Do's And Don'ts Of Material Handling When Retrofitting For ADCs
In the previous article we discussed the need for and, more importantly, how to evaluate processes and materials from a standpoint of protecting a wide spectrum of employees in the plant. This exercise must be done whether we are building a new facility or renovating a legacy facility.
However, if we are renovating a facility built for another modality, most of the design and layout lacks the features and functions that accommodate ADCs easily. We will need to adapt the facility, add equipment, and modify operational procedures to move forward. From this, we will dive into some of the individual processes and material transfer aspects to provide a series of recommendations. The following are some basic guidelines and recommendations for material handling and processing:
Incoming Payload API
API must be contained within a double- or triple-enclosed vessel depending on weight and travel method, where each layer’s exterior has been decontaminated with all procedures documented (see part 1 for our description of decontamination vs. sanitization). The travel from the delivery vehicle must be specific and defined in an SOP, minimizing the interaction with personnel in the facility. The material must be moved to a secure warehouse, separate from the normal material stock, where manual handling is provided. Automated or robotic warehouses raise the potential for pallet handling equipment to damage the container.
mAb Production
Materials for the antibody production must be in a separate facility from the plant that executes the conjugation and processing of the ADC, preferably or at a minimum, a separate part of the plant with separate gown/degown and material airlocks. There needs to be vigilance that the mAb plant runs with Annex 1 standards, performs normal sanitization, and eliminates potential cross-contamination with the downstream processes and the payload API. This may sound like a simple task, but it requires a dedicated supply of raw materials, operational and maintenance personnel, and disposables. Furthermore, other materials may not be shared with the payload API manipulation and downstream processing. In addition, the mAb plant must be fully scalable with single-use systems to assure capacity scale changes that we see in the market. The final point for capacity, flexibility, and safety is the mAb facility must have a storage facility, and freezers must be separate from the payload API, downstream ADC drug intermediates, and final product. The most prevalent cause of contamination of the mAb facility, and subsequent exposure to the mAb personnel, is the movement of undocumented contaminated equipment into the mAb site.
The Conjugation Reaction
The conjugation suite is the key risk area because the payload API’s OEL and OCEB are the highest.
The payload API container is moved into the suite and opened only within a sanitized isolator or within a pre-sterilized disposable polymer isolator. This isolator must be part of the main process isolator system or have a secure transfer port to the main process isolator. This could be a weigh/dispense isolator connected to the process isolator. This is because we do not want to withdraw that material and move it within the open process suite. During all operations with the conjugation/reactor suite, all personnel should be fully gowned in polymer protective suits (PPE) and powered air purifying respirators (PAPRs) for breathing.
Working in the PPE, using PAPRs, along with the chemical-resistant gloves through ports in the isolator, will be challenging for any operator from a dexterity standpoint. To reduce risk and improve efficiency, we recommend operators practice working the process several times with a placebo material (NaCl) and water for the fluids in the system. This practice activity can be done in a non-classified area in the initial training. This practice will prove critical because payload API species, drug-to-antibody ratio (DAR), and volumes will change over time with development and production, and what works with 100 mg may not work with 10 kg purely from a handling and size capability.
Part of the exercise in training and practice also involves learning how to control and coordinate the process interaction using the automation and preventing high temperature excursions as well as recognizing situations with product freezing/improper thawing to prevent the introduction of ice crystals. Additionally, the logistics in the suite with the components, materials, and assembly of the process in the isolator requires planning and choreography of the operator movement. We recommend pre-assembly and kitting as much of the process tubing, SUS, and connections to instrument sensors outside of the process suite and isolator as possible. These practice sessions also must include either the decontamination and sanitization cycles of the rigid isolator or the erection of the disposable isolator. In all, each team member in the process suite must understand the decontamination procedure and have all the materials, supplies, and decontamination liquid ready to be used if the isolator fails, an accidental spill occurs, or there is a process leak or failure. As a rule, the rigid isolator interior must be decontaminated after each process run and sanitized (VHP) prior to the next batch. Disposable or flexible isolators (or sections) when used are disassembled, carefully collapsed, bagged, and discarded with the waste.
Purification And Formulation
These downstream processes generally deal with a liquid bulk drug intermediate (BDI) or a drug substance (DS), and as such should have a lower OEL and potentially a lower exposure potential (EP). At each downstream process suite, a new OEL needs to be established, documented, and the EP calculated. This could reduce the EP to a 3 or lower, and some of the requirements for isolators and PAPRs could be reduced. This reduction of requirements is done especially if the purification, TFF, chromatography, or other formulation step is done in a suite other than the conjugation suite and has separate airlocks for personnel material. In addition, based upon the OEL of the BDI or DS, the decontamination process may also change, but like the other suites it must be tested and validated.
The Filling Operation
At this point, the DS is in liquid form and, as in the formulation suite, an evaluation of the OEL and EP is necessary, and commensurate levels of protection are needed. This is a place where retrofits often take a shortcut that imperils the product and operator safety. Utilizing an existing RABS system makes it nearly impossible to tear down and decontaminate the line after a run, and it creates additional dirty equipment/waste flows of potent compounds through the facility. An isolator that can be decontaminated in place should be the only consideration. Since filling will be done in an isolator, a negative pressure isolator should be considered.
As an industry rule, the filling suite will be separate from the other processing suites and not share airlocks with the conjugation suite or any suite with a higher EP. The filling systems also have some unique features that other processing suites do not have that add to the safety concerns to be addressed:
- Broken glass poses the potential for operators to get cut in proximity to a toxin.
