Scaling Up API Manufacturing: A Final Journey on the Road to Commercialization

So you’ve completed the R&D phase of your Active Pharmaceutical Ingredient (API) or New Chemical Entity (NCE).  You’ve successfully produced small batches with good yield and you’re ready to take it to the next level – scale-up. 

The successful transition of technology from the lab to current Good Manufacturing Processes (cGMP) suites or the plant for scale-up within a commercial production environment can be a daunting task. After all, during the R&D phase, you can keep costs lower, by producing smaller quantities, without the need for cGMP manufacturing (which can cost upwards of $80K per week). Yet, changing small-scale processes to meet regulatory requirements for commercial production is a whole new ballgame.

When you scale up, cGMP guidance requires that you meet stringent assay, quality, and purity requirements. The plant where scale-up occurs must have appropriate quality management systems in place that can detect and address any deviations to quality. Not adhering to these guidelines, or not having sufficient data can cause your Investigational new drug (IND) submission to be delayed.

Going Bigger Is Not Always Better

Despite the most thorough method development and testing, experienced scientists and meticulous attention to every detail, when a molecule moves to the scale-up stage, Murphy’s Law often kicks in and anything that can go wrong, will. Sometimes it’s because of the sheer fact that operating under cGMP can be slower and more painstaking and the longer time may cause different reactions.  Other times, producing larger quantities throws everything off kilter and allows new impurities to enter.  In addition, the geometry of the various vessels or agitation can have impact on GMP batches. Molecules are comprised of naturally occurring materials, and often nature has a mind of its own.  

Despite its common occurrence through no fault of anyone, when problems occur in scale-up it can translate to hundreds of thousands of dollars, delayed commercialization, loss of funding or the halt of your project.  

So how can you do everything in your power to ensure successful scale-up?  It begin with robust method development and thorough testing in the R&D lab, and then effective technology transfer for scale-up. 

Technology Transfer

Below are three key steps for ensuring a smooth and effective technology transfer: 

1. Create a detailed process summary. Assuming that the raw materials and API remain the same and are procured from the same supplier, a technology transfer usually begins with an assessment of the original manufacturer’s information – from raw materials through critical process parameters. 
2. Develop proper transfer protocols. CDMOs must develop transfer protocols that enable critical steps and scale-up equipment differences to be adequately challenged. It may be necessary to produce up to 3 batches in the Kilo Lab to see if problems arise, since often it takes that many to reveal problems. The more thoroughly a process is challenged in this early phase, the more robust that process will be moving forward to ensure reproducible quality. This information is included in a validation report, which is essential to FDA approvals.
3. Collaborate across teams. At Seqens CDMO NA our manufacturing engineers work directly, on-site with the technical manager in the lab during optimization and scale-up, to ensure that there is effective communication and collaboration through these critical steps, before being transferred to the GMP suite. Working together, the process chemists and GMP specialists can all be on the same page.  And, once the detailed process summary is in place, the R&D chemists should help get the scale-up process started, working with the engineers to make sure the right equipment, vessels and other instruments are used to run the process. Working with the same CDMO across R&D and manufacturing ensures that effective collaboration can take place. Yet, even if your R&D and manufacturing is done by different organizations, the same on-site collaboration should occur whenever possible.

Other considerations to ensure that problems in scale-up are minimized include the following:

• Conduct root-cause investigation.  When problems occur during scale-up, it’s important to conduct a root cause investigation to weed out the culprit. Having good analytical procedures and experienced scientists are important during root cause investigations when you take samples, test them and figure out what’s going on. 

• Ensure adequate equipment. While it can be difficult to have equipment dedicated to specific processes, it’s important to keep it running at tip-top shape. You should have sound methods for cleaning the residues generated by each process so that after each successful campaign, the equipment can be changed over to be used in the manufacturing of a different product. It’s important to work with a CDMO with excessive equipment, since you never know when you may need specific ones. 

Scale up can be the most expensive phase in your journey to product commercialization and requires expertise, experience and meticulous collaboration across departments, CROs and CMOs. While it’s impossible to predict how molecules will react when they are produced in larger quantities, implementing rigid protocols and best practices can go a long way to minimizing them.

For additional insights and observations, please check out: API Manufacturing Technology Transfer; Shattering 5 Myths About CDMOS; or Analytical Method Development in API Manufacturing.