CDMOs like Fareva Excella face the challenge of managing new APIs in development projects with incomplete toxicity and pharmacology data. Manufacturing processes must be developed to support the production of drug substances for clinical trials. In clinical phases II and III, additional data becomes available that further characterizes the API.
Fareva Excella has been working with potent compounds for decades and has extensive experience handling drug substances with OELs as low as 0.1–10 micrograms per cubic meters (μg/m3), which are considered to be HPAPIs.
HPAPIs generally have OELs below 10 μg/m3. The OEL is calculated with all available toxicological and pharmacological data from animal studies and clinical trials. At Fareva Excella, we place potent compounds into six different occupational exposure bands (OEBs) based on their OELs (see Table 1). Until recently, our experience has been developing and manufacturing OEB-4 and OEB-5 compounds. We have the facilities, containment equipment, procedures, and trained operators required to ensure safe handling of these high-potency molecules.
Recently, we worked on a clinical phase II project involving a compound that was thought be an OEB-4 or OEB-5 molecule. As the project advanced to phase III, however, more toxicity data was generated, and it was determined that the OEL for this anticancer compound was in fact 20 nanograms (ng)/m3, placing it at OEB-6. While Fareva Excella has appropriate containment capabilities in our development and analytical laboratories, we did not have the right equipment available in the production plant.
After discussions with our client and consideration of the expanding market for very highly potent drugs, we decided to obtain and install new isolators designed for containment of OEB-6 compounds for the entire production line, including sampling and packaging capabilities. Within one year from the time we decided invest in an OEB-6 solution, the system was planned, implemented, installed, qualified, and put into operation. The production line passed a pre-approval inspection by the U.S. FDA, and the product has been successfully commercialized.
Table 1: Fareva Excella Banding System for Potent Compounds
An OEL of 20 ng/m3 is nearly a thousand-fold lower than 10 μg/m3. While Fareva Excella is experienced with high-potency compounds, finding that a compound we had on sight was an OEB 6 molecule required us to be extremely adaptable. In addition to the new containment systems required in the production area, we also needed to overcome analytical challenges, train operators in new techniques, and establish appropriate protocols with respect to cleaning and scheduling within our multipurpose facility.
Ensuring a safe work environment when dealing with OEB-6 compounds with OELs below 100 ng/m3 is much more challenging than handling OEB-4 compounds. OEB-4 containment generally involves one layer of protection, like liner systems, gloveboxes or simple isolators. When working with compounds with OELs on the ng/m3 scale, a second layer of protection is needed within the primary containment, like double-chamber isolators or liner systems within an isolator.
For instance, weighing an OEB-4 compound can be completed in a glovebox. The glovebox can be charged with simple liner systems, like continuous liners or double-O-ring ports. The compound is weighed within the glovebox and can be transferred directly via split valves, liner systems, or alpha/beta ports into containers or vessels. For OEB-6 compounds instead, two separate isolator chambers with pressure cascades are used: one to weigh the material and a second one that is used as decontamination chamber in which the outside of the material container is cleaned. Only then the material is discharged using the transfer containment systems described above.
Another challenge is the verification process to ensure that the containment system is effective. While the same pump/filter system is used to collect the dust in the air for exposure measurements, analytical methods with the capability to detect those highly active compounds at 10% of their OELs require a very low detection limit. The filter is extracted, and the contents of the extraction solvent are analyzed. For OEB-4 compounds, that means detecting HPAPIs at 0.1–1μg/m3, while for OEB-6 HPAPIs, the detection level can be as low as 1 ng/m3. Depending on the sampling length and the volume of air that is sucked through the filter, detection limits for the analytical method need to be in the range of 0.5–0.1 ng/filter.
Double-chamber isolators are more complex than traditional isolators and, hence, more complicated to use. It is essential to properly train production operators about their operation. Equally important is training on the potency of the OEB compound and how this advanced equipment protects the operator from exposure.
Ergonomic issues must also be considered for operators working with OEB-6 compounds. The physical activities are more complex, and therefore operators should be involved in the design of those isolators, and mock-up studies need to be performed. When products are being discharged from a centrifuge, for example, they must perform the crimping and cutting of continuous liner systems within an isolator, which can be challenging.
