Success in the pharmaceutical industry is integrally linked with innovation. Advances in chemistry, biology, biochemistry, genetics and engineering are essential for both the discovery and manufacture of novel medicines. Innovative drug delivery and packaging technologies are also needed to ensure that complex large and small molecules in the pharma pipeline today are formulated into high-quality, safe and efficacious drug products. Representative examples of recent industry innovations are highlighted below.
Advancing API synthesis
Small-molecule drugs continue to dominate the marketplace and the drug pipeline despite growing demand for biologics. Advances in combinatorial chemistry are, in fact, leading to the discovery of novel, highly complex and efficacious active pharmaceutical ingredients (APIs). At the same time, there is a significant push to employ synthetic routes that are not only feasible at production scale, but also cost efficient, atom economical and more environmentally friendly.
One response of both sponsor companies and contract manufacturers is expanded use of flow chemistry and microreactor technology to achieve process intensification. Often this approach leads to reduced costs while increasing throughput and yields, and in addition, enabling the use of hazardous processes that are not possible to perform under batch production conditions. Lonza, for instance, has invested in a multi-million CHF facility for continuous flow and microreaction technology in Visp, Switzerland and developed its own proprietary Flowplate® Microreactor Platform.
Advances in catalyst technologies continue unabated as manufacturers seek more efficient routes to complex intermediates and drug substances. As the number of commercially available enzyme and transition metal catalysts expands, the development of more economical and sustainable processes for API production is more commonplace.
New chemocatalyst technologies include chiral transformations such as Grignard addition reactions, processes for the formation of natural and non-natural amino acids and their derivatives, and reactions that afford fluorinated compounds. The scope of asymmetric hydrogenations, C-H insertions and carbon-carbon coupling reactions are enabling the preparation of new chiral intermediates, including those that contain quaternary carbons.1,2 Attention is also being paid to ligand design, the reclamation and reuse of homogeneous catalysts, immobilization of catalysts on solid supports and encapsulation of toxic complexes without loss of selectivity and reactivity.3
Biocatalysts have numerous advantages for pharmaceutical manufacturers looking to implement “greener” processes. They not only proceed with high efficiencies and selectivities, they often mediate transformations that result in complex structures that would take multiple steps with conventional chemistry. These reactions also typically proceed at or near room temperature in water with minimal byproduct formation and emissions generation, generally without the need for expensive and toxic metals.4
As importantly, advances in genetic engineering have led to the identification of an ever-increasing number of enzymes that can be used to accomplish chemical conversions that are difficult, or not possible, with conventional catalysts. These enzymes are being carefully engineered using a number of state-of-the-art techniques (site-specific mutagenesis, directed evolution and computational de novo design) to have the structures and other properties that allow their production and use on a commercial scale.5
Advances in catalyst technologies continue unabated as manufacturers seek more efficient routes to complex intermediates and drug substances.
Recent examples of new enzyme-catalyzed reactions include reductive coupling of ketones with amines for protection and deprotection steps, imine reductases that reductively couple ketones with amines for the convergent synthesis of secondary and tertiary chiral amine drug targets, enantiospecific synthesis of primary amines and secondary alcohols, as well as the preparation of asymmetric sulfoxides. There are no chemocatalyst alternatives for many of these transformations, according to Jim Lalonde, Senior Vice President of R&D with Codexis in a recent Pharmaceutical Technology article.6 Other new reactions for which enzymes are being developed include the direct hydroxylation of unactivated C-H bonds, the direct synthesis of amides, the regiospecific glycosylation of hydroxyl groups and the site-specific conjugation of proteins.6
Many drug companies are also exploring the preparation of deuterated versions of existing APIs to extend the lifetimes of currently marketed products facing patent expiry. Replacement of hydrogen atoms with deuterium can lead to slightly different properties and allow novel formulations for new indications. Johnson Matthey is one CDMO that is developing this specialized expertise.7
Accelerating vaccine development
Serious diseases, including AIDS and malaria, continue to challenge vaccine manufacturers. The diversity of viruses and the need to identify the relevant antigen in order to determine an appropriate production method complicates the issue.8 The focus is consequently on gaining a greater understanding of which vaccine antigen features impart resistance to viruses.
The Ebola outbreak in 2014 underscored the significant need for accelerating vaccine development. It also created the incentive for vaccine manufacturers and regulators to find ways to move from phase I to phase III in months and be ready to achieve full-scale manufacturing of an approved vaccine. For instance, Janssen Vaccines — part of the Janssen Pharmaceutical Companies of Johnson & Johnson — received the 2016 Facility of the Year Award for Project Execution for its “Fast Track Refurbishment for Ebola Vaccine Production” from the International Society of Pharmaceutical Engineers (ISPE).
