The containment and handling precautions that are required when manufacturing active pharmaceutical ingredients (APIs) and their intermediates vary according to the hazards posed by the individual materials. Clearly, those that pose greater risk to human health must be handled much more cautiously than those that are less likely to cause problems. A current trend in the small molecule API market is the growth of the oncology pipeline, which is at about twice that of other indications, and various market data suggest as being between 30 and 40 percent of preclinical and clinical small molecules. Because of the clinical data available about developmental compounds, many oncology drugs are classed as “highly potent” and although by no means is this the only therapeutic class of compounds that are classified as such, these highly potent molecules require careful handling and specific containment facilities.

Handling and assessment of highly potent materials
Handling chemicals considered hazardous is more time-consuming and expensive than working with those that are not, and for contract development and manufacturing organizations (CDMOs),  simply treating every project as if it were highly dangerous is not appropriate. Instead, to ensure projects can be managed cost-effectively, a careful risk assessment should be carried out before any API manufacturing project is embarked upon.

The risk assessment weighs all of the information that is available, both about the API itself, and any raw materials or intermediates that are used in its manufacture, and this is particularly important for highly potent APIs (HPAPIs). Where there is a paucity of information at the outset for development compounds and scale-up projects, the risk assessment will take on board whatever data are available, and use it to determine an exposure limit that is likely to be safe for the operators, and the containment that will be required. However, the risk of being overly conservative and imposing far more controls than are truly needed can cause costs to escalate, so needs to be avoided whenever possible.

Different companies use their own classification systems in which the numbers of compound classes and their criteria vary, and at Cambrex we use a five category exposure control band (ECB) system to determine the handling requirements. ECB 1 includes chemicals that have a relatively high occupational exposure limit above 100 µg/m³. In ECB 2, the products will have exposure ranges at a level of 10–100 µg/m³. Containment will be required for these materials, but local ventilation will typically suffice, and open handling will remain acceptable. 

Those compounds that fall into ECB 3 and ECB 4 have substantially higher risk levels, and HPAPIs will always be placed in one of these categories. For ECB3, where the allowable exposure limit is 1–10 µg/m³, containment with no open handling will be necessary. If it falls into ECB 4, where the allowable exposure limit is 0.1-1µg/m³, full containment in an isolator will be essential.  Although very small quantities of ECB 3 and ECB 4 may be handled outside of containment in certain situations.

The greatest level of risk is posed by those chemicals that we place in ECB 4+ with allowable exposure limits at 0.01-0.1 µg/m³. No open handling whatsoever of such materials is permitted, even if they are in solution, and they must remain within barrier isolation at all times. This group will include products such as API warheads for antibody–drug conjugates.

There is also an additional sub-category. ECB 2* will include any compound that otherwise sits in ECB 1 or ECB 2 because of its toxicity levels, but which has a special hazard associated with it. It might be a mutagen, carcinogen, sensitizer, or a chemical that poses developmental or reproductive risks. It might also be prone to dermal absorption, pose an inhalation hazard, or have an adrenergic effect. In these cases, additional training, and physical or administrative controls, will be required.

The project safety dossier
The risk assessment is used to inform the creation of a project safety dossier (PSD) for each product. This will include every chemical substance involved in the process, other than common reagents, catalysts and solvents. It will provide the chemist or operator with occupational exposure bands (OEBs), and the rationale behind their determination. It is important to include the reasoning behind the classification because it will give workers an insight into the reasoning behind the handling requirements, and therefore increase buy-in within the whole project team.

Importantly, the PSD will also include presumptive or demonstrated destruction procedures for any ECB 3, ECB 4, or ECB 4+ chemicals. Presumptive procedures are acceptable for development activities, while demonstrated procedures will be required before the project moves into pilot and commercial manufacturing. 

The dossier will identify special hazards and especially hazardous reagents. Administrative controls and personal protective equipment (PPE) will be provided, along with ECB procedures.

The PSD uses a color-coded procedure on the front page for ease of identification, and this front page will be affixed to the door of the lab or suite where the product is being handled. In a multi-purpose facility where projects are undertaken for multiple different customers, this color-coding highlights hazards without disclosing any confidential client or chemical structure information.

