require unique equipment
  • Lyophilized drug product

Engineering runs may not be necessary for projects that meet all the following criteria:

  • A simple thaw, filter, & fill
  • Uses a common container closure that the CMO has experience filling in
  • Does not require lyophilization
  • Is non-viscous

There are other situations that do not require an engineering run. For example, repeat batches do not require an engineering run, and placebo runs that are like the active lot process or are a simple process.

Conclusion

Engineering runs are a fundamental step in ensuring your fill finish process is robust, efficient, and optimized for GMP production. Investing in developing, optimizing, and fine-tuning your process is critical to protecting the health of patients and ensuring that they receive the highest quality product. Practicing GMP runs under real-world conditions through engineering runs, the CMO can identify and address issues proactively, reducing the risk of failure and saving valuable time and resources. Embracing engineering runs as an integral part of the fill finish process demonstrates a commitment to quality and safety.

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