HPAPIs – from early development to full-scale manufacturing

Highly potent drugs represent a growing proportion of medicines, including therapies in development and those commercially available. HPAPIs offer a range of benefits over conventional APIs, including high target specificity, retention (in their active form) within the body for longer durations and fewer side effects.

At present, more than 40% of all drugs are highly potent in nature. Furthermore, 60% of HPAPIs are in the oncology field, and as approximately one third of all new drug approvals are currently cancer medicines, which represents a substantial market opportunity. Other therapeutic areas where drugs may be highly potent include asthma, diabetes, cardiovascular disease, hormone imbalances and autoimmune disorders. The demand for the capability and capacity to manufacture HPAPIs, particularly for CDMOs, is rising significantly. From lab to commercial scale, this article looks at some key considerations and best practices that are required for implementing the handling and manufacturing of these compounds.

In this article, discover some best practices and synthetic route considerations for delivering highly potent drugs.

> Discover the full article on Specialty Chemical Magazine <

Risk analysis

The EU regulatory guideline came into effect for all new pharmaceutical products on June 2015, and for all existing pharmaceutical products on December 2015. This guideline centres on the use of the acceptable daily exposure (ADE) and the operational considerations associated with implementation.¹

The ADE is defined as the dose of an API unlikely to cause adverse effects if an individual is exposed, by any route, at or below this dose every day over a lifetime. It is considered synonymous with the term permitted daily exposure (PDE).

The guidance states that APIs require an ADE. Hence, other substances such as starting materials, process intermediates and cleaning agents may benefit from an ADE. Problems in setting ADEs for these additional substances typically relate to toxicological data limitations precluding the ability to establish a formal ADE.

Established methodologies, such as occupational exposure limits (OELs) or bands (OEBs), can be used or adjusted as the availability of data for the API will increase throughout the drug development lifecycle. A compound is deemed to be potent in pharmaceutical terms if it has an eight-hour, time-weighted average OEL of ≤10 µg/m³ (Figure 1).

An OEB is a process intended to accurately assign chemicals into specific categories (bands), each corresponding to a range of exposure concentrations designed to protect worker health. These bands are assigned based on a chemical’s toxicological potency and the adverse health effects associated with exposure to it.²

Challenges for industrialisation

During process development studies, several technical challenges need to be addressed, due to the highly potent and potentially toxic nature of these substances. These include:

• Containment: HPAPIs must be handled in a highly controlled environment with stringent containment measures to prevent exposure to workers, the environment and the product itself
• Cross-contamination: There is a risk of cross-contamination when manufacturing HPAPIs because they are typically manufactured in the same facility as other products. This can occur during equipment cleaning, transfer operations and raw material handling
• Solubility: HPAPIs may have poor solubility, which can make it difficult to develop stable and effective formulations
• Analytical testing: Analysing HPAPIs requires specialised analytical methods and equipment that can accurately detect and quantify trace amounts of the substance. Indeed, the required specifications of potential genotoxic impurities are in the range of ppm or ppb
• Scale-up: Scaling up the manufacturing process for HPAPIs can be challenging due to the need for precise control and containment measures
• Engineering controls: Engineering controls such as air handling systems and ventilation can reduce the concentration of HPAPIs in the air. These controls can also help prevent cross-contamination and maintain product quality

Overall, manufacturing HPAPIs requires specialised equipment, expertise and strict control measures to ensure product quality and safety. Once the planning of measures has been defined and implemented, strict, rigorous and precautionary measures will need to be taken continuously in order to guarantee full control of high potency manufacturing.

Case study 1

For several years, Seqens has been manufacturing an API in the oncology area at OEB level 4. The route synthesis involves five chemical steps and the last two of these include potent intermediates. The final product is a salt derivative, isolated as a solid form.

This conducted us to implement stringent measures in order to prevent exposure at each step of the process. For designing the overall manufacturing process, a containment strategy was considered, with the objective of minimising direct or indirect handling within limited or repetitive handling, as well as the number of transfer steps.

Containment systems, especially for high potent compounds, such as isolators, glove boxes, and containment chambers are essential for handling HPAPIs safely. Based on the acceptable exposure risk, these systems prevent the release of the potent compound into the environment, protecting both workers and the surrounding areas. More generally, closed systems and automation will reduce the need for manual handling.

In order to avoid environmental contamination by HPAPIs, the potential of exposure has been evaluated. Among the key factors to be considered include the quantity of material handled and the percent active, the potential for dust and the duration of the task.

Other considerations include product sampling requirements such as size, quantity, location, container type and any limitations of the receiving lab. Workers must wear appropriate PPE, such as respirators, gloves, and protective clothing, when working with HPAPIs. PPE provides an additional layer of protection.

