What Could Go Wrong with Biologics Manufacturing?

We’ve got our Biologics License Application (BLA)

ready to file; is our contract manufacturing facility ready, too? The US FDA is to perform a Pre-License Inspection (PLI) during the BLA review. Per the FDA, inspection issues span a variety of topics, with insufficient quality oversight a recurring theme.

Per PhRMA, building a new biologics manufacturing facility can cost up to $2 billion and take 5 to 10 years before it is operational. While faster, introducing a new product to an existing facility via process transfer and scale-up, validation, stability protocols and regulatory filings can take several years. In 2023 there were about 320 active pharmaceutical ingredient (API) production facilities in the US.

At the time of the BLA submission, all facilities are to be registered with the FDA and be ready for inspection. A preliminary manufacturing schedule for intermediates, the drug substance and drug product is to be provided with the BLA submission to allow FDA planning for pre-license inspections. Note: Manufacturing facilities are to be manufacturing the subject product during the inspection.

During the PLI, be prepared to speak to:

– Membrane and resin reuse and cleaning,

– How reference and standard materials are qualified and replaced, and their stability programs.

– Monitoring procedures for cell banks.

So, how can I minimize the time for site transfer and scale-up of my breakthrough biologic? The FDA scrutinizes chemistry, manufacturing, and controls; these need to be right. That means first knowing your process and then developing controls to ensure the product is true. The process can be characterized as a series of blocks and arrows on a block flow diagram. For each block and each arrow, one is to perform risk assessments of the activity to identify the parameters that are critical to quality for your process and set limits on these parameters. Often overlooked are the process inputs and the arrows.

Process inputs such as raw materials have variation that can adversely affect the product. For example, the source of the water-for-injection (WFI) feed is known to potentially affect protein expression: extractables from bagged WFI may suppress cell growth during working cell bank expansion. WFI feed that is too hot can have similar effects. I know of development work which was performed using gas with the incorrect CO2 concentration, invalidating the work. Quality controls around the working cell bank are critical. Yes, environmental monitoring and microbial controls will be reviewed by the FDA.

The block flow diagram arrows are often under scrutinized. Risks associated with receiving, warehousing or storage of raw materials and in-process materials are not to be overlooked. Specifically, based on the manufacturing schedule, how much refrigerated and frozen storage will be needed? How long does it take to warm or thaw materials and where/how is this to be done? Facility HVAC is a notoriously bad choice to perform these processes. Are airlocks sized adequately to get materials in to and out of the cleanrooms in a timely fashion?

The median cost of commercialized biopharmaceutical manufacture is near $400 per gram with some products costing much more. This means that not only is the actual cost of manufacture substantial; the opportunity cost of lost manufacture is equally high. Anticipating redundancy of key manufacturing aspects can avoid failures that may result in another round of funding and diluting the founders’ ownership. Loss of a batch due to the failure of an inexpensive pH probe is difficult to defend. Having available redundant seed trains to back-up the loss of a seed batch may be justified and can help quality do-the-right-thing especially when every batch is vital.

And what about samples? Is the analytical lab on-site or is it remote? If it is remote, what shipping validation has been performed to ensure that the samples are not degraded by the time they arrive. What if they are delayed a few days by a snow storm (a real life occurrence)? Is there adequate stability sample storage?

Regarding logistics, shipping qualification is to be performed. Will any biologics be shipped through an airport or seaport? If the product is light sensitive, might the X-ray scanner at the port degrade the product? If RKN refrigerated shipping units are to be used, how many at one time?

Whether it is blocks or arrows, iCan-GMPs is here for you with experienced professionals that have lived the start-ups and can keep your project on target. Email us at sales@ican-gmps.com to set up a brief Hypercare call.