Scaling up production is a key stage in the lifetime of a monoclonal antibody (mAb), fraught with the risk of product quality issues, consistency challenges, and problems with low yield or line loss. Formulation and process development related challenges can be better avoided through partnerships with experienced contract development and manufacturing organisations (CDMO) early in the programme, though there are still critical points to navigate regarding line capacity, preservation of bulk drug substance, regulatory approaches, and the future of the programme.

Aimee Hodge is Vice President of Business Operations, Development and Manufacturing at PCI Pharma Services, a world-leading CDMO which is currently busy preparing to unveil a brand-new high-speed isolator-based vial fill-finish and lyophilization line with the ability to produce batches of up to 300,000 vials at a speed of up to 400 per minute. In this article, Aimee Hodge shares advice around the five most important considerations when scaling up mAbs to such large-scale, high-speed production.

1: Engaging manufacturing partners early

Timing is everything in scale-up. According to Hodge, PCI Pharma has seen the most success when sponsors begin planning their leap from clinical to commercial manufacturing in parallel with Phase III activities. Meanwhile, when scaling up commercial volumes, Hodge simply recommends starting conversations with the CDMO as soon as realistic forecasts are available.

“That [post-approval] type of scale-up activity can take a significant amount of time. Depending on complexity, it can take 12, 18, or even 24 months, so you certainly want to start those conversations as soon as your signals from the market have been validated,” she says.

Whether pre-approval or post-approval, leaving scale-up activities too late can result in stock-outs and an inability to enter the planned number of markets. To mitigate these risks, sponsors can work with their CDMOs to begin initial process development work earlier than needed, eventually progressing towards a commercially viable process without moving anything past an engineering run.

“That’s where you should look for a CDMO that is flexible in regards to doing activities in parallel and then maybe taking a pause,” advises Hodge. 

2: Regulatory submissions – PPQ or PAS?

Scale-up timing also impacts the type of regulatory submission involved. When moving from clinical to commercial, sponsors are required to conduct three process performance qualification (PPQ) batches scaled down to at least 10% the size of the commercial batch volume. These are often referred to as registration batches, and manufacturers must still perform process validation at full scale pre-approval in cases where breakthrough or orphan drugs concurrent validation with BLA submission may be appropriate, but this always requires prior regulatory body approval.

If scale-up is occurring post-approval or if a sponsor is bringing on a second manufacturing site or a new CDMO, prior-approval supplements (PAS) submitted in line with the FDA’s SUPAC guidelines are required. While pilot-scale batches may be accepted in certain cases, at least one production-scale batch is preferred by the FDA.

As sponsors navigate today’s volatile macroeconomic conditions, considerations relating to manufacturing location – and having a second source as a backup – have become increasingly crucial. “There are a couple different strategies that really impact where you want to be physically manufacturing your product,” says Hodge. “All of that plays into your overall strategy for prior-approval supplements.”

3: Understanding a CDMO’s capacity

Every successful scale-up depends on accurate and detailed forecasts. When working with CDMOs, this becomes particularly critical for framing initial conversations around manufacturing volumes and how they are expected to change. With robust forecasts, the sponsor and CDMO can begin to understand how the programme is likely to fit into the CDMO’s production lines and client base, both now and in the months and years to come.

“From our perspective on the CDMO side, it’s important that the client starts those conversations early to understand where the CDMO has capacity for them in the short term, medium term, and the long term,” says Hodge. But while the growing demand for mAbs is clear, Hodge emphasises the importance of realistic data. An increase from two batches to 20 batches between year one and two, for example, will soon be questioned by any experienced CDMO.

She also recommends sponsors come prepared with a range of information beyond initial batch size numbers. This includes regulatory strategy for launching the mAb in additional regions and an idea of the global outsourcing approach if additional CDMOs will be brought on to support supply in other regions.

