Strategies For Successful Manufacturing Of Highly Potent Oral Solids

Oral drug products that contain highly potent active pharmaceutical ingredients (HPAPIs) continue to be a driving force in the global pharmaceutical market. Here, industry experts discuss some of the challenges in HPAPI drug product manufacturing and the key issues sponsors should consider when partnering with a contract development and manufacturing organization (CDMO).

Q: Can you put the growing challenge of solubility and bioavailability into the context of HPAPI development today?

A: In recent years, due to their significant therapeutic potential, there has been a sharp increase in the proportion of HPAPIs in the drug development pipeline. HPAPIs are being increasingly utilized in pharmaceutical development to target specific diseases and improve patient outcomes.

Many HPAPIs have inherently poor solubility, which can present challenges in formulating them into drug products. Poorly soluble compounds often have inadequate absorption rates and low bioavailability when administered orally or through other routes.

As HPAPIs are increasingly prevalent in the development pipeline, innovators are turning to enabling technologies, such as lipid-based formulation, micronization, spray drying and hot melt extrusion to improve the bioavailability and solubility of these challenging compounds.

Solubility and bioavailability enhancement technologies could potentially aid in downstream containment necessary for potent compounds. The concentration of the HPAPI in the intermediate and bulk density are important considerations for downstream potent handling. Potent handling may significantly vary depending on the enabling technology employed. Some of these technologies, such as micronized HPAPI and spray dried dispersion, would also require densification.

Q: What are some of the key challenges in manufacturing highly potent oral solids?

A: Manufacturing highly potent oral solids presents unique challenges that require expertise, precision, and adherence to stringent regulations. Broadly, these can be divided into three categories – maintaining process containment, ensuring operator safety, and preventing cross-contamination.

During dug product development, it is important to ensure that the most appropriate technology is employed rather than the technology that is more easily available. Deciding the level of containment depends on a combination of API hazard, technology employed and unit operations.

As these substances possess high potency, often in microgram or even nanogram levels, they therefore require specialized facilities, equipment, and handling procedures to minimize the risk of exposure to workers and maintain product integrity.

CDMOs, such as Catalent, can provide specialized infrastructure, scientific expertise, risk mitigation strategies, regulatory services, and scalable manufacturing capabilities, to address the challenges of manufacturing oral potent drugs, ultimately supporting the successful delivery of safe and effective medications to patients.

Further, it is of utmost importance to align with containment and equipment manufacturers who can provide the most flexibility in terms of batch size while at the same time providing confidence of containment performance, within their design. With many designs consumable containment supplies are required for each product, so it is essential that the equipment vendor stocks these custom items.

Q: Where does particle sizing fit in when dealing with HPAPIs?

A: Micronization is an important tool in drug development, its primary advantage being that it is cost effective and easily scalable from early development through commercial manufacturing. Micronization leads to an increase in the surface area of drug molecules, enabling a faster dissolution rate while improving the bioavailability of poorly soluble compounds.

Typically, HPAPIs will need to be weighed in isolators in addition to closed manufacturing processes during micronization to ensure operator safety and prevent cross-contamination. Densification technology would be typically required for micronized HPAPIs to be further processed in a variety of dosage forms. Due to the reduced particle size and low bulk density, significant downstream potent handling of micronized HPAPIs is required.

Catalent employs custom-designed isolators that can house an Airjet Micronizer flexibly, while guaranteeing protection from exposure to its operators. As the use of HPAPIs becomes more prevalent in pharmaceutical development, so too does the manufacturing expertise needed to safely handle and micronize these challenging compounds.

Q: How do you ensure proper containment and handling of potent substances during manufacturing to protect the health and safety of workers?

A: By implementing robust measures, pharmaceutical manufacturers can ensure the proper containment and handling of potent substances, safeguarding the health and safety of their workforce. The design of manufacturing facilities plays a crucial role in containing potent substances and dedicated areas equipped with isolators, glove boxes, or containment booths help prevent the release of potent substances into the environment. Additionally, the provision of Personal Protective Equipment (PPE) is essential to protect workers from exposure to potent substances as well as comprehensive Standard Operating Procedures (SOPs) to ensure that workers are equipped with the necessary knowledge and guidelines to handle potent substances safely. These measures mitigate risks associated with potent substances and foster a culture of safety, enabling manufacturers to produce life-changing medications while prioritizing the well-being of their workforce.

Not only is it mandatory that the performance capability of equipment containment be measured during a standard cycle time (inclusive of set up, running, breakdown and cleaning) through Industrial Hygiene monitoring, but it is also important to continuously monitor the same containment over time, in a rigorous preventative maintenance and performance qualification program.

Q: What are the key considerations for sponsors when outsourcing their HPAPI to a CDMO?

A: CDMOs offer specialized expertise, infrastructure, and resources needed to handle the complexities associated with HPAPI development and manufacturing. When selecting a CDMO partner for outsourcing HPAPI production, sponsors consider several critical factors to ensure successful collaboration and achieve their project goals. Firstly, a strong quality system is paramount, and innovators should prioritize CDMOs with robust quality systems that comply with stringent regulatory guidelines, ensuring product integrity and patient safety. Secondly, experience plays a crucial role as experienced CDMOs with expertise in handling HPAPIs can optimize manufacturing processes, implement necessary safety protocols, and provide guidance on regulatory requirements throughout the project. Lastly, sufficient scale and capacity are important considerations. Innovators should choose CDMOs with dedicated manufacturing facilities, specialized containment systems, and efficient supply chain management with the flexibility to adjust production volumes as needed. By considering these factors, sponsors can partner with a trusted CDMO that meets their requirements for quality, experience, and capacity. This ensures a smooth collaboration in outsourcing HPAPI production, leading to successful outcomes in the development and manufacturing of these compounds.