Scaling up to the commercial stage demands strategic thinking – but it can also bring significant new opportunities.

Once a viable active pharmaceutical ingredient (API) has been developed, and clinical trials have delivered promising results, the next step is to scale up the manufacturing pipeline to produce commercial-scale batches of the drug. However, this scaling-up process involves a number of key challenges, which may prove highly costly and time-consuming if not addressed up front.

For example, equipment that works perfectly for small batches may not operate at the same speed or efficiency when dealing with larger quantities. The end product’s physical and mechanical parameters may vary at large volume. And most importantly, a failed US Food and Drug Administration (FDA) inspection can lead to a temporary facility shutdown, or perhaps even a ban on sales of the drug.

All these challenges can be avoided with careful planning, and with the expertise of a contract manufacturing partner who knows how to navigate the commercial manufacturing and regulatory approval processes. The following article summarizes the key considerations in a commercial drug manufacturing scale-up, along with practical steps to help ensure upscaling success.

Small-batch analyses may not extrapolate to commercial-scale drug manufacturing.

Small-batch analyses may not extrapolate to commercial-scale drug manufacturing.

Before a single pilot-scale batch of a drug is manufactured, standard practice is to create a target product profile (TPP) that defines the drug’s ideal quality, safety, efficacy, bioavailability, and other factors. As small batches are produced for initial testing and trials, samples of the drug are tested and compared against the TPP, so adjustments in formulation and manufacturing practices can be made accordingly.

By the time commercial-scale manufacturing is being seriously considered, the drug has most likely already been closely aligned with the TPP in laboratory-scale batches; as well as in the pilot-scale batches used for toxicity screening and clinical trials. However, even a large pilot-scale batch only represents approximately ten percent of a commercial batch; and a sudden upscaling may produce a range of unexpected results.

For example, suppliers of some of the drug’s necessary raw materials may prove incapable of delivering the necessary quantities for commercial batches, due to logistical or regulatory challenges; requiring the use of a substitute material that impacts the drug’s chemical or mechanical properties in undesirable ways.

In short, positive results of small-batch analyses may not extrapolate to commercial-scale batches. Thus, it is recommended to produce with a single commercial batch, and carefully analyze every aspect of its production, before proceeding further.

An initial commercial-scale test batch offers helpful data on the performance of the drug manufacturing pipeline.

An initial commercial-scale test batch offers helpful data on the performance of the drug manufacturing pipeline.

Before launching a full commercial-scale manufacturing pipeline, it is highly informative to manufacture a single commercial batch of the drug. This commercial test batch will provide valuable insights on a wide variety of aspects of the production pipeline, from equipment and workflow to storage and transportation.

Processes that worked flawlessly at the pilot scale may cause unexpected issues at the commercial scale. For example, a large V-blender purchased specifically for commercial production may require much more time than the smaller blender used for pilot batches. A shear granulator that easily handled a small batch in a single load may require several successive loads to produce the necessary volume for a commercial batch.

Such unexpected delays in large-scale blending or granulation can create problematic issues downstream in the pipeline. While the machinery works, other workstations may sit idle, waiting for the necessary material to arrive. Temperature-sensitive excipients may melt or break down. Staff teams who worked in perfect synchrony on pilot batches may have to learn an entirely new rhythm.

Even after a commercial batch has been successfully manufactured, a significant amount of fine tuning still remains to be done. Data from the first commercial batch must be carefully analyzed for potential hazards, as well as for opportunities to fine-tune efficiency for future batches. This data also serves another equally important purpose: to demonstrate to regulatory agencies that the drug is being manufactured in a safe, compliant manner.

Regulatory approval should be a key consideration throughout commercial upscaling.

Regulatory approval should be a key consideration throughout commercial upscaling.

While some analysts describe regulatory approval as the final step in commercial drug manufacturing, the truth is that regulatory considerations are essential throughout the design of the manufacturing pipeline. Any change in manufacturing scale, equipment, excipients or other aspects of the pipeline requires a new filing with the FDA, in addition to the Prescription New Drug Application (NDA) or Abbreviated New Drug Application (ANDA) that must be filed prior to commercial manufacturing.

For this reason, a growing number of pharma developers are choosing to partner with contract manufacturing organizations (CMOs) who have experience securing regulatory approval for commercial drugs, and involving those CMO partners in the facility and pipeline design from an early stage. The sooner a manufacturer becomes aware of potential regulatory issues, the sooner those issues can be addressed with minimal cost and downtime.

Even if no significant regulatory challenges arise during commercial upscaling, a successful FDA filing still requires meticulous documentation of all ingredients, equipment, and other components used in the manufacturing process. The FDA and other regulatory agencies will also want to inspect a validation batch produced on the commercial-scale pipeline, in order to verify that the product’s performance, efficacy, safety and physical properties are as advertised.

Although successful pilot batches and clinical trials may be strong indicators of a drug’s commercial-scale success, a misstep in logistics, equipment, regulatory application, or any other aspect of commercial upscaling can put the developer’s investment at risk. All these factors must be considered as components of a cohesive whole, orchestrated to produce a commercially viable stock of drug product. The more foresight is demonstrated by the developer and their CMO partners, the great a drug’s chance of success in the commercial market.