Mind The Potent Compounds When Retrofitting Facilities For ADCs
The recent proliferation of antibody-drug conjugate (ADC) therapies provides a new and quickly expanding avenue for lifesaving treatment. With this, many new and legacy biotech organizations are scrambling to acquire, develop, and ultimately deploy these processes. With the urgency to deploy and succeed, organizations are analyzing the options to either outsource the process to a CMO/CDMO or construct it in-house. We see the rush to market; however, we are not seeing new ADC facilities being constructed. This typically means organizations are cautious with their capital funds until some positive early-stage results are obtained. This means organizations are relying on small-scale retrofits, whether with one of their facilities or via a CMO. Either way, we are seeing process development and process implementation within an existing facility.
This article is the first part of a three-part series that explores the basic concepts of facility conversion to accommodate ADC manufacturing. This installment covers the critical nature of the potent compounds being used in ADC production.
Most organizations see the ADC process as just another process that they must shoehorn into a building and get it up and running as soon as possible. However, ADCs present a completely new challenge around the area of safety, and our normal concepts of material handling, processing, facility systems, material transfer, and operator interaction are no longer valid.
The key aspect of ADC manufacturing is the use of a payload material in the processing, which is typically a highly potent compound. The design and specific construction must be evaluated for the entire process, since the payload API is present in some form throughout the process and frequently impacts all product-related materials from material receipt through intermediates to final drug product distribution.
An in-depth paper on potent compounds, “Handling & Processing of Potent Compounds: A Holistic Approach,” which we published in May 2017 on Bioprocess Online, is an approachable reference. We will use some of the material from that publication to orient our discussions herein. For more detailed guidance, see ISPE's Good Practice Guide “Containment for Potent Compounds” and your insurer (e.g., FM).These should be your guidelines for evaluating safety at every step of the process.
Every chemical and biological compound we work with has a material safety data sheet (MSDS) and an occupational exposure limit (OEL), which dictate how we must handle the compound. We must evaluate not only our raw materials but each of our intermediates that we produce, store, and transfer, and develop a specific exposure potential (EP). Clearly, contamination and exposure impact our process operators; however, it can occur not only on the processing floor but throughout the plant. Consideration must be given to the personnel who often work outside the process suite and are not directly involved with the process equipment:
- Maintenance workers who must disassemble equipment and change HEPA filters
- Material handling personnel who move material in and waste out
- Warehouse personnel collecting and storing raw materials, intermediates, and product
- Packaging line operators and vial inspectors
- Contracted waste handlers
- Adjacent office employees
- External staff who come into contact with the water, soil, and air adjacent to the plant
The first step in understanding the handling of any potent compound is finding out the key safety and health parameters of the material from the MSDS or establishing new parameters for the intermediates created in the new ADC process. These parameters are:
- OEL and the designation of the occupational exposure band (OEB),
- permissible exposure limit (PEL), and
- long-term and short-term exposure limits (LTEL/STEL).
OEBs are calculated from the OELs and, together, provide a direct and easy way of establishing a compound’s toxicity to reach a control solution. The banding schemes (such as the occupational exposure control bands [OECBs] in Chart 1 below) relate a compound’s level of toxicity to effective engineering/operational controls by classifying compounds with similar exposure levels into a group. In ADC process applications, we typically see the raw material payload API in Band E and Band F, the most toxic, which will require the most engineering effort to operate with and contain.
CHART 1
Occupational Exposure Control Bands
| Potency Band | Description | OECB (μg/m³) |
|---|---|---|
| Band A | Not harmful, not irritating, low pharmacological activity. | 10,000 – 1,000 |
| Band B | Harmful may be irritant and/or moderate pharmacological effect. | 1,000 – 100 |
| Band C | Moderate toxic and/or high pharmacological effect. | 100 – 10 |
| Band D | Toxic. May be corrosive, sensitizing, or genotoxic and/or very high pharmacological activity. Often termed potent. | 10 – 1 |
| Band E | Extremely toxic. May be corrosive sensitizing or genotoxic and/or extremely high pharmacological activity. Often referred to as highly potent | 1 – 0.001 |
| Band F | Life-threatening. Radioisotopes | <0.001 |
Hazard
Hazard
Decontamination vs. Microbial Sanitization
In the cell culture/mAb production world, we are always concerned with microbial contamination within the process suites, processes, and ultimately the product. We are always cleaning, sanitizing, and decontaminating. In this case, our decontamination is the destruction of microorganisms and washing away of endotoxins. In the case of ADCs, we are also concerned with microbial contamination throughout the process as we would in any Annex 1 drug making process. However, in the arena of ADCs we must be concerned with decontaminating the toxic chemical residue from the equipment, facility (walls/floors/ceilings), exterior garments of the employees, tools, instruments, and the packaging of the product. We must also be concerned with not contaminating any of the drug components (mAbs, buffers, etc.) prior to use in the process.
