Continuous manufacturing: Could 2021 be year of the first biologic approval?

GlobalData Healthcare 2 December 2020 (Last Updated December 2nd, 2020 15:55)

Continuous manufacturing: Could 2021 be year of the first biologic approval?
To date the FDA has approved continuous manufacturing for six finished dose, innovative products, all small molecules. Credit: Gorodenkoff/Shutterstock.

With regulators widely accepting continuous manufacturing of small molecule drugs, the industry is looking ahead to the next frontier: continuous manufacturing for biologics. The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) will publish guidelines in 2021 for continuous manufacturing of biologics.

To date, the FDA has approved continuous manufacturing for six finished dose, innovative products (Table 1), all small molecules. Approximately 50 other national regulators have made at least one such approval, showing that this technique has earned worldwide acceptance, at least for small molecules.

Table 1: Marketed Drugs Approved for Continuous Manufacturing.

Credit: GlobalData, Pharmaceutical Intelligence Center Drugs database; FDA; EMA; PMDA.

Note: PMDA = Pharmaceuticals and Medical Devices Agency.

There are signs of an industry appetite for continuous manufacturing, said Christine Moore, global head of CMC at Merck & Co (Kenilworth, NJ, US), in a keynote session entitled “Flexible Manufacturing in a Rigid Regulatory Environment” at the American Association of Pharmaceutical Scientists (AAPS) 2020 PharmSci 360 event on October 27, 2020.

Importantly, ICH is working on an update to its 2018 “Q13” continuous manufacturing guidelines, due out in Q2 2021. This document is expected to include updates on continuous manufacturing for both small and large molecules.

The FDA has also shown its willingness to consider large molecule continuous manufacturing. In 2018 it awarded several grants, using Cures Act authorities, to institutions to advance biologic continuous manufacturing. It has also promoted the use of non-destructive analytics such as water proton NMR (wNMR) to inspect biologics manufactured in this way. Continuous manufacturing of APIs will be the most in-demand type of specialised manufacturing in the near future, experts predicted last year (DCAT: Continuous Manufacturing Is At ‘Inflection Point’).

Some regulations still need to be modernised to accommodate continuous manufacturing, and in turn, ICH will need to harmonise these standards between national regulators, said Moore, who previously worked for the FDA and Pfizer (New York, NY, US).

Manufacturers need to consider what to do when there is a problem during manufacturing, so they can segregate potentially non-conforming materials from the rest of the process, she said. Real-time testing also needs further development, she added.

Furthermore, continuous manufacturing requires different control strategies depending on dosage form and the accompanying process. So far, continuous manufacturing approvals have been for small molecule, solid oral dose drugs, with processing steps related to powder flow. A liquid drug, which has diffusion steps, will need different measurement techniques.

Flexibility in continuous manufacturing will be another regulatory point to consider. In batchless continuous processing, manufacturers can demarcate artificial batches to help with QC. Batch sizes within continuous manufacturing should be flexible so that that different run lengths can be manufactured within the validated ranges, Moore said.

Regulators should also allow sponsors to combine traditional and continuous manufacturing in the same application, Moore said. This could be for products that are already approved for traditional batch production where the manufacturer wants to add continuous manufacturing.

Continuous Advantages

The advantages of continuous manufacturing have been touted by regulators and some pharma companies for some time. The method can create a smaller equipment footprint because equipment is being used for longer—without breaks between batches. It also typically achieves larger quantities by running the same equipment for longer.

Continuous manufacturing need not mean retrofitting an entire facility. “If you compare traditional batch manufacturing with continuous manufacturing, oftentimes they have the same unit operations,” explained Moore. “In fact sometimes they even use the same equipment, such as a tablet compression machine.”

“With batch manufacturing, you stop after every unit operation. You may then test the product and you hold that product until the test results come back. So you have constant stop and go.”

“In continuous manufacturing, we’re looking at integrated unit operations where material flows from one unit to the next. Typically the testing and controls are built into the system.”

For more on continuous manufacturing trends, listen to GlobalData PharmSource’s Fiona Barry in conversation with Dawn Ecker, managing director of bioTRAK Database Services at BioProcess Technology Group, on the CPhI Media Debate Podcast.