A CDMO Perspective on Developing Biological Modalities from Discovery to Commercialization

Jim Huang, PhD and Shaukat Ali, PhD- Ascendia Pharma

Introduction

Biological modalities with poor solubility and bioavailability are presenting challenges to drug manufacturers to move them from discovery to manufacturing. Drug sponsors are looking to contract manufacturers to help them overcome this problem as many offer tailored and customized approaches to expedite the launch and commercialization of these drug molecules.¹ As the cost of developing new chemical entities (NCEs) keeps rising, reaching over $2B for a single molecule and taking over 10 years with fear of a patent cliff, drug manufacturers are also weighing options for outsourcing the formulation development to get better return on investment (ROI).² Together with the rising cost and risks on development, drug manufacturers are exploring all avenues to reduce time and cost to expedite the commercialization and marketing of drug molecules, while focusing on prioritizing projects and investment on their most innovative and blockbuster products. This trend is contributing to a seismic shift in the industry that is fueling potential growth in the contract drug manufacturing organization (CDMO) industry.³

Weighing Options for a CDMO

As costs continues to rise in development of new molecules, finding a CDMO partner that “fits for all” with the expectation of saving time and resources, and meeting project deadlines, continues to be challenging. For instance, molecules with poor solubility and bioavailability, weighing options on employing an appropriate formulation technology and finding a right partner with technical know-how and expertise, remain an impediment. For example, developing a drug in liquid or solid oral, and/or in parenteral form, requires a careful design of experiments (DOEs) for an optimal formulation to meet the critical quality attributes and the clinical end points to satisfy the FDA's guidelines. This creates the opportunities for CDMOs with enabling technical capabilities in developing multiple dosage forms for different modalities with their proprietary formulation and development capabilities. In those cases, early phase development, as a feasibility to proof of concept (POC) followed by evaluation for scale-up, bear risks but is highly plausible and rewarding with a CDMO partner offering the right expertise in formulation development, analytical services and processing capabilities. With continued interest in the development of biologics, identifying one CDMO from early stage to scale-up and manufacturing could also require full assessment of their internal technical, analytical and cGMP manufacturing capabilities.

CDMO’s Capabilities and Relationship with Clients

Technological challenges stemming from physico-chemical properties of new molecules coupled with limited resources within the contract manufacturers, and/or a reliable supply chain, can lead to additional delays in development and manufacturing of clinical supplies, initiation of clinical trials, and hence, the approval and marketing of new drug candidates. Thus, adapting the strategies with a first tier and second tier approach to CDMOs based on their capabilities and expertise, should be a prime consideration for building trust and partnership while aiming to mitigate the timeline and meet the developmental processing and cost.⁴ For example, building trust and a better relationship based on their offerings will lead to further business potential and expedite the drugs faster to market, and hence, ultimately lead to multiple business opportunities in the future. With both the R&D expertise, and cGMP manufacturing capabilities suited for a particular dosage form, those CDMOs will help guide the drug manufacturer to make the right decision. It is equally important to continue building the relationship in earnest with CDMOs to define tasks and deliverables to achieve the long-term goals, in general.

Sterilization and Aseptic Processing

Sterilization is a key step in the manufacturing process to ensure that pharmaceuticals and biopharmaceuticals are safe to use.⁵ The key parameters considered during sterilization are temperature, time, and pressure to minimize the bioburden assay. Other parameters are holding time between vial/bag filling and sterilization. The hold time depends upon the media used; for instance, saline for injection could be held longer than dextrose in water due to the possibility of microbial growth and increasing bioburden. Terminal sterilization of drug products is often carried out at 121°C for 15 minutes but if the API is sensitive to higher temperature, the moist heat sterilization can be conducted at lower temperature (ca. 115°C) for a longer duration or opted for sterile filtration, if required.

