Breaking Down Barriers to Achieve HPAPI Manufacturing Success

Catherine Wilkes, Executive Director of Environmental, Health and Safety at Quotient Sciences explores how containment protocols shift when dealing with HPAPIs to meet the required safety standards.

Use of highly potent active pharmaceutical ingredients (HPAPIs) is on the rise in the pharmaceutical industry. The market share of these was valued at $26.85 billion in 2023 and is forecast to grow to reach $41.83 billion by 2028. The ability of HPAPIs to effectively target and prompt a pharmacological response at low concentrations makes them promising drug candidates, especially those for oncology and orphan and rare disease indications.

As interest in HPAPIs continues to evolve, challenges surrounding their safe handling arise. These substances pose a significant risk to the operator throughout their use, and strict safety measures are required to minimise the risk of exposure. Operator safety has always been a priority in the industry, but as substances become increasingly potent, more stringent, and robust safety control measures are required. These controls must also be designed to meet the regulatory expectations of the good manufacturing practice (GMP) guidelines that define the required standards for drug manufacture for ensuring patient safety.

Determining Potency of an API

Prior to identifying the safety control measures required for handling an active pharmaceutical ingredient (API), the potency must be evaluated.  To do this, properties such as pharmacological activity, mutagenicity, carcinogenicity and reproductive toxicity need to be taken into consideration.

A good understanding of the toxicological characteristics of an API, allows occupational exposure limits (OEL) and acceptable workplace exposure limits (AWEL) to be calculated. OELs are regulatory values which indicate the level of a chemical substance in the air that an employee could be safely exposed to in the workplace. With these limits known, safety controls can be designed to ensure these limits are not exceeded during handling i.e., minimising the risk to operators to exposure levels which would not result in adverse effects to them.  

However, this can be challenging for drugs in the early stages of development, where little of this toxicological data is available and meaningful OELs and AWELs cannot be calculated. This is where occupational exposure banding (OEB) systems are helpful. There are numerous OEB systems in use which have been designed to help categorise API with limited data available, based on any known toxicological properties and predicted potency.

One OEB system is the Performance-Based Level of Exposure Classification or Control (PBLEC) system.  In this system API are assigned to one of five categories:

Once assigned to a PBLEC category, appropriate levels of handling controls are put in place to control risk of operator exposure and facility contamination. The controls should be designed to reduce operator exposure to the bottom end of the corresponding OEL range.

When is an API Classified as Highly Potent?

Defining whether an API is classified as highly potent is complex, especially when handling novel compounds with limited data. Extensive analysis and characterisation are required to better understand these API to define where they fall in terms of potency. At Quotient Sciences, API which either default into (due to limited data) or where a calculated OEL places them into the PBLEC 4 or PBLEC 5 categories, are considered highly potent for handling.  When considering the corresponding OELs (<10µg/m3), it is at these low OEL levels where powder particles in the air are invisible to the naked eye which makes safe handling all the more challenging.

Overcoming HPAPI Containment Challenges

Once an HPAPI has been classified, the control measures employed for safe handling must be sufficient to control operator exposure to below the calculated OEL or the bottom end of the OEB band. Effective engineering controls designed to contain substances at the point of use are essential for primary protection of operators, supported by further facility/administrative controls and personal protective equipment (PPE) as secondary and tertiary controls, respectively. 

Primary containment strategies (e.g. closed transfer systems, flexible / hard shell isolators, ventilated balance enclosures etc.) will differ depending on the unit processes involved and the scale of handling.  For example, the controls required for manipulating solutions will be different to those required for manipulating solids in the development and manufacturing of tablets.  Similarly, the controls required to manage analytical scale work will be different to those required at the development and manufacturing scale.

The PBLEC system is supported by matrices which define all the controls required to safely conduct tasks for each PBLEC category at each scale. To further assist with this, each unit process is assigned a risk category (low, medium, or high) with respect to the potential of operator exposure to the API.

This must all be backed up by a robust and comprehensive training program for operators, which should include regular refresher training. 

In addition, control performance target (CPT) testing is required to quantitatively assess and evaluate the effectiveness of the containment strategies in place.  The results from this testing enables us to understand the limitations of a control, support risk assessments and guide discussions as part of a continuous improvement safety program.  

With these systems in place, the risks to the operator from handling these substances is significantly minimised, as well as the risks associated with cross-contamination within a GMP facility.  

Guiding HPAPI Manufacture

Navigating the HPAPI space to ensure appropriate safety controls are in place is essential.

Partnering with a specialist contract development and manufacturing organisation (CDMO) can help to overcome the challenges of HPAPI containment. With access to specialised knowledge and guidance on determining API potency, classification, and how to establish safe working practices, meeting safety regulations is assured. Outsourcing to a CDMO with the appropriate facilities and practices in place can help to meet these requirements cost-effectively, assuring safety measures are adhered to, and the production of high-quality HPAPIs at speed.

At Quotient Sciences, we have over thirty years of experience in developing and manufacturing small molecule HPAPIs. Our facilities in the US and UK are configured with the necessary controls required for the handling and processing of these types of molecules and we offer our customers a complete, global end-to-end development solution from early phase drug substance and formulation screening through clinical and commercial manufacturing.  We are able to handle PBLEC 1 through to 5 depending on the type of compound, dosage form, manufacturing process and batch size required and consider ourselves to be a trusted partner when it comes to supporting our customer’s highly potent molecules.