New Product Introduction and Technical Transfer in a High-Potency Facility

The pharmaceutical industry is increasingly focused on drug products containing highly potent active pharmaceutical ingredients (HPAPIs).

These compounds are highly effective at very low doses, but due to their toxicity, they also pose significant risks to operators. The introduction and scaling up of HPAPIs in manufacturing facilities involve complex challenges requiring specialized expertise and stringent safety protocols.

Drug products containing HPAPIs account for around 40% of authorized drug products on the market today. In 2023, the OSD market was approximately $36.5bn and is poised to register a compound annual growth rate (CAGR) of around 6% by the year 2030[1]. Within this space, the main drivers for growth include oncology, diabetes, and obesity drugs, the latter experiencing a boom due to the role of GLP-1 therapies in weight loss management. As the demand grows, a robust approach to new product introduction (NPI) and technical transfer (TT) becomes increasingly essential. The processes for handling and onboarding HPAPIs can be difficult due to the inherent risks associated with these substances, with the key challenges including categorization, risk classification, containment, process flow, and ensuring robust cleaning methods to prevent cross-contamination in a multi-product facility.

Handling HPAPIs

HPAPIs are designed to elicit a biological response at very low doses, making them highly potent but also highly toxic. Whereas during administration, the product’s highly targeted yet toxic profile ensures that fewer side effects are experienced by the patient, they pose a significant risk to CDMO production operators if they’re not handled correctly. Ensuring the safety of production workers and patients, therefore, requires meticulous control and monitoring, which begins during TT and NPI, but the lack of standardized monitoring tools and methods to ensure the safety of production environments remains a challenge.

When developing and manufacturing highly potent drug products, there should always be an OEL (occupational exposure limit) monitoring program at each stage of the process. Strict cross-contamination controls are essential, with a risk assessment performed in accordance with four principal modes:

  • Airborne;
  • Mechanical;
  • Personnel transfer;
  • Retention of product on contact surfaces.

With traditional non-potent drug products, avoiding contamination from personnel involved in the production process is, of course, critical. However, when manufacturing drug products containing HPAPIs, operating in rooms under negative pressure isn’t enough. High-grade specialized containment equipment is also required to protect employees from the API itself – and to ensure drug product integrity in a multi-product facility.

Understanding the levels of containment is important when performing TT and NPI as it helps to determine the appropriate handling of any highly potent compounds that are brought into the CDMO. Primary containment requires suitable contained equipment, running under negative pressure and effectively serving as a ‘clean room’ in its own right, with secondary containment being the facility itself. The necessary solution depends on the product potency and batch size being handled, as there may also be a need for different considerations for laboratory-scale, small-scale, and commercial-scale use. Containment must, therefore, suit the product potency, with careful consideration of heating, ventilation, and air conditioning systems (HVAC), dust extraction systems, effluent treatment, and purified water plants.

Technical transfer in the context of HPAPIs revolves around managing risk and layering safety controls. Effective risk management strategies begin with facility and utilities design, including designing the ability to segregate materials and people within the facility to achieve cross-contamination prevention from one product to another.

NPI

When managing potent materials, the introduction of new products (NPI) becomes a critical factor. A leading CDMO should have well-established protocols to evaluate all new molecules for their OEL and PDE (permitted daily exposure) before they are approved for site integration. For instance, API impact assessment procedure will delineate the molecule’s characteristics, its mechanism of action, and the necessary handling protocols to ensure operator and environmental safety at all times. Conducting toxicological and pharmacological assessments for every molecule is essential not only for safeguarding scientists and operators but also for establishing appropriate cleaning assessments and verification parameters, which are crucial to preventing cross-contamination between products. Additionally, a GMP Failure Mode and Effect Analysis (FMEA) is performed, utilizing data from safety reviews, licensing, equipment, and premises evaluations to ensure the safe processing of the product. For technical transfer projects specifically, Excipient Gap and Process Equipment Gap analyses are conducted to assess the site’s capabilities in comparison with the transfer site, identifying any gaps that need to be addressed before the project begins. A molecule will only be issued its API impact assessment for handling within the facility after all necessary reviews and evaluations have been completed

Cleaning Validation

Cleaning Validation (CV) plays a crucial role in the TT process by ensuring that cleaning methods are effectively transferred and adapted to the new manufacturing environment. During TT, the established cleaning procedures from the original site or development stage must be validated in the new facility to confirm their effectiveness in removing product residues, cleaning agents, and potential contaminants. This involves not only replicating the cleaning methods but also tailoring them to the specific equipment, materials, and operational conditions of the receiving site. CV provides immediate assurance that these processes work correctly from the outset, while validation ensures long-term consistency and regulatory compliance.

