Rachel Griffiths & David O'Connell outline the challenges of handling drugs containing HPAPIs, from drug development to distribution.

Hard to handle? As the R&D in oncological therapies continues to grow, so does the demand for the specialist manufacturing, packaging and distribution of such products whether they contain highly potent actives or are biological in nature.

An introduction to highly potent actives in oncology

Cancer therapies have significantly evolved since the first forms of chemotherapy were introduced in the early 20th century. While earlier treatments would typically destroy both healthy and cancerous cells, newer advanced therapies are capable of targeting the specific sites that contain malignant tumors without damaging the surrounding healthy tissue leading to an improvement in the side effect profile.

As specificity increases, the dosage loading decreases, leading to an increase in potency of the active pharmaceutical ingredient (API). The development and manufacturing of drug products containing potent and highly potent APIs require specialist expertise and technologies to minimize risk both to operators and the environment.

The very nature of highly potent active pharmaceutical ingredients (HPAPIs) means that they may evoke an adverse response at low concentrations, including respiratory issues and skin sensitivity. Any facility involved in the development, manufacture, packaging and distribution of drug products containing highly potent actives needs to ensure they have the right equipment, technical expertise and guidelines in place at every stage of the product lifecycle to ensure safe handling.

In this report, Pharma IQ and PCI Pharma Services outline the challenges of handling drugs containing HPAPIs, from drug development to distribution, and how contract development and manufacturing organizations (CDMOs) can facilitate the process from beginning to end. In addition, we look at the challenges and key considerations that arise in the packaging, storage and distribution of the biologic class of oncological therapies.

Highly potent actives and determining occupational exposure limit (OEL)

There is no single, standardized definition of what constitutes a highly potent compound, however, the most widely used assessment is for occupational exposure limits (OEL) over an eight-hour time-weighted average. This states that an airborne concentration of 10 micrograms (μg) or less over an eight-hour period is deemed potent; in other words, 10 μg/m3 is the maximum concentration of the compound someone can be exposed to over eight hours without it posing a risk to their health.

Before starting production, manufacturers require several documents such as a Safety Data Sheet (SDS), a toxicology package and a Material Evaluation Form (MEF), along with details of strength, batch sizes and the anticipated method of manufacture. This information enables the manufacturer to perform a risk assessment that includes a process exposure calculation to ensure that any person involved in any part of the process is suitably protected.

During the early stages of development, the OEL of a compound may not have been accurately established. David O’Connell, Director of Scientific Affairs at PCI Pharma Services, says that in these cases it is important to err on the side of caution and treat them as if they were potent. In addition, it is important to gather as much information relating to the mode of action/therapeutic area as possible, as this can assist with the risk assessment. As a product moves through the development and manufacturing cycle and more data becomes available, the OEL should be reassessed and as a result, may change; OEL assessment should be a continual process.

“With pre-clinical packages or from human clinical studies and then post-marketing data, there is an opportunity to have an OEL reassessment,” David O’Connell says. “Within the PCI network, we’ve found a number of products that were classed as potent molecules during the clinical development stages based on the limited data available at the time of the initial assessment, but were then reassessed to a less potent classification later in the process due to the increase in toxicology knowledge and understanding as we progressed.

“One example would be a product where the initial OEL assessment was around 7 μg/m3, but by the time it came to commercialization, the OEL was raised to 30 μg/m3 because of all the data that had been generated,” he adds.

David O’Connell explains that at PCI, a contract development and manufacturing organization (CDMO) that works closely with pharma and biotech companies, a full risk assessment is carried out for each compound that arrives at their facilities, including assessments performed internally and by third-party industrial hygienists to determine the OEL.

“We use the particulate data from the containment equipment, [telling us] the proposed concentration of API within the formulation, the mode of action, dosage form and its dosage strength,” O’Connell explains. “We use all the data provided to complete a full risk assessment, following which, the product is given a “potent passport” which stays with the product as it moves through the facility.”

Once all this data has been acquired and potential risks have been determined, the organization can move on to the next phase of development, such as manufacture.

