Chris Spivey is director of Industry Relations and Strategic Partnership, MJH Life Sciences.

Chris Spivey

In a tightly regulated industry, certifying that a drug is authentic, safe, and effective requires passing through several different thresholds of proof. In the 2011 

Guidance for Industry, Potency Tests for Cellular and Gene Therapy Products

 (CGT) (1), FDA states, “No lot of any licensed product shall be released by the manufacturer prior to the completion of tests for conformity with standards applicable to such product, (21 

 610.1), which include tests for potency, sterility, purity, and identity (21 

 Part 610, Subpart B).” These requirements apply to all biological products, including autologous and single patient allogeneic products, where a lot may be defined as a single dose.

The need to meet this guidance, and especially for rising levels of instances of single dose production for CGT, can create a burden in terms of time, economics, and staff training. The biopharmaceutics classification system (BCS)-based biowaiver approach is intended, along with other measures, to reduce the need for 

 bioequivalence studies (i.e., it can provide a surrogate for 

 bioequivalence). The International Council for Harmonisation’s (ICH) M9 guideline states, “

 bioequivalence studies may be exempted if an assumption of equivalence in 

 performance can be justified by satisfactory 

 data. The BCS is a scientific approach based on the aqueous solubility and intestinal permeability characteristics of the drug substance or substances” (2). In practical terms, CGT fields are moving so rapidly many identification and potency tests are being invented alongside the drug therapies themselves. It is an increasingly hopeful time for critically ill patients and also for the pharmaceutical industry, but this growing trend places a strain on scientists, suppliers, manufacturers, hospital staff, regulators, and insurers. In a industry insider survey (3), nearly half of all respondents replied that CGTs represented the largest opportunity for growth in terms of potential new therapies. While the surge is clearly a highly positive step, it also means taking care to solve inherent present challenges becomes more urgent.

Only a certain amount of past knowledge is useful

A typical strategy is to apply lessons learned from more mature therapies, particularly the use of monoclonal antibodies (mAbs), where much has been optimized due to popularity, length of use, and to some degree (arguably), less complexity residing in these systems. But even here more work on potency assays is evidently required. An article offering a novel mathematical approach for fitting concentration-response curves on mAbs for potency data concludes, “the future strategy for bioassay analysis should include investments both in the development of the best Mechanism of Action (MoA) reflecting assay and the identification of cost-effective techniques for implementation; this investment should begin in the early phases of clinical development. There have been some noteworthy achievements in the utilization of mathematical models in the bioassay evaluation strategies in various segments, but there is a long way left to go. Because the mechanism behind monoclonal antibody development is complex or poorly understood, mathematical models, which are relatively simple, could be used to reduce time and expenses” (4).

Vibha Jawa, executive director, head of Biotherapeutics Bioanalysis in Nonclinical Disposition and Bioanalysis (NDB) Organization, Bristol Myers Squibb, describes which types of products require the closest watch for potency fluctuations. “I would say the novel complex modalities where we don’t know what expression levels are needed for these new targets in order to validate that the drug is adequately binding to the intended target. So, definitely novel modalities like multidomain biologics and CGT therapies require more consideration for potency.” So, ab initio, increased biological complexity itself, plays a central role in making these therapies more difficult. If we cannot match on a one-to-one basis the expression levels required for MoA, how then does one model an effective potency regime at the point of origin?

Jawa goes on to build on this observation, saying, “a common thread for these new modalities is that the drug product itself is a cell. And it’s a patient’s cell that we are talking about. So, it’s not a Chinese hamster ovary cell or antibody that comes to us already being well defined. In this case, the Chimeric antigen receptor T cell (CAR-T) for example, where we are taking cells from the patient, we are going to engineer them outside of the body, and we have to understand if the CAR we have transduced into these cells, are they going to be able to bind the tumor target, so for potency you are using this CAR-T cell, or a cell line which is very similar, which can go kill a tumor, and we have to do all potency testing upfront to know this receptor is dedicated or efficient enough.”

And as if to put an exclamation point on the issue of complexitiy, Jawa concludes, “so herein lies the complexity—each person has their own T cell, with its own level of T-cell antigen receptor variability. We just don’t know how the T cell receptors are going to interact with the tumor cell, and same for major histocompatibility complex class one and class two molecules which are the proteins present, which present the peptides. So, potency is, shall we say, a completely different question to answer for CAR-T therapies.”