Successful TT and NPI hinge on this robust validation, as it safeguards against cross-contamination and ensures that new highly potent products can be manufactured safely without compromising the quality of other products in the facility. Each new molecule entering a multi-product facility adds further complexity, requiring a robust cleaning philosophy. Starting at NPI, the process should include methods to test and detect detergents and drug substances with swab and rinse samples and any additional cleaning that may be required.

Equipment capabilities should be constantly reviewed, with oversight of all cleaning verification and validation, resulting in a science- and risk-based approach to the prevention of cross-contamination. Employees should be provided with general GMP personal protective equipment (PPE), such as laboratory coats/suits and footwear, hairnets, eyewear, face masks, and gloves, whereas powered air-purifying respirators (PAPR) should be considered as part of a breach control and system failure program. However, PPE should never be considered as part of the primary protection barrier during potency assessment or normal operations. Operator safety is of critical importance, resulting in a new way of thinking to develop drug products in a specialty-contained facility with no open process equipment.

Emerging Challenges and Opportunities

The future of HPAPI manufacturing presents several opportunities and challenges, which are fundamental considerations for TT and NPI. One significant area of interest is the potential role of artificial intelligence (AI) in enhancing risk assessments, toxicology evaluations, and process validation.

AI could potentially streamline data gathering, protocol writing, and validation report generation, with its predictive capabilities enabling more accurate modeling of toxicological impacts and optimization of risk management strategies, which could enhance safety profiles and operational efficiency. Additionally, the rising demand for customized therapeutics presents the need for adaptable manufacturing systems capable of efficiently managing various HPAPIs. This shift towards personalized medicine provides CDMOs the chance to stand out by developing quick prototyping and small-scale production capacities essential for niche, high-potent OSD products. Therefore, despite the demanding nature of the industry, there lies vast potential for innovation and expansion in specialized CDMO services, propelled by advancements in AI and digital technologies.

Regulatory discrepancies across different regions pose further challenges for CDMOs operating in the highly potent space. Navigating differing regulatory requirements can complicate compliance for CDMOs that operate on a global scale. For instance, the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA) might have varying requirements for clinical trials, manufacturing processes, or even the submission of regulatory documentation, which requires CDMOs to adapt their strategies for each market. Such discrepancies may lead to increased cost and time to market, and developing products that meet the specific regulations of multiple jurisdictions can limit the ability to use a one-size-fits-all approach, potentially restricting the ability to standardize processes and leverage economies of scale.

Conclusion

As the pharmaceutical industry continues to advance in high potent drug product manufacturing, companies must adopt rigorous scientific standards and best practices to ensure safety and efficacy. Embracing innovative technologies and maintaining stringent risk management protocols will be key to successfully navigating the challenges of HPAPI production. The ultimate goal is to deliver ground-breaking therapies while safeguarding the health of workers and patients. The successful NPI and TT of new products containing HPAPIs are pivotal to meeting the growing demand for advanced therapeutics. The complexity and risks associated with HPAPIs necessitate a meticulous approach to facility design, risk management, and process validation. As the pharmaceutical industry continues to evolve, integrating cutting-edge technologies like artificial intelligence and adapting to regulatory challenges will be crucial for CDMOs. By maintaining stringent safety protocols, embracing innovative solutions, and navigating regulatory landscapes effectively, CDMOs can not only safeguard operator and product integrity but also leverage emerging opportunities for growth and advancement in the high-potency pharmaceutical sector.

References

  1. https://www.contractpharma.com/issues/ 2024-04-01/view_features/industry-expertsweigh-in-on-oral-solid-dosage/

New Product Introduction & Technical Transfer in a High-Potency Facility by David O’Connell, Director of Scientific Affairs at PCI Pharma Services | As seen in International Pharmaceutical Industry Magazine – Autumn 2024


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