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Regulators And Standards Groups Take Steps To Address Emerging Technologies In Biopharma
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Last year was a banner year for new drugs, with 46 new molecular entities approved by the FDA, compared to 22 in 2016. 2017 also saw the approval of two CAR-T cell therapies, Kymriah and Yescarta, and one gene therapy, Luxturna.

On the technology front, there were four applications that included continuous manufacturing.1 Industry figures indicate that almost 7,000 medicines are in development, 74 percent of which are first in class, and there are hundreds of programs introducing novel scientific approaches such as cell therapies (529), gene therapies (202),  DNA and RNA therapies (173), and conjugated antibodies (188).2

New technologies are transforming the way we manufacture products. Notably, process intensification has increased titers and decreased volumes, which has facilitated widespread use of single-use technology.

Manufacturers, suppliers, and regulators have recognized that introducing new technologies also introduces a degree of unfamiliarity and uncertainty, and as a result, they are working collaboratively through industry groups to address the technical and regulatory challenges.3,4 Compliance frequently lags science for understandable reasons. Science has a responsibility to justify changes to current practices.

Recently, ASTM International, a global standards organization, hosted a workshop aimed at identifying and developing standards for emerging technologies.5 The use of standards is encouraged by regulators, as they are developed in a consensus process by knowledgeable subject matter experts in a rigorous process that ultimately provides consistency, predictability, and credibility. The FDA encourages participation in voluntary consensus standards bodies (when compatible with missions, authorities, etc.). Four main interconnected areas were discussed — single-use technology (SUT), continuous manufacturing (CM), multi-attribute method (MAM), and cell/gene-based therapies.

Single-Use Is An Enabler

Single-use technologies have been available for some time, and their use is advancing beyond developmental stages to widespread application in commercial processes. Furthermore, they are eminently suited for use in support of emerging technologies such as CM and cell/gene-based therapies. They provide an enhanced level of assurance of sterility and decrease the probability of cross-contamination by significantly reducing or even eliminating the requirements for cleaning, and they provide for closed operations.

Single-use systems (SUS) are used as pieces of equipment but are reinstalled prior to each use. This means that traditional equipment validation is no longer appropriate, and there is heavy reliance on supplier quality systems and documentation.  In order to provide guidance to manufacturers, members of ASTM International’s committee on manufacture of pharmaceutical and biopharmaceutical products (E55) developed and approved an overarching standard guide to verification of SUS in 2016 (E3051-16).6

As equipment, it is required that materials should not be reactive, additive, or absorptive. This means that soluble materials (leachables) should not interact with the product or process, nor should surfaces shed particles. Patricia Hughes (FDA CDER) noted that introduction of SUS can result in additional concerns, such as compatibility with the process, leaks, change management, and issues with packaging and transportation to ensure that what has left the supplier’s facility retains its key attributes through transportation, receipt, and installation at the manufacturer’s facility.5

In addition to the E3051 standard, additional workstreams are underway or being initiated for leak identification, integrity of the microbial barrier, particulates, biocompatibility, and extractables and leachables by teams from suppliers, end users, and regulators.

Continuous Manufacture In Biopharmaceuticals

Regulators have been enthusiastic to see the introduction of CM technology into pharmaceutical processing, with the perceived benefits of manufacturing efficiencies bringing lower costs and a higher level of consistency, and therefore quality. Art Hewig (Amgen) and Patricia Hughes (FDA CDER) provided a manufacturer’s and a regulator’s perspective, and both noted that in the biopharmaceutical space, cell culture for drug substance production has been run in a continuous/extended batch mode for decades as continuous perfusion cultures followed by batch purification, notably for labile proteins from low-yielding expression systems.5

The critical attributes for upstream processes are to maximize productivity through a combination of productivity, cell viability, cell line stability, and culture time. Cell lines used in biomanufacture are subject to cell death,7 and, furthermore, can be subject to genetic drift.8 This requires rigorous work to identify the appropriate mix of cell line, medium, and culture process optimization in terms of use of, for example, customized media, selection drugs, and the amount of time cells are allowed to acclimate to media. Developing standards in this area could provide clarity as to what supporting work is required to ensure the robustness of the process.

Downstream processes are more readily modeled based on an understanding of centrifugal, chromatographic, and filtration processes (as appropriate). Certain steps require defined holds (such as viral inactivation at low pH9) and hold times can be simulated by defined residence times in continuous flow reactors. Here again, there is room for standards to clarify what is appropriate in CM.

CM and BioCM require the extensive development and deployment of in-process controls and control strategies. There is a framework in place for the control of small molecule processes;10 however, there are some differences in biomanufacture.

First and foremost, product is not made by the bioreactor; it is made by the cells in the bioreactor. As such, the critical attributes of the upstream process are as noted above. In addition to controlling the physical and chemical parameters of the process, the manufacturer must also consider cell viability, cell mass, and accumulation of product.