The company took the daring approach of running parallel accelerated manufacturing scale-up and clinical development programs, including the simultaneous refurbishment of an existing production facility and the technology transfer and optimization of the process, according to Dirk Redlich, Vice President and Global Head of Technical Development for Janssen Vaccines, in a recent BioPharm International article.8 He noted that successful scale-up of vaccine production can be attributed to the relentless effort of Janssen employees, the intensive collaboration between all parties involved in the project and the in-depth knowledge that the company has of its technology. The result: production (and freezing) of 2.4 million doses of its vaccine regimen.
While some large pharma companies are investing in manufacturing capabilities for cell therapies, many, along with most smaller and emerging firms, are seeking support for large-scale cell therapy production from outsourcing partners.
The use of advanced processing capabilities, including high-throughput and single-use technologies, also contributed to the project’s success. The development of chromatography-based purification processes and the use of microcarriers for cell growth are also improving vaccine production.9 Continuous processes for vaccine manufacturing are under development and expected to accelerate production startup once proof of concept has been established, according to Sangeetha Sagar, Assistant Vice President for R&D with Sanofi Pasteur, who commented in the same article.8
Several innovative technologies for vaccine production that have the potential to more rapidly provide vaccines in response to pandemic situations are currently being worked on. Cell culture, synthetic DNA, virus-like particles, chimeric antigens, recombinant protein nanoparticles and subunit vaccines are all examples of alternatives to traditional egg-based vaccine manufacturing, which typically is a many-months-long process.10
Recently, researchers at the University at Buffalo, The State University of New York, reported the development of a pneumococcal disease antigen comprising a bacterial core electrostatically coated with a cationic polymer.11 The design results in natural adjuvant properties and allows passive and active targeting of antigen-presenting cells plus in situ antigen production and consolidation within the bacterial component of the vector, eliminating the need for dedicated antigen production and purification prior to vaccination, according to the authors. The easy-to-formulate hybrid vector was successfully tested against a range of clinically relevant Streptococcus pneumoniae strains; the results compared to those for several traditional vaccine formulations.
Other interesting work includes the production by researchers at the University of California, San Diego School of Medicine, of a properly folded malaria parasite protein (Pfs25) in algae typically used for biofuel production.12 Algae is advantageous because it is inexpensive, easy to work with and environmentally friendly. Most importantly, when combined with an immune-boosting cocktail suitable for use in humans, the algae-produced protein generated antibodies in mice that nearly eliminated mosquito infection by the malaria parasite.
Solving drug delivery challenges
Both the highly complex small-molecule and biologic drugs on the market today present significant challenges to formulators in terms of drug delivery. According to Kline & Company, 40% of currently marketed drugs and 80% of pipeline candidates have low solubility (Class III/IV according to the Biopharmaceutical Classification System.)13 In addition, effective technologies for the targeted delivery of protein-based drugs have yet to be developed. CDMOs with specialized capabilities in solubility, bioavailability enhancement and targeted delivery are therefore well positioned for success.
Choice of a specific technology is molecule-dependent. Whether the compound is to be administered as a solid, liquid, parenterally or via inhalation also influences the decision. Extensive experience in formulating solutions for poorly soluble APIs is therefore a real competive advantage. Fortunately the available range of drug delivery technologies is expanding and now includes the formation of salts or co-crystals, particle manipulation, the use of lipid-based carriers and the generation of amorphous dispersions.14
Cryogenic spraying, which includes spray freezing onto cryogenic fluids, spray freezing into cryogenic liquids, spray freezing into vapor over liquid and ultra-rapid freezing, is an example of a newly introduced particle engineering technology. The low-temperature process yields nanocrystals of APIs with significantly enhanced surface areas.14
Car-T cell therapies moving from the clinic to the patient
There are over 500 companies involved in cell therapy technology, according to Jain PharmaBiotech.15 Some of the most promising therapies are based on adoptive cell transfer using T cells (T lymphocytes) harvested from patients and then genetically engineered to have chimeric antigen receptors (CARs) that recognize specific proteins (antigens) on tumor cells.