- PUPSIT and the movement and testing of a wetted filter with toxic liquid needs a contained transport mechanism and a testing rig that collects the filter and residue post-test. This should also deal directly with a final container and disposal.
- Logistics support for the supply and the removal of vials and RTU components must be specified. In this case, once the materials enter the filling suite, they either go out as product or are discarded as waste.. Materials from a potent compound filling suite cannot be restocked.
- The final step in the process is external washing of the vials to protect personnel handling them from any fill residue on the outside. The vial inspection team or machine needs to be aware if there is post-fill vial breakage and how to react and decontaminate.
The filling operation should focus on using SUS for the DS reservoir, flexible polymer tubing for transport, peristaltic pumps (no liquid contact), and disposable filling needles. This will minimize the level and complexity of the filling process as the entire filling contact system from reservoir to the needles can be removed and bagged at batch-end and taken out with the solid waste.
Lyophilization
The use of lyophilization is becoming increasingly important in the final drug product form, primarily to stabilize and preserve the final product. While this is necessary for the product delivery, it transforms the lower OEL/EP liquid back to a higher OEL/EP powder that is very fine and easily aerosolized. This transformation raises two serious concerns:
- Increased EP with vial handling outside of the lyophilizer and
- EP within the lyophilizer regarding clearing broken glass, cleaning, and maintenance of the compressor systems, downstream piping, and the receiver vessel.
The condensation of the liquid and reversion back to a powder with a new potentially higher hazardous OEL forces us to devise a cleaning scheme for the lyophilizer and build in separate inspection, cleaning, and decontamination methods for its interior, assuming there may be broken glass and toxic powder inside.
Beyond normal sanitization cycles for the lyophilizer, a decontamination cycle within the CIP process must be implemented to assure worker access to the unit as well as batch-to-batch integrity. The most difficult issue is the maintenance of the lyophilizer’s mechanical system, due to the condensation and retention of condensables. During any maintenance, the mechanical area must be isolated in a negative HVAC envelope with exhaust air HEPA-filtered. Maintenance workers must don full polymer PPE operating suits with PAPRs. As equipment is disassembled, each pipe section and others must be decontaminated individually. To avoid this, the lyophilizer must be dedicated to this product type and must be mechanically designed to adapt a unit wide decontamination system.
Waste Removal
Waste presents another material handling issue that requires planning and design. In an ADC facility, all process waste must follow a dedicated exit path, so it does not cross pathways for raw materials, cleaning supplies, new SUS, and operators. Solid waste (wet or dry) of any kind must be double- or triple-bagged inside the process suite with each consecutive bag decontaminated. The bags of waste should then be placed in the exit material airlock (MAL) and labeled to identify their contents.
While in the MAL, the operator should spray down the MAL interior with decontamination solution. Then, they or another operator should enter their personnel exit airlock (PAL) and spray down the entire exterior of their operational suit with decontamination liquid before removing it, bag their PAPRs for recycling, and put on a new clean gown to escort the bagged waste out from the exit MAL into the hazardous waste disposal area. Then, the PAL must be decontaminated.
When no dedicated waste pathway exists
In legacy facilities dedicated exit pathways may not exist. In that case, waste removal from process suites must be delayed until the production shift ends. At that point all non-waste traffic along the hallway out to the warehouse must be stopped before waste removal commences. At this time, any non-dedicated equipment (special instruments, PAPRs, etc.) must be moved out to a decontamination center for decontamination. When the waste removal is completed the entire exit hallway must be washed with decontamination liquid. The method will also depend on the training, execution, and testing program of this validated effort.
When there's liquid waste
In the case of liquid waste, a dedicated process waste disposal system needs to collect wastewater from all process suites, including waste liquid from decontamination flushes, lyophilizer decontamination cycles, vial washing processes, formulation permeate, and any other large decontamination effort. The waste liquid is collected in the system, monitored, treated, and tested for further decontamination.
Any small volume of waste liquid in a SUS can be double- or triple-bagged and moved via solid polymer container into a solid waste disposal area, assuming the waste remediation organization approves of the volume.
Summary
- In general, it should be obvious at this point that all material handling and operational methods need an evaluation of the OEL and an equipment type (and decontamination method) and gowning requirements must be assigned.
- ADC production highly favors the use of SUS from process equipment to isolators to filling systems. This allows the use and discarding of process contact elements without decontamination and testing.
About The Authors:
Herman F. Bozenhardt has 50 years of experience in pharmaceutical, biotechnology manufacturing, engineering, and compliance. He is a recognized expert in aseptic filling facilities and systems and has extensive experience in the manufacture of therapeutic biologicals and vaccines. His current consulting work focuses on aseptic systems, liposomes, biological manufacturing (BL-1, BL-2, BL-3), and automation/computer systems. He has a B.S. in chemical engineering and a M.Sc. in system engineering, both from the Polytechnic Institute of Brooklyn (now NYU). He can be reached via email at hermanbozenhardt@gmail.com and on LinkedIn.
Erich H. Bozenhardt is the associate director of process engineering for Untied Therapeutics in Raleigh, North Carolina. He has 20 years of experience in biotechnology and aseptic processes and has led several biological manufacturing projects, including cell and gene therapies, mammalian cell culture, and novel delivery systems. He has a B.S. in chemical engineering and an MBA, both from the University of Delaware. He can be reached via email at erichbozenhardt@gmail.com and on LinkedIn.