Aseptic processing is a process that involves careful and well controlled engineering for the equipment used, facility, and assemblies including the filling stations and chambers, and closures of the vials or bottles to prevent any unwanted consequences of batch failures and compromise quality risks. In most cases, human borne contaminants are most critical and require immediate control to mitigate the risk factor in aseptic processing.⁶

Regulatory guidelines are recommended for drugs in closed aseptic container systems to reduce the risk for cross-contamination with microbes that could lead to possible batch failures. The manual sampling is also a cause for cross contamination, and therefore, the FDA is advocating for closed single-use sampling systems.⁷ European agency recommends that the bioburden should be monitored before sterilization and the working limit on the efficiency should be defined before the sterilization.⁸ In addition, the sterilization of drug products in premixed bags requires further scrutiny by the agency to confirm that no leachables or extractables are generated during terminal sterilization.

There are two ways for achieving sterilization, one in which the products filled in the containers are sterilized and second, the drug product is preferably sterilized before filling under aseptic processing conditions to avoid any cross contamination. Cundell reviewed the justification for use of aseptic filling for sterile injectable products and compared with terminal sterilization using moist heat conditions.⁹ A better and more efficient sterilization can be achieved by terminal sterilization only if the compatibility, physicochemical stability and packaging and storage of products and suitability of delivery systems are met for APIs and excipients. Unlike terminal sterilization, aseptic sterilization can be widely applicable to all products highly sensitive to higher temperatures, as a result the API’s degradation can be minimized, and stability can be maintained.¹⁰ It is widely practiced within the guidelines set forth in the FDA’s aseptic processing manual.¹¹

General Considerations for Selecting a Partner for Sterile Products

Key considerations in identifying the right CDMO partner require a level of mutual understanding about the scope of work (SOW). CDMOs with innovative technologies, for instance, have generated the opportunities with the clients interested in aseptic manufacturing of sterile products, providing assurances in formulation development and overcoming the challenges to deliver high quality medicines for temperature sensitive APIs. In cases where APIs are thermally stable in containers and packaging, sterilization by steam or moist heat or irradiation is an option for preventing contaminants from microbial growth or microbes. On the other hand, APIs sensitive to higher sterilization temperature, the aseptic filling is ideally used to maintain the sterility of all components. Lyophilization of certain molecules could further improve the stability of drug products that aid in storage, shipment, and shelf life of drug products. Thus, a CDMO with enabling capabilities in lyophilization and sterile fills through aseptic processes, can offer services to clients working on small and large molecules and biologics as well. A one-stop-shop CDMO, having the integrated lyophilization and aseptic manufacturing capabilities under cGMP that meets the ISO 5, ISO 7 and ISO 8 classifications as shown in Table 1, can further expedite the development and marketing of drugs faster.

Ascendia’s Capabilities in Formulation Development and Manufacturing of cGMP batches

As sterile manufacturing demand continues to rise and remain strong, CDMOs continue to expand their capacities by investing in high-speed, latest isolator manufacturing technology with fully automated packaging lines. Ascendia, like other CDMOs, has been expanding its footprint in sterile manufacturing capabilities by providing services to emerging and specialty and biopharma companies requiring cGMP manufacturing from pre-clinical tox studies to first-in-humans (FIH) and late-stage clinical batches as shown in Table 2.

With proprietary platform technologies in long-acting injectables, lipid nanoparticles, or nanoemulsions for complex therapeutic modalities, Ascendia’s capabilities are at the par.¹³ Ascendia’s cGMP manufacturing capabilities, for example, include oral liquids, capsules and tablets, and sterile injectable dosage forms for Phase 1 and Phase 2 and Phase 3 clinical supplies with commercial launch readiness by Year 2023. Ascendia’s capabilities and commitments to B.E.S.T. customer service principles (brilliant technology, excellent service, superior quality and trust), therefore, can bring the innovative molecules to human trials faster, leading to expeditious commercialization of drugs for its clients.