As a CDMO, Fareva Excella works in a multipurpose plant with many different APIs, including not potent, moderately potent, and very highly potent APIs. Fareva is equipped to manufacture OEB-5/6 compounds in 250-L and 800-L reactors, down to an OEL as low as 10 ng/m3.
Effective management of the cleaning of equipment and scheduling of production runs is crucial to prevent cross-contamination from batch-to-batch.The extent of cleaning depends on the toxicity and pharmacology of the API, because these properties are used to determine the allowable level of residual API. The lower the OEL and the higher the potency, the lower the cleaning limit will need to set. Scheduling must be done very carefully so that APIs with a high maximum daily dose are not produced in equipment that was just previously used to manufacture an OEB-6 product. With OEB-6 compounds, therefore, cleaning protocols can be challenging, as can the development of analytical methods capable of accurately detecting compounds at these very low levels.
Some companies choose to use dedicated equipment for certain very highly potent compounds, thus avoiding concerns about cross-contamination. Another option is to leverage disposable technologies. The liners that Fareva Excella employs with our isolators are dedicated to a specific product and in some cases are the only material that comes in contact with OEB-6 HPAPIs. Since only the isolator or the liners come into contact with these substances, less extensive cleaning procedures are needed, as production compartments are not contaminated.
While there are many CDMOs that support projects involving OEB-4 compounds, fewer have the capability to manufacture and store OEB-5 HPAPIs, and the capacity for OEB-6 molecules with OELs at the ng/m3 level is quite niche. As a result, for highly potent APIs, it becomes more difficult to transfer projects from one CDMO to another or from a CDMO to a service provider that only provides contract manufacturing support.
When very highly potent HPAPIs are involved, it is essential to select a CDMO with knowledge, expertise, and the facilities/equipment for handling these challenging compounds in a manner that ensures operator safety across all of the potential development and manufacturing scales that could be involved in the project. In addition, the CDMO should have a successfully demonstrated containment strategy for very highly potent compounds that includes not only production, but sampling, quality control, and safe transport throughout the facility — essentially a comprehensive, full-site system.
On the flip side, CDMOs that have those all-encompassing containment strategies want to work with customers that recognize the need for their specialized facilities, equipment, and expertise and expect their suppliers of highly potent APIs to have appropriate systems in place so that operators are safe and their products can be produced in the safest manner possible.
One of the main trends in API development is to design highly selective drug substances that target a specific site of action, providing greater efficacy with reduced side effects. Their greater selectivity also makes them more potent, and thus the development of increasingly potent compounds is expected to continue.
The increasing complexity of APIs is another important trend, and it is driving pharma companies to leverage outsourcing providers with the specialized expertise to produce and handle them. Not all projects involve highly potent APIs; many are challenging from the process side without the added need for high containment. Increasingly, though, these challenging APIs are also highly potent. The majority of projects today, therefore, involve niche, small-volume products, such as orphan drugs or very-low-dose drug substances, that require specialized skills and equipment to produce.
Fareva Excella has been handling highly potent APIs since the 1980s. Over those nearly four decades, we have established a significant understanding of the challenges presented by HPAPIs and how to overcome them. That knowledge has positioned us to take the next step in processing very highly potent compounds.
As a company, we are always seeking opportunities to invest in new equipment and capabilities in support of our customers. The new equipment line — including four double-chamber isolators and liner systems within isolators installed to produce OEB-6 HPAPIs — is just one example of this approach. Fareva has invested more than €33 million in the last two years to expand high-containment capabilities for highly potent R&D, API, and oral solid dose, including roller compaction. Additionally, Fareva Excella invested €7 million in analytical labs to handle highly potent molecules. Indeed, Fareva is continuously advancing through the upgrading or addition of equipment at our existing facilities to successfully manage the increasing complexity of our clients’ projects.
Daniela Kovats is the Manager of Environment, Health, and Safety at Fareva Excella. She is a chemical engineer and has additional education as safety engineer and toxicological expert. She has 18 years of experience in the pharmaceutical industry and is specialized on industrial hygiene and containment strategies. She is involved in all containment projects at Fareva Excella. Before specializing on EHS, she was in charge of analytical method development and validation. She is part of the steering committee in the CoP (Communities of Practice) Containment ISPE D/A/Ch.