Next-generation treatments have shown immense success in early clinical studies. The challenge today is getting these novel medicines into the hands of patients in need. In many cases, the development of new manufacturing, delivery and logistics technologies must occur first. Partnerships between all members of the pharmaceutical value chain are therefore crucial to realizing the true potential of these promising next-gen therapies.
Many of the most promising next generation drug products are based on biologic active pharmaceutical ingredients that require new technologies that enable their manufacture, characterization (identity, viability, purity, potency, viral safety) and other testing (sterility, release, etc.) and distribution at the large scales required for commercial drugs. To date, these new treatments have only been produced for the most part on very small scales for early (phase I and II) clinical trials, either in in-house bio / pharma company process development labs or academic laboratories that provide small-scale contract manufacturing services. The methods used to produce, analyze and handle such small quantities are generally not economically viable or practical at the commercial scale.
For cell therapies, for instance, live cells are harvested as the active agent, rather than being separated from the desired protein or antibody. Technologies related to tissue processing, cell selection, expansion, activation and genetic modification and cryopreservation are all needed. While allogeneic cell therapies, which are based on cells from healthy donors and are intended to be produced in large quantities as “off-the-shelf” treatments, can theoretically be produced in large quantities using conventional bioreactors,1 autologous — or patient-specific — cell therapies cannot.
In the latter case, high-throughput systems run in parallel and processing multiple separate products at one time will be necessary.2 Highly automated, functionally closed systems are of particular interest for autologous therapies in order to minimize operator intervention and prevent contamination.2 Many also believe that cell therapy manufacturing will not be economically sustainable without the extensive use of automation to reduce costs, but the development of needed technologies will require cooperation among equipment vendors and with cell therapy manufacturers.3 Such systems will need to be designed to enable multiple manufacturing functions in an integrated manner.
Given that many next-generation therapies will require new manufacturing capabilities, significant investment in infrastructure will be required to support current Good Manufacturing Practice (cGMP)- compliant manufacturing processes and testing capabilities. The largest bio / pharma companies involved in the development of novel treatments are electing to keep those investments in-house (through construction of new facilities or acquisition of existing capabilities). However, many next-generation therapies are being developed by smaller, emerging companies backed by venture capital. Most of these firms lack the capabilities required to manufacture cell and gene therapy products on a large scale and do not have the resources to establish their own inhouse facilities. As a result, there will be significant need for the support of specialized contract development and manufacturing organizations (CDMOs) focused on the production of novel medicines.4
Regulatory questions
Uncertainties regarding the regulatory requirements for novel medicines such as cell and gene therapies and the lack of standardization of regulations from agencies in different geographic regions represent additional challenges to the commercialization of next-generation therapies. Most notably, both in the U.S. and Europe, existing regulations require that pharmaceutical manufacturers establish and maintain comparability of drug products produced at multiple sites, which would make the production of patient-specific treatments at more than a couple of locations very difficult.5 The picture is further complicated for autologous cell therapies where appropriate manufacturing and distribution approaches may be dictated by the characteristics of the disease that is being treated and other factors, such as the capabilities of the clinics that will be administering the treatments.5 In addition, regulatory requirements for cell-based therapies differ in the EU and the U.S., adding additional costs for compliance; it is widely considered that existing regulations do not take into account the unique properties of personalized medicines and thus place impractical requirements on pharmaceutical companies, many of whom are small and lack the resources to meet them, particularly given the lack of harmonization between regulatory bodies.5 Managing the outsourcing of manufacturing to CDMOs adds yet another layer of complexity.
