Are You Taking The HPCs In Your ADCs Seriously?
By Matthew Pillar, Editor, Bioprocess Online
It’s hard to surprise Herman Bozenhardt. For years, the long-time biopharmaceutical facilities design expert and Bioprocess Online contributor has chronicled the often outrageous facilities faux-pas he’s seen – from pigeons in the plant to cats in the warehouse and dozens of other blunders not involving wild and feral animals. While he often puts a signature and entertaining “now I’ve seen it all” twist on these adventures, he also acknowledges the dire consequences of poor design that come in the form of regulatory scrutiny and the ensuing expense of time and remediation, but also, and more importantly, human risk.
It's far too common for small biotech laboratories, in particular, to play what Bozenhardt calls dangerous games. “It wasn’t uncommon to see violations and their consequences from the start of my work in the biologics space,” he says. “People working with virulent organisms under a hood, with their cell phone and a Starbucks in the room with them, no gloves, and no face protection, in the clothes they wore to work and would wear back home. That’s a pretty common sight.”
In those small labs, often borne of academic pursuits and discoveries, he says the refrain is predictable. No worries, we’ve been doing it this way. This is how we did it at the university. This is how we work in the hospital. CDC and OSHA regulations? What are they?
One day, a scientist at a client site was rigging up an experiment and caused a serious release of a virulent organism which endangered the scientist and the fellow workers. Bozenhardt is too professional to say, “I told you so,” but he did find satisfaction in the adherence to safety protocols – gowning, gloves, and face protection, in particular – that followed the incident. He laments that it took an employee’s physical harm to spur the action.
“The reality is that I know there are a lot of folks working like this under the radar and it takes a near miss or an accident to enforce simple and practical safety procedures,” says Bozenhardt.
Big Bio Is Guilty, Too
While small biotech facilities often present the most egregious violations, big bio is far from faultless. In fact, the wave of ADC (antibody-drug conjugate) development and manufacturing activity we’re currently witnessing, and importantly, the HPC (high-potency compounds) comprising the payloads in these therapies, is giving Bozenhardt plenty of new material.
“The unfortunate prevailing attitude around ADCs is that small batch sizes don’t necessitate concern,” says Bozenhardt. He begs to differ. “The first questions that you need to ask about any process handling potent compounds is, what is the payload, what is the OEL, and what is the OECB band? In today’s biopharma industry, we are routinely confronted with compounds that are in Bands E and F. That should sound alarm bells in everyone’s mind.”
The reality is that most companies haven’t worked with potent compounds like this before. Most of the commercial liposome-based oncology products contain Band B, C, and D materials. Those require downflow booths or ventilated balance enclosures (VBEs) and flowhoods in production environments, and fume hoods and cytotoxic safety cabinets in R&D and QC capacities.
Bands E and F, on the other hand, are reserved for next-level, ultra-potent stuff. The processing equipment it requires reflects that. It calls for ACTIs (aseptic containment isolators) and unidirectional CBIs (containment barrier isolators) in production, and GPPIs (general processing platform isolators), turbulent CBIs, roRABs (reverse open RABs), and VBEs for small quantities in R&D and QC.
“Folks working in low volumes in the laboratory forget a lot of these fundamentals when they introduce a new compound,” says Bozenhardt.
Those forgotten fundamentals go beyond materials handling in the lab. There, says Bozenhardt, you put a great deal into the process, and you put a lot of effort into making sure any residual goes away in the product solution. “But,” he asks rhetorically, “How are you getting that material in? How are you opening it up? Where are you storing it? What if it is mishandled and spilled in the hallway? You’d have to evacuate the building and call the HazMat team. The real killer question is when you are all done and the process went well, how do you capture and remove the waste?”
ADCs Challenge Cleaning & Validation
Cleaning is another aspect that many new-on-the-scene HPC handlers haven’t fully considered. “A stainless-steel isolator is a nice idea, but how do you clean it? The washing it with WFI, wiping it down with alcohol, and even running a VHP cycle doesn’t do it,” says Bozenhardt. The residual compound must be neutralized and rendered inert for safe cleaning and disposal. “This can be done with chemical washes, but can you do it within the isolator? Do you have to apply it by hand? Can it be incorporated into the isolator CIP? The better solution is to use a flexible disposable isolator,” he says.