“A number of products classed as potent molecules during early clinical development may be reclassified as non-potent at some stage prior to commercialization.” David O’Connell Director of Scientific Affairs at PCI Pharma Services.

Manufacturing of drug products containing highly potent APIs

Manufacturing facilities that process highly potent drug products must comply with Good Manufacturing Process (GMP) requirements, a global system designed to minimize risks in pharmaceutical processing that covers all aspects of production, from the receipt of raw materials, the facility itself, the equipment and processes through to the training of staff.

The way facilities manage the development and manufacturing of highly potent drug products will differ. Many rely on traditional processes whereby operators are protected using personal protective equipment (PPE) with a closed system airflow. Newer technologies, however, that deliver fully contained engineering solutions employing the use of disposable isolator solutions and glove box equipment, combined with room and facility airflow management with airflow pressure systems is deemed now to be best practice.

An important consideration when handling any product classified as being potent, is the level of containment and the processes in place, especially when selecting a potential third-party vendor.

A facility specifically designed for the containment of hazardous compounds will have a heating, ventilation and air conditioning system (HVAC) designed with one-way airflow, filters to capture contaminants and airlocked areas with negative pressure to surrounding corridors and other areas for both the processing suites themselves and in gowning rooms for staff changing. Care must be taken when transferring HPAPIs by using containment methods to minimize potential exposures.

Depending on the containment systems in place, facilities will have different abilities in terms of the OEL level they are able process. Some facilities may for example be able to manage an OEL as low as 10 μg/m3, some as low as 1 μg/m3 and in some extremely specialized facilities, as low as 0.01 μg/m3. To safely process a product with an OEL as low as 0.01 μg/m3, a facility will need to have the very latest in fully contained, specialized, engineering solutions with validated cleaning processes, best practice air control systems and specialist trained operators.

“The manufacturing of highly potent drug products is a truly specialist area, because these medicines are generally produced to help people who are very ill,” O’Connell says. “The knock-on effect is that they can be very potent in very low concentrations, so we have to protect every member of our workforce who come into contact with these potent molecules as well as the environment. This entails a very specialized facility, specialist equipment and highly trained operators.” Any equipment used in the manufacture of high potency drug products needs a complete assessment before use. The Standardized Measurement for Equipment Particulate Airborne Concentrations (SMEPAC) testing is used to demonstrate that the equipment installed at a facility is able to reduce the presence of potentially dangerous particles in the air during all stages of the manufacturing process.

David O’Connell stresses the importance of reliable equipment and procedures, noting that “it entails very specialized facilities and equipment.”

“We’re reliant on the data that is produced by the technology and on the standard operating procedures (SOPs) of the processes,?he says. “We also need to have confidence in the equipment’s ability to protect the operators when they are working with them.”

The expertise and time required by these facilities can place a strain on manufacturing companies. Ulrich Rumenapp, Head of Launch Preparation and Product Supply at Bayer, says that many manufacturing companies are experiencing capacity constraints and that he expects many will require increased flexibility in their facilities, new operating models and new equipment. At the same time, many CDMOs are growing in scale, capacity and capabilities providing additional capacity and expertise.

Rumenapp notes: “Biopharmaceutical companies look toward CDMOs as a strategic option to outsource due to the large investments required to build and operate state-of-the-art facilities.”

In terms of producing medicines for commercial launch, there are a number of considerations for both the onward processing and packaging, as well as distribution and patient safety. When developing a highly potent drug product in tablet form, for example, David O’Connell explains, “If you take an uncoated tablet versus a film-coated tablet containing a highly potent API, a simple coating of two or three percent provides significant protection to the operators who will then go on to package into blisters or bottles. Although this process extends the manufacturing time, it ultimately provides more protection to both the operators, healthcare professions and ultimately the patient as the end-user.”

In addition to these practical procedures, regular staff training and updated guidelines must be implemented. All such measures mean that manufacturing drugs containing HPAPIs presents a high-cost investment, specialist equipment and expertise, therefore outsourcing to a specialist CDMO is often seen as the most cost and time-efficient option.