Recent developments have focused on increasing the safety of CAR-T cell therapies (to avoid cytokine release syndrome and on-target, off-cancer toxicity) and address the challenges associated with the large-scale manufacture of cells as therapeutic products.16 Solutions to the safety problems include the incorporation of safety switches that allow for destruction of the cells in the event of severe toxicity; the development of bispecific CAR-T cells that deliver activating signals upon binding to desired tumor cells and inhibitory signals upon binding to healthy cells; and CAR-T cells for which activity is modulated using small-molecule drug inducers.
Juno Therapeutics has licensed Strep-tag technology from the Fred Hutchinson Cancer Research Center, which is used to select T-cells with the appropriate CAR protein, allowing highly pure cell samples that when expanded are more potent and have better regenerative capabilities within patients.17
With respect to manufacturing challenges, Novartis, which was the first health-care company to initiate phase II CAR-T therapy trials across the U.S., Europe, Canada and Australia, has reported the successful transfer of cell processing technology from the University of Pennsylvania to the company’s cell manufacturing center in Morris Plains, NJ.18
The appropriate cell expansion technology for a given therapy will depend on the type of product (small-scale autologous or large-scale allogeneic), with 2D culture processes likely for the former and 3D processes using microcarriers expected for the latter.16 Closed, disposable systems provide the needed flexibility and low cost. Automation of the production process, particularly for patient-specific autologous products, will be crucial for minimizing space and cost while increasing consistency.
While some large pharma companies are investing in manufacturing capabilities for cell therapies, many, along with most smaller and emerging firms, are seeking support for large-scale cell therapy production from outsourcing partners. There are only a few firms focused on this sector — newly formed Brammer Bio, WuXi PharmaTech (which is building its third cGMP cell-therapy production facility in Philadelphia, Pennsylvania), PCT and Lonza.16
- Challener, Cynthia A. “Advances in chiral Grignard and organolithium chemistry.” Specialty Chemicals. 18 June 2012. Web.
- Challener, Cynthia A. “Asymmetric Chemistry Continues to Advance.” Pharmaceutical Technology. 2 Sept. 2014. Web.
- Challener, Cynthia A. “Asymmetric Chemocatalysis: Going for the Lowest Loadings.” Pharmaceutical Technology. 27 Mar. 2013. Web.
- Challener, Cynthia A. “Synthetic Biology: The Next Frontier in Chiral Chemistry for API Synthesis.” Pharmaceutical Technology. 2 Mar. 2014. Web.
- Challener, Cynthia A. “Mimicking nature.” Specialty Chemicals. 6 Aug. 2014. Web.
- Challener, Cynthia A. “Going Green with Biocatalysis.” Pharmaceutical Technology. 6 Aug. 2014. Web.
- Shanley, Agnes. “Specialty Markets and Services Drive API Growth.” Pharmaceutical Technology. 2 Mar. 2016. Web.
- Challener, Cynthia A. “Lessons Learned Accelerate Vaccine Development.” BioPharm International. 1 Apr. 2016. Web
- Lundgren, Mats. “Bringing Vaccines into the 21st Century.” The Medicine Maker. Web.
- Challener, Cynthia A. “Novel Vaccine Technologies Are Meeting the Need for More Effective Pandemic and Therapeutic Solutions.” BioPharm International. 1 May 2014. Web.
- Li, Yi, Marie Beitelshees, Lei Fang, Andrew Hill, Mahmoud K. Ahmadi, et al. “In situ pneumococcal vaccine production and delivery through a hybrid biological-biomaterial vector.” Science Advances 2.7 (2016). Web.
- Medtech Meets Cleantech: Malaria Vaccine Candidate Produced from Algae. UC San Diego. 18 Feb. 2015. Web.
- Low Solubility Concern in the Pharma Industry Drives the Solubility Enhancement Excipients Market, Finds Kline. PR Newswire. 15 Apr. 2015. Web.
- Tiene, Guy. “Formulation Challenges Driving Interest in CDMOs.” Manufacturing Chemist. 13 Jan. 2016. Web.
- Cell Therapy - Technologies, Markets and Companies. Rep. Jain PharmaBiotech. Aug. 2016. Web.
- Challener, Cynthia A. “Realizing the Potential of CAR-T Cell Therapies.” BioPharm International. 2 May 2016. Web.
- Hutch, Fred, “Crafting a better T cell for immunotherapy.” Fred Hutch. 22 Feb. 2016. Web.
- Boyd, Jeffrey A., Bruce L. Levine, Kathrin Jinivizian, Margit A. Jeschke, Megan M., et al. “Successful Translation of Chimeric Antigen Receptor (CAR) Targeting CD19 (CTL019) Cell Processing Technology from Academia to Industry.” Blood Journal 126.23 (2015). Web.