Regarding our terminology, from here on we use the term “decontamination” for the neutralization and removal of any toxins in any form and “sanitization” as the destruction and removal of any microbials.
The decontamination process must be a validated method of spraying, deluging, or washing a surface with a chemical solution that neutralizes the toxin to a safe or inert chemical and removes any residual. Prior to accepting any payload API into the facility, this method must be in place. This method must be tested on all possible surfaces that may come into contact with the API toxin, including all materials of construction (walls, floors, ceilings), stainless steel, gown fabric, and any polymer surfaces. We validate each type of surface because we need to assure ourselves that we can decontaminate any surface inside the process suite and, in an emergency, we can decontaminate outside the suite, such as along the path of waste removal or in the warehouse.
Understanding All The Materials: Payload, Linker, BDI, BDS, Product
One of the biggest misconceptions is we need to be concerned only about the granular or powder payload material. That is one of the most serious mistakes from a safety and handling aspect. Let us examine some of the materials in our process, with scrutiny on the manipulation and pathway. Each process intermediate, whether conjugated mAb or a buffer exchange fluid, has a payload component and/or residual. Each process step must be evaluated with the process materials present against the exposure potential (see Chart 2) below.
CHART 2
Exposure Potential Matrix
| Scale of operation? | Material Form? (Dust Potential) | Duration of Task | ||
|---|---|---|---|---|
| Low | Medium | High | ||
| Small (gm to kg) | EP 1 | EP 1 | EP 2 | SHORT |
| EP 1 | EP 2 | EP 3 | LONG | |
| Medium (10-100 kg) | EP 1 | EP 2 | EP 3 | SHORT |
| EP 2 | EP 3 | EP 3-4 | LONG | |
| High (+100 kg) | EP 2 | EP 3 | EP 3 | SHORT |
| EP 3 | EP 4 | EP 4 | LONG | |
Once the exposure potential level EP 1 to EP 4 is known, we combine that point with the data on the OEL. See Chart 3.
CHART 3
Equipment Selection Matrix
| Potency Band | EP 1 | EP 2 | EP 3 | EP 4 |
|---|---|---|---|---|
| OECB Band A 10,000 – 1,000 μg/m³ |
1 | 1 | 1 | 2 |
| OECB Band B 1,000 – 100 μg/m³ |
1 | 2 | 2 | 3 |
| OECB Band C 100 – 10 μg/m³ |
2 | 3 | 3 | 4 |
| OECB Band D 10 – 1 μg/m³ |
3 | 3 | 4 | 4 |
| OECB Band E 1 – 0.001 μg/m³ |
4 | 4 | 4 | 4 |
| OECB Band F <0.001 μg/m³ |
5 | 5 | 5 | 5 |
The equipment aspect of the matrix refers to the equipment used for containment of the process and protection of the operations, maintenance, and quality personnel associated with the operation. Most ADC operations today have Band D/E and F, and the requirement focuses on isolator technology, personnel in hardened powered air purifying respirator (PAPR) systems, and/or, potentially, robotic manipulation.
While each process is different, and the process materials can vary along with the quantity, we must make our EP calculation and determine the OECB at each step of the process. With the EP known, and the nature of the equipment (from chart 3) we must use to protect the plant personnel, we can now make some decisions on how we will run the plant and how we will deal with material handling and the inevitable failures in the material handling routines. Clearly, within the equipment selection matrix above, group 4 equipment focuses on isolator technology, and group 5 will require isolators plus additional safeguards. Part two in this series deals with the various processes and material handling.
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.S. 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 United 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.