“Biopharmaceutical companies look toward CDMOs as a strategic option to outsource due to the large investments required to build and operate state-of-the-art facilities.” Ulrich Rumenapp Head of Launch Preparation and Product Supply at Bayer

The requirements for safe packaging and storage of highly potent drug products and complex biologics

As the research and development of oncology therapies continues to grow, we have seen a significant increase

in the number of biologics for the treatment of cancer. Many such biologics are frequently temperature sensitive, requiring refrigeration at constant low temperatures, usually in the range between 36–46°F (2–8°C) but often lower, particularly in the early stages of development where the stability is unknown. In these cases, the cautious approach is to process and package at frozen temperatures. Additionally, many components of oncological drugs are light-sensitive, and/or have high absorption rates that require storage in low-humidity environments.

Maintaining low temperatures for labeling and packaging can be achieved using validated cold plates, maintaining a constant airflow that enables the temperature to be monitored every 10–15 minutes. In the case of frozen products, dry ice may be used. Then there are the more extreme cases where certain compounds require specialized cryogenic storage, capable of maintaining temperatures of between -150°C and -200° C.

Rachel Griffiths, Director of Technical Services at PCI, explains that maintaining the temperature of drugs at the right temperature in all stages of the clinical packaging, storage and distribution cycle for clinical trial programs is critical. “You cannot have a drug that has been exposed to the wrong temperature at any point in the process, as that will affect the trial and compromise patient safety,” she says. “We need to store therapies at their specified temperature otherwise they may result in a false positive. If we do not have stability data from the manufacturer, everything has to be meticulously assessed.”

Where low-humidity environments are required, processing suites can be fitted with a humidity control box and capsules can be pre-conditioned in humidity-controlled cabinets prior to filling. Light-sensitive products must be stored in bottles made of high-density plastic PE, in glass containers or blister packaging that has light-sensitive barriers. Other considerations would be the use of window protection pads, amber lighting or LED bulbs which do not emit UV rays.

An example of why these measures are important would be in the case of rituximab, the monoclonal antibody (MAB) used to treat multiple cancers including non-Hodgkin lymphoma. Rituximab is a sterile liquid supplied in glass vials to be administered via injection. As it is preservative-free, it is required to be stored away from direct light and refrigerated to avoid losing efficacy. Therefore, fulfilling all requirements for a product of this nature is critical to ensure the efficacy of the product and ultimately patient safety. As this is another area where specialist expertise and technology is required, when potentially choosing a third-party CDMO, it is critical that an assessment is made as to the required capabilities for every need of the drug product.

The specific packaging required for oncological drugs can be expensive. This may be driven by the dosage form, which in turn may lead to more complex packaging requirements, particularly in the case of biologics where the drug product may be provided as a patient kit containing multiple components required for administration.

This complexity may mean that there are a number of individual processes within the packaging labeling operation itself, particularly during the clinical stages, when the end-user dosage form and subsequent patient pack are still being established. Also, as therapies become more targeted, the actual batch sizes maybe be significantly smaller than their historically less targeted counterparts, leading to overall increased costs of production.

“You cannot have a drug that has been exposed to the wrong temperature at any point in the process, as that will affect the trial and compromise patient safety.” Rachel Griffiths Director of Technical Services at PCI.

Distribution of oncology drug products containing highly potent APIs and their biologic counterparts

The distribution of oncology drug products whether they contain highly potent APIs or are classified as a biologic will almost always be more complex than more traditional or standard therapies. This may include an increase in lead time, as in the case of ultra-cold chain distribution due to additional preparation time, the potentially hazardous nature of the drug product itself and complex regulatory requirements.

Legal standards must be met by all medicinal products before they are released from the manufacturing facility. Regulation varies around the world; in the European Union, for instance, a qualified person (QP) must certify that each batch of a medicinal product meets all necessary provisions before it is released. Next-generation oncology treatments are temperature-sensitive, time-sensitive products that need particular expertise in terms of QP releasing before they can be distributed. This step of the process can be outsourced to a CDMO, even if other aspects of manufacture and distribution are being done in-house, or by a third party.