Ascendia’s most advanced aseptic fill stations include ISO qualified clean rooms and isolators, to fill up over 9000 vials per hour with complete automation. In addition, the lyophilization unit provides the extended capacity of over 5000 vials for each freeze drying cycle.

Conclusion

Ascendia continues to play an important role as a specialty CDMO in formulation development and cGMP manufacturing of complex dosage forms such as lipid nanoparticles, liposomes, nanosuspensions, nanoemulsions, and long acting injectables based on its proprietary technologies: Emulsol®, Amorsol® and Nanosol®, leading to translation of novel therapy modalities from discovery to clinical phases and commercialization at a faster speed. Its state-of-the-art facility, processing equipment and technical know-how in lyophilization, aseptic processing, and sterilization under cGMP demonstrates its full commitment to clients seeking support in human clinical trial supplies and commercialization for oral and parenteral dosage forms.

References

1. J. Huang and S. Ali, Lipid nanoparticles, Drug Development and Delivery, https://drug-dev. com/formulation-forum-lipid-nanoparticles-tackling-solubility-challenges-with-lipid[1]based-technologies-for-oral-injectable-formulations
2. C. Molineaux et al., The Life Sciences Future – BioPharm Conference, Philadelphia, October 6, 2022
3. M. Le Bars, CDMOs on the rise, Contract Pharma, 2019.
4. D. Toops, Choosing and managing a CDMO, Contract Pharma, 2021 (Sept.)
5. L. Twose, Terminal sterilization for parenteral drugs: Finding the right CDMO Partner, Phama’s Almanac, October 2, 2018.
6. J. Agalloco, J. Akers, and R. Madsen, Aseptic Processing: A Review of Current Industry Practice, Pharm. Tech., 2004, October, 126-150.
7. M. A. Kagg and J. Anant, Traditional vs closed single use sampling in aseptic pharmaceutical manufacturing, Am. Pharm. Rev., 35(6), Sept/Oct., 2022.
8. EU GMP Annex 1: Manufacture of Sterile Medicinal Products (Draft), December 2020
9. A.M. Cundell, Justification for the use of aseptic filling for sterile injectable products, PDA J. Pharm. Sci. Tech., 2014, 68, 323-333.
10. Terminal sterilization of pharmaceutical products, The Altascientist, Issue 21 (https:// www.altasciences.com)
11. FDA, “Guideline on Sterile Drug Products Produced by Aseptic Processing” (1987).
12. Guidance on the manufacture of sterile pharmaceutical products produced by terminal sterilization, Chaired by M. Muroi and T. Sasaki (Japan, 2006).
13. Considerations in Development & Manufacturing of Complex Injectables (www. ascendiapharma.com)

Author’s Biographies

Jim Huang is the founder and CEO of Ascendia Pharmaceuticals, Inc. Dr. Huang received his Ph.D. in Pharmaceutics from the University of the Sciences in Philadelphia (formerly Philadelphia College of Pharmacy and Sciences) under Joseph B. Schwartz. He has more than 20 years of pharmaceutical experience in preclinical and clinical formulation development, manufacturing, and commercialization of oral and parenteral dosage forms. Dr. Huang’s research interests are centered on solubility/bioavailability improvement and controlled delivery of poorly water-soluble drugs through nano-based technologies.

Shaukat Ali joins Ascendia Pharmaceuticals Inc. as senior director of scientific affairs and technical marketing after having worked in the pharma industry for nearly 30 years. His areas of expertise include lipid chemistry, liposomes, surfactants base drug delivery systems, SEDDS/ SMEDDS, oral and parenteral, topical and transdermal drug delivery, immediate and controlled release formulations. He received his PhD in Chemistry from the City University of New York and carried out his postdoc training at the University of Minnesota and Cornell University. Dr. Ali has published over 45 articles in the scientific journals and is inventor/co-inventor of several US and European patents. He is the recipient of IPEC’s Henk de Jong industrial research award and serving as a member of the USP panel of expert for Excipient Test Methods committee.

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