Among the different chemical steps, two generated solid forms. Compounds leading to dust are more difficult to contain, so process design that permits limit light and fluffy materials will help to ease the selection of contained equipment.

Overseeing as early as possible, the physical characteristics of solid forms, such as particle size, adhesion, viscosity properties, the selection of salts and the level of residual solvent content for intermediates, can help to target the right equipment. Indeed, whether intermediates or product are liquid or solid will affect the choice of containment control strategies.

Case study 2

Seqens has developed another oncology API that is classified OEB 4, due to its low-dose effect.

It is noteworthy that, based on toxicological data, there is a difference between potency and toxicity. Potency is a measure of how much of the API is required to have a therapeutic effect; toxicity is a measure of its adverse effects. A cytotoxic drug to treat a specific pathology may be extremely toxic but its potency might be low and therefore, side effects are likely.

Synthetic route design remains a case-by-case product strategy, but it appears that developing a convergent synthesis may be a way of limiting the synthesis of highly potent intermediates. In this case, by applying this chemical strategy, only the final product and the N-1 intermediate were classified as OEB 4.

Through bond disconnections and employing enabling synthetic methodologies to maximise convergence, one will not only deliver process efficiency but could also minimise the risk of developing high OEB intermediates and/or starting materials, while defining the route strategy.

Knowing that quantitative structure-activity relationship models based on chemical structure information can aid to predict hazard in the absence of experimental data, we systematically evaluate the risks based on structure’s intermediates and potential impurities. Two complementary methodologies are required: statistics-based and expert rule-based. Other in silico models can also be considered in order to fill in data gap.

For implementing the final crystallisation stage of the product, kinetic models were developed during the scale-up studies in order to determine the unique seeding time precisely. This leads to a single addition in the media and ensures crystal growth for yielding efficiently in the final product.

Containment strategies involve glovebox isolators with a rapid transit port, an appropriate transfer system and a closed or dust-tight system with closed transfer. The containment strategy that is chosen is verified with EHS personnel prior to selection of the containment equipment and technologies to be used.

The powder transfer system with integrated dosing and dispensing valves mounted inside the isolator enables the automated transfer and dosing of compounds that are contained in an external bulk container. The isolator chambers are also connected to IBCs capacity to the underside of the isolator. This system works for all powders, regardless of their characteristics.

The isolator and process equipment have been designed for wash-in-place. Each chamber can be connected to an external clean-in-place (CIP) system.

Upstream and downstream processes also contribute to containment strategy selection. For waste treatment, we privileged incineration. For cleaning procedures, it is essential to determine whether a process is dedicated or not, which cleaning materials will be used for deactivation and which cleaning methods is used, such as CIP.

Applying engineering controls in the manufacturing process reduces the risk of contamination of the manufacturing environment and is the preferred method of controlling employee exposure. Occupational hygiene monitoring techniques and methods of analysis can then be used to verify the performance of the engineering controls.

Conclusion

The manufacturing of HPAPIs requires an adequate working environment (to prevent cross contamination within multi-product assets), stringent manufacturing protocols (to comply with the established regulatory standards) and a trained workforce (to handle highly potent materials satisfactorily).

Chemical process development that optimises safety and efficiency from lab-scale to full commercial production, along with appropriate process equipment, the use of advanced cleaning and trace analytical testing methods, are all key considerations. It requires comprehensive management systems, including industrial hygienists, maintenance teams, quality assurance experts, operations teams, and engineering and automation personnel for risk prevention, such as occupational exposure or cross-contamination.

In addition, it requires an expensive infrastructure, which is often complex to engineer, install and maintain. Track record experience in manufacturing through a broad technology portfolio, excellence in process engineering and safety standards are the ultimate criteria.

For these reasons, many pharmaceutical companies rely on third party service providers to leverage their technologies for manufacturing highly potent and achieve greater operational flexibility. The essential expertise of integrated CRDOs and CMOs is believed to be capable of enabling reduction in the time-to-market a product and offer significant cost-benefits.

References:

1. E.P. Hayes, R.A. Jolly, E. Faria, E.L. Barle, J. Bercu, L. Molnar, B. Naumann, M. Olson, A. Pecquet, R. Sandhu, B.K. Shipp, R. Sussman, P. Weideman, Regulatory Toxicology & Pharmacology (2016), doi: 10.1016/j.yrtph.2016.06.001
2. The NIOSH Decision Logic for OEBs, The Synergist, American Industrial Hygiene Association, March 2016

Juliette Martin, Scientific Communication Manager at SEQENS