There is some good news, however, when it comes to viral gene therapies. There is an intrinsically more consistent manufacturing base to pull from, and the adeno-associated viruses or lentivirus being used to transduce the modification into a cell of interest can therefore be manufactured more consistently, and with less variability, than for CAR-T therapies. Another direction would be to question if there is a significant rise in complexity, yet again, when dealing with emerging therapies such as allogenic CAR-Ts, Natural Killer cell-based CARs, or armored CARs. These new modalities require ingenuity in setting up biorelevant test systems for target cells, because the screening of multiple new test cells lines will be required. The further we go on this path, the more variability we need to account for in order to engineer consistency into these new products.

M9 Biopharmaceutics Classification SystemBased Biowaivers Guidance for Industry

3. Playter, G. Crossing the Same River Multiple Times. 

Mathematical Modeling of Cell-based Potency Data for mAb Biotherapeutics,

Articles

The further we pursue CGT, the more variability we need to account for in order to engineer consistency into these new products.

Designing Potency Assays for Complex Novel Modalities

Messenger RNA (mRNA)-based vaccines have been largely optimized for stability, structure, and delivery. Integration of naturally occurring modified nucleosides, such as pseudouridine (ψ), reduces cytokine production by masking recognition of toll-like receptors, while improving translation and stability through decreasing activation of protein Kinase R and 2′-5′-oligoadenylate synthetases (1). To the lay person, these seem esoteric and weirdly fringe pathways. To immunologists and molecular biologists, for decades these have been pedestrian highway blockages to progress in the field. Success here has sent this message, “efforts to expand applications to other disease states will pay off in a big way.”

Inside boardrooms and laboratories, fervent activity continues to push the boundaries for both vaccine applications, and mRNA more generally. With regard to novel delivery in particular, but in tandem with efforts to ramp up (by orders of magnitude) dose loading capabilities, new intellectual property filings abound. Novel strategies from related fields have been tested, rejected, modified, and integrated. Cancer vaccine activity has seen huge efforts and, to some degree, positive results. While none are currently approved for standard treatment, early clinical trials with mRNA vaccines as monotherapy and in combination with checkpoint inhibitors look encouraging (2). There is a cross pollination between the fields. But direct translation requires new biological thinking. For example, while checkpoint inhibitors appear to work most effectively when dealing with multiple DNA damage repair mutations in patients, it is unclear what that means when combining with mRNA treatments. 

Fundamentally, the industry is at the early stages of unraveling what similarities and differences can be taken advantage of for mRNA modalities in oncology, infections disease, or neural degeneration indications. This new pioneering phase of mRNA is loaded with potential, but also obstacles and false dawns. That’s what makes commercial mRNA prospects so captivating—the hidden biology being unpacked behind the headlines. The message here is that success begets success, and biological understanding has driven that whole process forwards.

1. Gal-BenAri, S.; Barrera, I.; Ehrlich, M.; K Rosenblum. PKR a Kinase to Remember. 

 Sec. Molecular Signalling and Pathways. 

, Jan. 9, 2019, 11. https://doi.org/10.3389/fnmol.2018.00480

2. Lorentzen, C.; Haanen, J.; Met, O.; Savane, I. Clinical Advances and Ongoing Trials of mRNA Vaccines for Cancer Treatment. 

When referring to this article, please cite it as C. Spivey. The Commercial Message mRNA Products Send. 

This new pioneering phase of mRNA is loaded with potential, but also obstacles and false dawns. 

The Commercial Message mRNA Products Send

PR agencies perspectives lightening round: buy/hold/sell on mRNA beyond Vaccines, Organ on a chip, Artificial Intelligence (AI) and Machine learning (ML), Viral Vector Yield Improvements, Quality Management Maturity (QMM), Near Patient Manufacturing. The role of a PR agency dissected: are you a coach, a resource, a creative inspiration, a connector, a battering ram, secret sauce, an authoritative stakeholder, experienced guide? How has getting a message out has changed in the last 5 -10 years for pharmaceutical companies. What pharma industry trends do you see as important and want to emphasize, or are simply excited by?

Debra Harrsch, President and CEO, Brandwidth Solutions

Brandwidth Solutions’ holistic approach to scalable, science-focused, and customized marketing starts with in-depth industry knowledge and the full scope of services that enable you to get where you need to go. We speak science®.

Beth Willers, Principal, White Matter Communications

WMC was built to deliver a different type of agency experience to the B2B Life Sciences mark.et. Our focus is on developing quality content while building good habits across the PESO spectrum and making deeper connections both internally and externally to sustain a healthy brand evolution.

Kevin McCarthy, Senior Consultant, Orientation Marketing

Orientation Marketing is a life science and pharmaceutical marketing agency operating within specialist B2B scientific sectors. We help drug, ingredients, packaging, medical technology, contract manufacturing, development and research organisations uncover marketing opportunities to become visible, increase engagement and generate more leads.

 presents the Drug Solutions podcast, where the editors will chat with industry experts from across the pharmaceutical and biopharmaceutical supply chain. Join us as experts share insights into your biggest questions—from the technologies, to strategies, to regulations related to the development and manufacture of drug products.