Considering commercial-scale needs from the start
One of the crucial factors creating challenges for movement from process development to commercial-scale production of next-generation therapies is the intense focus that most companies and academic laboratories take regarding the immediate process involved. Lack of consideration of the needs for large-scale production at the earliest stages of product development can hamper the translation and commercialization of such processes.5 Recognition of this need to consider commercial-scale engineering and manufacturing issues is increasing somewhat, however, as greater numbers of novel biologics proceed from early-phase trials to late-stage evaluation and require the production of larger quantities of drug product.6
There is a careful balance that must be maintained, however; addressing manufacturing issues at early development phases adds additional cost to a project (i.e., for equipment, controls and cGMP facilities) that many pharmaceutical companies cannot afford. On the other hand, significant regulatory and other hurdles must be overcome if a process must be changed at later development stages.6 At a minimum, though, raw materials should be selected that will be appropriate for cGMP manufacture. The development effort should focus on identification of a robust, reliable manufacturing process that is suitable for largescale production, and characterization data should be developed that supports release testing.7
Many collaboration partners
With all of these challenges, it should not be surprising that most bio / pharma companies involved in the development of next-generation technologies also participate extensively in a wide range of partnerships designed to facilitate bringing these novel medicines to the market. Collaborations with academic research groups, research institutes, technology developers (such as for gene editing methods, nanobodies, optides, etc.), other pharmaceutical companies, government funding agencies and regulatory bodies and contract service providers are all commonplace and necessary for the successful translation of developments in fundamental science to commercial therapies produced at large scale.
New types of partnerships are generally necessary to bring the latest generation of novel medicines from initial discovery to commercialization.8 In particular, the complexity of these advanced technologies is driving the need to bring together many different groups and technical experts with wide-ranging skills and expertise. Many large pharmaceutical companies are, for instance, establishing centers of excellence or innovation focused on the development of next-generation technologies. Patients and clinicians must also be part of the development process for many of the latest cell and gene-based therapies.8
Importance of contract service providers
To ensure that the initial successful research results obtained for many next-generation therapies are translated into affordable medicines that can be produced reliably at commercial scale, many bio / pharma companies are turning to equipment suppliers, contract research organizations and CDMOs to help them develop optimized processes and analytical methods.9 The challenge is to find service providers with the knowledge and capabilities needed to take such advanced therapies from the lab to the commercial scale. CDMOs must not only have lab and production capabilities, but also scientists with specialized development, manufacturing, and analytical expertise and robust quality systems to ensure compliance and product safety.1 To have an impact, however, CDMOs must be able to apply existing process knowledge and large-scale manufacturing expertise to the emerging technology platforms underlying next-generation therapies and work closely with scientists that have the experience in developing novel therapies at the process development and early clinical trial scales.2
References
- Challener, Cynthia A. “Upstream and Downstream Operations Can Impact Biologic API Uniformity.” Pharmaceutical Technology. 2 May 2016. Web.
- Burger, Scott R. Commercial Manufacturing of Cell Therapy Products – Considering the Options. Rep. World Stem Cell Report 2009. 5 Apr. 2009. Web.
- Stanton, Dan. “Vendors Must Collaborate to Develop Cell Therapy Production Automation, Experts.” BioPharma-Reporter. 2 Feb. 2016. Web.
- Bamforth, Mark, Steve Kasok and Richard Snyder. “Achieving Large-Scale Cell and Gene Therapy Manufacturing.” Pharma’s Almanac. 30 Apr. 2016. Web.
- Hourd, Paul, Amit Chandra, Nick Medcalf and David J. Williams. “Regulatory Challenges for the Manufacture and Scale-out of Autologous Cell Therapies.” StemBook. 31 Mar. 2014. Web.
- Dodson, Brittany P., and Aaron D. Levine. “Challenges in the Translation and Commercialization of Cell Therapies.” BMC Biotechnology 15.1 (2015). Web.
- Brandenberger, Ralph, Scott Burger, Andrew Campbell, Tim Fong, Erika Lapinskas, et al. “Integrating Process and Product Development for the Next Generation of Biotherapeutics.” Cell Therapies Technology (2011): 30-37. Web.
- “Gene, Stem Cell Therapies Bring New Players to Partnering.”Partnering360. 13 Aug. 2013. Web.
- Forte, Miguel. “A Call for Cell Support: Engineered Cell Therapies Hold Exciting Potential for the Pharmaceutical Industry – but Only if Contract Manufacturing Organizations and Vendors Play their Part in the Revolution.” The Medicine Maker. Web.