OUTSOURCING PHARMA DEVELOPMENT - Harnessing CDMOs for Innovation & Efficiency

INTRODUCTION

The global pharmaceutical industry is evolving rapidly with continuous new therapeutic modalities and manufacturing tech­nologies in development. Progress has transformed patient out­comes by facilitating access to much needed treatment options across diverse therapeutic areas. This progress brings opportu­nities and challenges for developers.

Most notably, increased demand for innovative pharmaceu­ticals has required focus on maximizing drug development effi­ciency and cost-effectiveness. Developers must also navigate the ever-evolving regulatory landscape and ensure consistent manu­facturing of safe, efficacious products at the scale required to meet global patient needs.

Contract development and manufacturing organizations (CDMOs) have become an integral part of the pharmaceutical industry by supporting developers to manage the growing intri­cacies of process development throughout the drug lifecycle.¹ CDMOs offer specialized services and technologies to solve the challenges of complex development and manufacturing projects from early drug development stages through to scale up. They excel in facilitating efficient and cost-effective project delivery, sup­plying integrated end-to-end capabilities and providing dedicated expertise, which all reduce time to market and ensure continuous high quality.

INCREASING ACTIVE PHARMACEUTICAL INGREDIENT (API) COMPLEXITY

The demand for novel pharmaceuticals has grown across the industry to reach more medical indications with high specificity and efficacy. While this delivers significant benefits for patients, it presents a new challenge for developers – increased API complexity.

For example, more complex API molecules with higher mo­lecular weights and more chiral centers are increasingly popular drug candidates due to their improved stereoselectivity, enhanced target specificity, and increased drug activity. However, these same molecular characteristics can tend toward poor solubility and bioavailability. Challenges are further compounded by the continued preference for solid dose forms which require devel­opers to overcome inherently low absorption of these complex APIs within the gastrointestinal tract.²

Alongside chemically complex APIs, highly potent APIs (HPA­PIs) are also growing, especially in the development of antibody-drug conjugates (ADCs). ADCs consist of a monoclonal antibody attached to a cytotoxic HPAPI via a chemical linker. The antibody delivery mechanism targets specific cancer cells for drug release, which helps to increase efficacy and reduce the side effects of conventional chemotherapy. This therapeutic advancement in­volves careful management of HPAPIs, as they present additional safety and regulatory challenges compared to traditional APIs due to their high toxicity.³

These trends have led to a significant paradigm shift in the development process. To mitigate the challenges associated with more complex and potent APIs, developers are looking to utilize advanced delivery systems and state-of-the-art engineering tech­niques. Niche, complex drug substances and forms require spe­cialized knowledge, equipment, and technologies that would require large investments for many developers to add to their core drug discovery and product management foci.

OVERCOMING API CHALLENGES WITH A CDMO

Many challenges can arise when de­veloping and formulating therapeutics with complex APIs. CDMOs’ specific capabili­ties and expertise help developers success­fully overcome formulation difficulties and may be demonstrated by exploring three challenge areas and their solutions through CDMO expertise and capabilities: (1) improved physiochemical properties through solid form selection, (2) increased stability, solubility, and bioavailability through particle engineering, and (3) safe and effective handling of potent com­pounds through established expertise and infrastructure.

Solid Form Selection
One of the primary challenges during the early stages of API development is identifying the optimal crystalline structure of the drug compound. Different crys­talline/polymorphic forms often exhibit dif­ferent physiochemical properties. Solid form selection represents a key opportunity to optimize drug performance.

The importance of crystalline form is underscored by the regulatory requirement for polymorph assessment to validate the final drug product stability, efficacy, and safety for patients. Notably, solid form se­lection and control reduces off-target ac­tivity caused by interactions of different polymorphic forms of the drug compound within the body. The polymorphic form also influences the yield and purity of the active drug substance as well as formula­tion options for the final drug product. The latter is especially vital to optimize phar­macokinetic properties such as absorption.⁴

CDMOs can provide a wide range of services to help accelerate solid form se­lection, ensure consistent manufacture of the optimal form, and maintain regulatory compliance. This includes offering special­ized skills and state-of-the-art equipment to leverage advanced screening tech­niques such as single-crystal x-ray diffrac­tion (SCXRD). Specific chiral screening services can also be provided to support developers working with chiral APIs and intermediates.