Secondly, due to the complexity of biotherapeutics, it is not always possible to directly monitor product quality throughout the process. UV monitoring is used extensively to track the presence of product (and contaminants); the use of more process analytical technology (PAT)-like applications such as at-line UPLC and mass spectrometry are now appearing more frequently.

Patricia Hughes concluded that from a product quality microbiology perspective, areas for further development include vulnerability to leaks; fully integrated, fully closed systems; advances in aseptic filling; and more PAT.

Multi-attribute Method

Jette Wypych (Amgen) gave a perspective on the use of an emerging analytical technology, multi-attribute method (MAM).  Biological products have very complex structures and product profiles, which require the use of numerous test methods during development and production. In order to better capture the selective and specific monitoring of biologically relevant quality attributes, and to reduce the number of assays required for process development and product disposition and in-process control, companies are turning to high-resolution approaches using mass spectrometry. MAM has the potential to replace several methods used currently to determine purity for clips and charge variants, for glycans, and for identity (replacing an immunoassay). The technology is capable of real-time monitoring of PQAs.

As with other emerging technologies, there are challenges in the technology and in compliance/regulatory acceptance. In order to realize the improvements to product quality and efficiency, it is necessary for compliance to keep pace with the advances, as the benefits of MAM are fully realized when implementing it as a replacement rather than an additional technique. Here again, best practices can be captured as standards to give regulators the confidence, consistency, and credibility to move forward.

Cell And Gene Therapies

Cell and gene therapies are novel technologies offering unique capabilities for treating and curing some of the most pernicious diseases. Unlike traditional biotherapeutics, the drug is in the form of live cells or virus.

Nirjal Bhatterai (FDA CBER) listed the special considerations for cellular and gene therapies. They often require invasive delivery procedures, the in vivo mechanism of action is not always known, and cells or genes may persist for an extended period or produce a sustained effect. This can be beneficial for the therapeutic effect, but it can also result in intensified or prolonged adverse reactions.

These therapies have enormous potential, and products are moving rapidly from labs to clinics. The products are exceedingly complex, as is their manufacture and testing; however, GMP is still a requirement.5 Consideration must be given to every stage of the process, from donor/starting material selection, shipping, manufacture, vector production, cell line expansion and formulation to release testing and dosing.

Here too, SUS offers significant advantages in support of these applications, specifically in the higher assurance of sterility and in the avoidance of cross-contamination. However, some of the concerns with single-use may be exacerbated.11 For biocompatibility, volumes will be smaller than in conventional processes, so the surface area to volume ratio will be higher, and unlike in CM, the bioreactor will not be flushed with multiple volumes of fresh media. Given the absence of downstream purification steps, everything added to the process can be considered an excipient. Additionally, in autologous therapies, variability will be introduced based on the patient history.

Although not part of the workshop, two further factors influence our industry.

Industry 4.0

Industry 4.0 refers to the current trend of automation and data exchange in manufacturing technologies. The four basic design principles are: interoperability, information transparency, technical assistance through information aggregation, and decision making and decentralized decisions. This applies most notably for cyber systems to make decisions on their own and to perform tasks as autonomously as possible (within limits). The concept is not specific to any one manufacturing discipline, but how it impacts a regulated industry like pharmaceuticals poses some interesting challenges — how do you validate a system that is learning from itself and constantly adapting?

Standards have been developed for the exchange of information between suppliers and end users;12 however, the content of such information exchange currently focuses on information available on the certificate of analysis, but in future could extend to in-process information from the manufacturer.

Global Harmonization

The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) exists to bring together regulatory authorities and experts from the pharmaceutical industry to discuss scientific and technical aspects of pharmaceutical product registration. Member countries strive to harmonize and align the content of, for example, compendia (USP, BP, JP, EP).  ICH guidelines have been adopted as laws in most member countries and are used as guidance in the U.S.  It is, however, important to note that the member countries do not include significant markets, such as China, India, and Russia, and for geopolitical reasons, as well as scientific and technical aspects, compendia may not fully align. Different expectations, although well meant, can impose a significant burden on manufacturers as they strive to meet them.  

International societies and collaboration through standards development can help resolve differences and bring effective medications for patients with unmet medical needs. Those interested in participating in standards development are invited to visit the ASTM website or contact Travis Murdock.


Duncan Low, Claymore Biopharm LLCDuncan Low is an active member of several industry groups and scientific advisory boards, including the ASTM E55 Executive Committee developing consensus standards for Manufacture of Pharmaceutical Products, the ISPE Executive Committee for PAT, and the Biophorum Operations Group. He also has been a significant contributor to the PDA Task Group for Single Use Systems and the USP’s Committee of Experts.

He was co-chair of the 2009 IFPAC Conference. His most recent role was as scientific executive director at Amgen (2003 – 2017), where he led the Raw Materials Global Network and Materials Science teams. Prior to joining Amgen he held VP positions at Millipore and Pharmacia Biotech. He has an M.A. in biochemistry from the University of Cambridge and a Ph.D. in microbiology from the University of Glasgow.

Duncan Low, Claymore Biopharm LLC

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