With the threat of the BIOSECURE Act continuing to loom over US drug sponsors and the US-China trade war adding fuel to the fire, flexible terms are worth considering when contracting with CDMOs. “It might be something that’s phased in, with the CDMO dedicating capacity and the sponsor committing volume. Being creative and thinking outside of the box is becoming increasingly important nowadays,” says Hodge.

4: Conserving bulk drug substance (BDS) when working with larger equipment

While techniques to minimise line loss have advanced in sterile manufacturing, a degree of bulk drug substance (BDS) loss is inevitable in the production of monoclonal antibodies. When large-scale equipment is introduced into the process, this effect can be particularly significant during the filtration step, where the filter’s increased size can have direct impacts on a manufacturer’s ability to conserve BDS effectively.     

“If you’ve been manufacturing for a Phase III study at a smaller scale, you’re probably using a line that has less complexity,” explains Hodge. “When you’re scaling up, you’re looking at higher volume equipment that might have things like surge vessels or an eight-headed filler instead of a two-headed one. Your line loss can grow exponentially with all the capabilities that come with that high throughput.”

While this is mostly just a constraint of the systems, it’s worth considering possibilities to preserve BDS earlier in the process. During at-scale engineering runs and other studies, for example, sponsors should work with their CDMO to ensure that high-value BDS is substituted with a surrogate or placebo when appropriate.

“That’s where those open dialogues are very important upfront before even committing to a CDMO,” states Hodge.

5: Communication is key

While aligning scale-up activities with regulatory and drug launch strategies is pivotal, the importance of communicating this plan to all internal and external groups both upstream and downstream of the fill-finish process cannot be understated.

“Is the first scale-up going to be EU and US followed by rest of the world later, for example? We’ve certainly seen clients struggle when not everybody knew what the strategy was,” recalls Hodge.

Defining and communicating this strategy upfront is also key when establishing production processes. As an example, Pre-Use Post-Sterilization Integrity Testing (PUPSIT) is a requirement of GMP EU Annex 1, making it an essential work step for any sterile drug product entering the European Union (EU).

“If you have any programmes that are going into the EU, PUPSIT is a must,” says Hodge, but companies should start thinking about it way ahead of their EU launches. Hodge explains it’s a good idea to implement PUPSIT during an initial US or AUS launch, even if the sponsor has no immediate plans to enter the European market.

“That way, you don’t have to revisit it for the EU,” she explains. “It’s a little bit more costly upfront, but it saves time when you’re doing your EU submission in 18 to 24 months’ time.”

Developing a scale-up strategy with PCI Pharma Services

Headquartered in Philadelphia and with facilities across the US, Canada, EU, UK, and Australia, PCI Pharma Services is a world-leading CDMO with a reputation for sterile fill-finish excellence.

The company recently established a brand-new purpose-built facility for Annex 1-compliant fill-finish and lyophilization of monoclonal antibodies and other sterile pharmaceuticals at its Bedford, New Hampshire campus.

“Spanning a total area of 50,000ft2, the facility itself houses a high-volume Groninger fully-isolated fill line featuring an eight-headed filler and two 430ft2 lyophilizers with automated loading and unloading systems. It brings some of the highest volume in lyophilization capacity across the entire PCI network,” says Hodge.

The facility is expected to commence full-scale GMP production in the coming months, but how will the company help sponsors hoping to avail its expanding sterile manufacturing capacity approach their high-risk scale-up activities?

“It all starts with a robust process,” believes Hodge. “PCI can work with clients to develop their scaled-up process, but if the client already has a scaled-up process we work with them to review that, share recommendations, and provide input on how to fit that into the PCI capabilities.”

Overall, when scaling-up mAb production, careful consideration of a range of factors is critical for ensuring an effective transition to high-volume manufacturing. But when sponsors start with the end goal in mind, communicate a realistic plan to all involved, and give the CDMO the information – and time – that they need to succeed, scale-up doesn’t need to be so scary.