The same goes for containing a spill, be it in the lab or in a storage facility compromised by an errant forklift that speared the container. “Even once the residuals are neutralized and the isolator is clean, you have to develop an analytical technique to measure how well you’ve done with the swabbing to prove to the FDA and any other concerned parties that you don't have any residual left, whether it was from a decontamination clean up or from one batch to the next,” he says.
Is Outsourced Manufacturing Of ADCs Off The Table?
Dealing with compounds so potent they could kill a person who inhaled them creates a whole lot of roadblocks to leveraging existing biopharmaceutical manufacturing facilities for the production of ADCs. That’s why Bozenhardt says the outsourced manufacturing community is loath to touch an ADC project. “Once a CDMO has processed a compound this potent, it can be bad for future business. If a developer walks in with a mAb or cell therapy project and asks what products have been processed in that facility prior, and an ADC with a Band D, E, or F material is the answer, that developer wants to run out the door,” he says.
This creates a conundrum for ADC developers who don’t operate their own development and manufacturing facilities, and Bozenhardt says it also invites some hard decisions for those who do. “There are a couple of large, outsourced manufacturers with multiple dedicated facilities that will take on ADC projects, and a small handful of upstarts with specialization in handling potent compounds,” he says, “but capacity is limited, and demand is high and growing.”
Naturally, clients with existing manufacturing sites want to tap into that pre-sunk investment to accommodate their ADC projects. Not so fast, says Bozenhardt. “If you’re processing a monoclonal antibody under your manufacturing roof, and in particular, if you’re filling it there, how are you going to justify the handling of HPCs in the next suite?”
Bozenhardt’s recommendation for highly-potent ADC development and manufacturing is to deploy modular equipment – such as offered from G-CON, CleanSpace, and Germfree – in a wholly separate facility. If there’s no time or money to build that facility from scratch, acquire an existing one to dedicate – a warehouse, an abandoned Kmart, a deserted factory – and place your module there.
Systems Impact Of ADCs
Bozenhardt says we all have a responsibility to look at the facility we expect to place the ADC or any highly potent compound into and look at the entire process, personnel interaction, material movement, and importantly, waste removal. That might sound like the modus operandi of any consultant, but this isn’t scope creep for the sake of job security. It’s scope creep for the purpose of practicality and safety. “I’ve basically shown many clients on paper why the existing facility won’t work, not just because of the adjacency to other products, but because of the way their HVAC system works, the way ADCs are handled, the equipment contamination, equipment maintenance practicality, the physical space required for storage, remediation, and disposal of safety and single-use equipment, and more,” says Bozenhardt.
The HVAC system, for instance, requires backup in the event it fails and loses negative pressure. The lyophilization condenser, pumps, and other mechanical systems need a maintenance plan all their own. After every step in the process, the product, its intermediate forms, the filled vial—every form it takes—must be reestablished via the OEL and a plan put in place to mitigate exposure in the event a vial falls and breaks, or a capping machine gone haywire begins to tear vials apart. On the PPE front, a dedicated gowning room and a system to bag and treat outbound gowns must be established. Suddenly, the space allocated for the ADC operation needs to be doubled, and that’s before addressing the challenge of sealing off the entire operation from the antibody or cell therapy production happening on the next line over, which is likely to become an architectural issue.
Are You Working On The Fringe?
During our lengthy talk, Bozenhardt and I also discussed the impact that these ADC HPC containment and remediation considerations would have on the burgeoning landscape of ADC developers and their manufacturing plans. Stay tuned for his prognostication on market dynamics in part two. In the meantime, Bozenhardt suggests some honest self-examination is in order.
“Compared to antibodies, there are so many more aspects to consider when you’re dealing with potent compounds that we’re into, and much of this ADC market is in what I'll call the fringe of biotech,” says Bozenhardt. “ADC progress is being made by scientists, biochemists, and microbiologists who do not have a full understanding of how to deal with this type of material. We must shift our thinking from the pure science we are deploying to the pure safety of our employees and patients.”