Many CDMOs also offer additional testing capabilities to help developers identify further opportunities for enhancing physical properties of their compound. Using techniques such as salt and co-crys­tal screening, CDMOs can provide tai­lored recommendations to help improve solubility, bioavailability, stability, and pu­rity, which supports the development of an optimized drug product.

Particle Engineering
Optimizing the physical properties of complex drug compounds may also chal­lenge API development. By enabling the formulation of compounds into forms with more favorable shapes, sizes, and surface areas, particle engineering can enhance solubility, stability, and bioavailability.

It is key to optimize the physical prop­erties of complex compounds as early as possible in the development process. Pro­gressing compounds with poor solubility, instability, or low bioavailability can result in considerable additional work to over­come these deficiencies. If physical prop­erties are optimized later in the development process, the costs can in­crease and ultimately delay commercial­ization.⁵ Taking a proactive approach has become a priority for developers. How­ever, the knowledge and technical capa­bilities required can present a high barrier to entry.

For instance, creating an amorphous solid dispersion (ASD) using a polymer matrix is a popular approach to increase solubility and bioavailability. ASD requires consideration of many interacting vari­ables, which requires extensive experience and knowledge for its successful use. De­velopers need to ensure that the overall physical stability of the drug is not nega­tively impacted. This involves having the expertise to identify, screen, and validate a suitable polymer that delivers the re­quired drug properties and scales to an optimized large-scale production process.⁶ Likewise, for developers looking to reduce the physical particle size of their APIs, iden­tifying the optimal particle size can be dif­ficult without previous experience within this area.

In addition to characteristic selection, ascertaining the best manufacturing ap­proach to achieve the desired physical and functional properties of the drug com­pound can present difficulties. Spray dry­ing and hot melt extrusion have emerged as effective options for ASD development.⁷ Similarly, for developers looking to achieve sub-micron particle sizes, promising op­tions include state-of-the-art approaches like nano-milling and high-pressure ho­mogenization.⁸ Each of these techniques require specialized equipment. Therefore, without considerable investment, develop­ers can struggle to independently imple­ment these technologies in their development and manufacturing work­flows.

Working with a CDMO with particle engineering experience can help develop­ers find the optimal solution for their API’s physical properties. As a long-term man­ufacturing partner, a CDMO can enable developers to reap the benefits of ad­vanced particle engineering techniques without the need for costly additional equipment or time-consuming in-house training.

Handling Potent Ingredients
For developers working in the field of personalized medicine, ADCs offer consid­erable opportunities to innovate new, tar­geted therapies for a range of different types of cancer, but working with ADCs and their HPAPI constituents requires the utmost care and specific experience with relevant regulations, analytical techniques, separations, and complex chemistry.

HPAPIs need to be carefully managed throughout the entire process lifecycle of ADC manufacturing to ensure safety for manufacturing staff and patients.⁹ This in­cludes building specialized containment infrastructure that often requires significant investment. Additionally, regulatory bodies are increasingly focused on ADC manu­facturing process optimization to ensure consistent quality.¹⁰ As a result, working with a CDMO that is equipped to safely handle HPAPIs and manufacture consistent ADCs can help developers to reduce over­all costs and ensure regulatory compli­ance.

ADCs are multi-component therapeu­tics, and their development can present unique complications. A complex part of an ADC’s design is the linker molecule, which must maintain stability during preparation, storage, and systemic circu­lation. Then, it must release the HPAPI at the specific target site within the body. In addition, accurately characterizing these therapeutics is difficult, because it requires combining several analytical, biochemical, and biophysical techniques.¹¹ Within this area, chromatography expertise and ca­pacity are especially valuable to support developers in accurate compound charac­terization and effective ADC purification.