The second part of the dossier is a single page that highlights the top-line hazard information, including chemical-specific information. Part 3 includes more detailed information, such as chemical structures of all raw materials, intermediates and final products, along with their OEB range, and ECB control procedures.

In part 4, the detailed information from the chemical-by-chemical risk assessment is laid out. This is where we feel Cambrex differentiates itself, including the justification for each chemical’s OEB rating and ECB strategy in a fashion that is easily understood by all coworkers all the way to the operator level to achieve buy-in. Coworkers end up with a high level of respect for the chemicals they are handling and the controls/procedures to keep them safe. Finally, in part 5, there will be a list of references.

For high ECB category projects, employee training takes place as the scale of manufacture increases to ensure operators and chemists are aware of specific risks prior to working with the materials. It is valuable to involve toxicology specialists in training sessions to allow discussions to take place and for affected employees to raise any queries, or clarify any specific protocols.

Building and designing a containment facility
For CDMOs looking to design a multipurpose facility, there are a number of challenges in the process. Cambrex has just completed the building of a HPAPI manufacturing facility at its site in Charles City, Iowa. Reviewing the project highlights the following considerations were taken into account in the design and construction:

1. Cross functional design team
The project design team should be set up to ensure that existing knowledge about HPAPIs of both internal experts and external partners are leveraged. These should include project engineers, maintenance, equipment vendors, experienced operators, and representatives from environmental health and safety (EH&S) and operations functions, as well as engineering design specialists, and the general building contractor.

The design team can then develop the equipment sizing, the layout of the facility and the equipment within it, as well as the unit operation capability, based on both prior API experience and customer input. Engineering partners can assist in ensuring that the building codes and regulatory requirements – which are constantly evolving – are met, and can offer up-to-date information and experience about these.

2. Future needs
For a CDMO, a facility is built on specifications and matches the needs of current demands, with no knowledge of what will be made within it in coming years. Substantial assumptions about the future capability needs have to be made, informed by past experience. Projections about previous requirements and demands against actual experience can ensure that a facility does not become obsolete or in need of further expansion as soon as it is completed.

3. Scale and Containment Capabilities
Understanding the market influences the design criteria for a facility.  Considering the target batch size for materials being manufactured is important as this affects the level of containment that is economic to achieve. To have appropriate containment below an OEL of 0.1 µg/m³ becomes very difficult and expensive to achieve, particularly for the mid-scale to large batch sizes (100-300 kg). Few batches this large are likely to be so potent that they are below that OEL, because such minuscule doses are required that no more than a few kg may ever need to be made.

As with any plant design, the target batch size dictates the equipment size such as filters for isolation steps. Reactor choice is influenced by the types of chemistries being performed, and the concentrations needed – so it may be that various sizes and material of construction (Glass Lined / Hastelloy) are considered.

4. Isolator technology
In terms of the isolator technology, there are advantages and disadvantages for both rigid and flexible alternatives. With a fixed or rigid isolator, the capital cost will be high, there will be a long lead time, and it will be difficult to modify for different operations, but the operating costs could be lower and it will generally be more robust and easier for the operators to manipulate. In contrast, flexible containment or isolator alternatives will have a lower initial cost and shorter lead time, but operating costs might be higher and more delicate operator technique will be necessary. Furthermore, no modifications are possible; any changes must be made by purchasing a different item from the vendor.

It may be appropriate to have a mixed approach, depending on the needs of the facility and assumptions about volumes being handled. If the end product is likely to be low OEL and high volume, a fixed isolator may be appropriate for final product packaging and sampling, with a flexible approach for material charging that can handle a wide variety of OELs, volumes, reactor destinations and methods.

There are more drugs and therapies being developed and coming to the market that are classified as “highly potent,” as well as a number of commercial products reaching patent expiry. For CDMOs wishing to capitalize on this market opportunity, having appropriate assets to manufacture the molecules effectively and efficiently is crucial, as is the level of expertise to handle the projects safely.