PCI’s Rachel Griffiths explains: “We are not always involved in the supply chain, but we may be asked for example to perform the QP release of complex therapies such as stem cell therapies being trialed inpatient specific tumors. For other therapies, we may have 12 different versions of each all with specific storage and distribution requirements. Then when a patient is screened, the sponsor will advise us as to which is the best match for the patient, which we will then release and ship.”

Materials used in patient-specific therapies such as stem cell treatment may require special conditions for shipping such as vapor phase nitrogen to ensure very low temperatures are maintained, posing the challenge of finding and selecting a distributor with cryogenic shipping capabilities. Additionally, the supply chain of such products is often complex involving multiple stakeholders around the globe, given that samples are often taken from a patient in one country and sent to another country for processing before being returned to the individual patient.

Drug products containing highly potent actives classified as cytotoxic may be classed as dangerous goods, limiting the quantities that can be transported at any one time, particularly via aeroplane. It is important for the product status to be easily identifiable to handlers, and to implement mechanisms to ensure all labeling and shipping information is accessible.

Many oncology therapies are extremely high value and can be scarce in terms of supply during clinical development. To help manage this, CDMOs collaborate with technology providers and specialized distribution networks to ensure accountability, reconciliation and traceability of each individual product. “We may have 12 different versions of each therapy, all with specific storage and distribution requirements.” Rachel Griffiths Director of Technical Services at PCI

Conclusion

How outsourcing may lead to a more cost and time-efficient process

There are many challenges in the manufacturing, packaging, storage and distribution of both small molecule drug products containing highly potent actives and their biologic counterparts such as those used in oncological therapies.

As discussed in this report, due to the specific requirements of HPAPIs, many pharmaceutical companies rely on specialist CDMOs with both the technology and historical expertise to help them overcome the challenges that such products present. Many companies feel that the level of investment to deliver such complex services in-house make it prohibitively costly. CDMOs specializing in the processing of drug products containing highly potent actives have the technologies, systems, processes and trained personnel in place to maintain the integrity of the product and ensure the safety of the workforce with the required environmental controls in place.

Luiz Barberini, Head of External Manufacturing for Latin America at Bayer, remarks: “CDMOs work with multiple customers-companies, naturally this brings a huge amount of experience to the project and a wealth of knowledge which means alternative ways of looking at challenges and multiple solutions and ideas to our business while maintaining confidentiality requirements. They tend to better know about a breadth of core processes, thus are more prone to innovation.

“The most recognizable benefit of working with CDMOs is not having to invest our own capital on production lines and development processes, particularly at the clinical stages when the product is more of an unknown entity. The technology and capacity is already available within the CDMO, with the added benefit of reducing timescales. In our experience, by using a specialist CDMO partner we can convert a ‘fixed cost’ into a ‘variable cost’ which for us is advantageous as we pay for what we need, with the flexibility to change course if needed.” The scientific and technical knowledge CDMOs can bring to the supply chain as specialists is streamlined, from the initial handling phase through to manufacture, packaging, storage and lastly shipping to customers and patients.

As oncological treatments become increasingly targeted and complex while supply chains face growing challenges and the costs of production rise, outsourcing to CDMOs offers a way to get specialized products both into clinical trials and on to commercial launch in a cost and time-efficient way. This option negates the need for complex capital build projects by the client company – which is expensive and takes time, especially during the clinical stages when projects are time-critical and ultimate product success is unknown. Selecting the right partner with a scalable solution able to take a successful product seamlessly through the clinical phases and on to commercialization, may offer a preferred and faster route to market.

“The most recognizable benefit of working with CDMOs is not having to invest our own capital on production lines and development processes.” Luiz Barberini Head of External Manufacturing for Latin America at Bayer.

Hard to handle??The challenges of handling and delivering highly potent oncology drugs – First published in?Pharma IQ , February 24, 2022, Written by Leila Hawkins.

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