CHOOSING A CDMO TO SUPPORT SUCCESS

A strategic partnership with a trusted CDMO can provide many benefits rang­ing from experts’ insights to state-of-the-art equipment. However, there are several considerations that developers should evaluate prior to engaging with a CDMO to maximize their partnership.

Developers must carefully assess the need for a CDMO partner before com­mencing their project. Early involvement of a CDMO ensures valuable partnered input into the planned development approach. Leveraging a CDMO’s expertise at an early stage can significantly reduce the risk of unforeseen challenges and associated costly delays arising down the line.

Developers need to choose a CDMO that is capable and adept at the unique re­quirements of their project. The CDMO should have specific expertise and propri­etary technology to support particularly complex areas of development such as solid form selection, particle engineering, and highly potent API handling. To maxi­mize confidence, developers should search for CDMOs with capabilities in these areas and a proven track record of successful project delivery and quality.

In addition to the CDMO’s develop­ment capabilities, developers should eval­uate its technology transfer approach to ensure streamlined project delivery. Knowl­edge and technologies need to be shared at multiple phases of the development process and throughout the product lifecy­cle. Due to the complexity of pharmaceu­tical manufacturing, close collaboration between process engineering and devel­opment, analytical chemistry, quality, and production teams is essential at every stage. Choosing a CDMO with a well-de­fined technology transfer approach that is managed by an experienced, multi-disci­plinary team is essential to ensure efficient scale-up and support long-term success.

The capacity and regional capabilities of the prospective CDMO should also be considered. Working with a CDMO that has a network of sites offering specific ca­pabilities with established technology transfer processes between them, ensures developers can access specialized support in line with their needs. Moreover, with multiple sites, developers can be confident that the CDMO has the bandwidth to pro­vide dedicated and responsive service at every stage of the development and man­ufacturing process.

While evaluating a CDMO’s experi­ence and capabilities should be a priority, the importance of aligned working prac­tices should not be overlooked. For exam­ple, developers should ensure that the CDMO can provide an integrated project management approach. This approach facilitates the CDMO to work seamlessly with the developer’s internal team. Evi­dence of the CDMO’s commitment to col­laboration, transparency, and clear communication can reassure developers that they are working towards a shared goal with a dependable partner.

MANAGING COMPLEXITY WITH CONFIDENCE: THE NEED FOR OUTSOURCING

As innovation continues across the pharmaceutical industry, developers must keep pace with new technologies, emerg­ing research, and evolving regulations. However, with many companies managing short timelines, tight budgets, and limited internal bandwidth, this can be difficult.

CDMOs offer specialized expertise and advanced technical capabilities to support developers on the growing com­plexities of drug development. Developers that partner with a CDMO successfully and cost-effectively navigate the challenges of innovative pharmaceuticals development. Moreover, with CDMOs increasingly offer­ing agile and specialized services, devel­opers can receive targeted, expert support to help overcome specific development challenges, from particle engineering to HPAPI handling.

Ultimately, by partnering with a trusted CDMO, developers can confidently embrace innovation, overcome develop­ment challenges, and accelerate commer­cialization to drive the delivery of life-saving treatments to the patients who need them.

REFERENCES

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Dr. Rohtash Kumar joined Veranova as SVP, Development Operations and Chief Technical Officer in May 2023. He brings deep experience in the CDMO industry, leading technical teams engaged in the discovery and development of new products for use in clinical trials, as well as successfully running programs for commercial supply of APIs in the branded market. Prior to joining Veranova, he served as Site Head at Bachem Americas Inc., where he worked for 8 years holding different positions including VP of API Manufacturing. Prior to Bachem, he worked with Sigma-Aldrich as Manager of R&D and Manufacturing. In the early part of his career, Rohtash worked at Toronto Research Chemicals as a Group Leader, and at Apotex as Senior Research Scientist. He earned his PhD in Organic Chemistry from Delhi University, and an MBA – Production Management from Chaudhary Charan Singh University. He completed post-doctoral work at the University of Alberta, and at the National Research Council of Canada.