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Public relations agencies dissect pharmaceutical trends: Brandwidth Solutions, Orientation Marketing and White Matter Communications

Drug Solutions Podcast: Pharma Trends Dissected by 3 PR Agency Luminaries

Devoting time to track what developments will impact bio/pharmaceutical manufacturing isn’t easy, unless (like an editor of this publication) it’s your primary task. In a framework of descending order of impact, the first trend discussed in this article is messenger (mRNA) applications beyond vaccines. At the end of this list is bringing pharmaceutical manufacture right to the patient’s bedside. For near-patient and distributed manufacturing, FDA calls for not only fresh approaches but the willingness to use new ways of thinking to achieve this goal. Being focused on the year 2026, we allow the reader time and space to better reset, and prepare for only the most seismic events.

“The very essence of what makes mRNA a great way of delivering vaccines is the very real challenge of making them anything other than fit for that purpose, namely their inherent ability to cause activation and alarm within our highly sophisticated adaptive immune systems,” says Stephen Rapecki, director, Experimental Therapeutics, UCB. “We need to devise improved means to disguise and deliver both mRNA itself and also it’s delivery packaging, if that can be accomplished,” continues Rapecki. “The second challenge is delivering mRNA to its chosen cell or organ. mRNA vaccines administered subcutaneously most likely deliver their immunogenic payload to antigen presenting cells at the site of injection and to draining lymph nodes. This allows small and targeted doses of vaccine to be amplified as the immune reaction is the intended outcome not the production of the protein per se. To deliver a protein to correct a condition or replace a defective version of a protein will require much larger amounts than for immunization, perhaps by factors of up to a thousand. Such manufacturing challenges though are not insurmountable given the exciting opportunities mRNA offers drug hunters,” he contends.

The next hurdle, common to any drug therapy, is liver metabolism and toxicity. An approach here, Rapecki continues, “is to attach a targeting portion to your LNP [lipid nanoparticle], which typically could be a peptide, antibody, or antibody fragment. This doesn’t avoid the liver but can potentially swing the selectivity in favor of your cell type of interest. The final challenge to expanding mRNA beyond vaccines could be a strength or weakness depending on your point of view. This is the transient nature of mRNA expression which can vary from hours to many days but not the months or years that might unlock applications which currently are the domain of viral delivery. The iterative development of non-natural mRNA sequences, self-amplifying mRNA and now circular mRNA are beginning to extend the length of protein expression delivered by mRNA, but it is still envisaged that mRNA therapies outside the vaccine field will need repeat dosing to be truly effective. This leads to which applications will come after infectious disease vaccines. The low hanging fruit will be not to avoid an immune response, but to rely on it and deliver cancer vaccines, many of which could be personalized through sequencing tumour antigens to discover which give the best anti-tumor responses ... Beyond vaccines lies the non-immunogenic applications already mentioned. Assuming, and it’s a very big if, immunogenicity is greatly reduced, the next application is likely protein delivery to enclosed organs such as the eye, brain, etc. These will need larger doses and repeat administration so the durability of these responses will be key. In the periphery non-immunogenic targeted LNPs, which have the most scientific hurdles to cross, also have the potential to open the largest therapeutic space. Here you can envisage altering your own T cells to temporarily become CAR-T [chimeric antigen receptor T cell] cells circumventing the need for expensive cell therapy and with a safety profile that could work outside of oncology. Delivering a protein to cells in the blood altering their sensitivity in the case of autoimmunity should also be a possibility giving dosing regimens similar to current biologic drugs.”

Donald Ingber, founding director, Wyss Institute for Biologically Inspired Engineering at Harvard University, believes Organ Chip technology is at the tipping point when it comes to drug discovery and personalized medicine. He points to a study where scientists performed a comparison between animal models and human Liver Chips that shows these chips offer a way to predict drug-induced liver toxicities (1).

“Perhaps even more important for their acceptance by regulatory agencies and the pharma world, this study included an economic analysis that estimated drug developers would save about $3 billion per year if this one animal model were replaced by Organ Chip technology, given the huge costs of drugs failing once they get into clinical trials,” says Ingber. “My hope is that this will catch the eye of those in C-suites, which would ensure this transition towards a faster and less expensive way of developing safer and more effective drugs. At the same time, the ability to create Organ Chips lined by patient-derived cells, which we do standardly, opens the possibility of an approach to personalized therapeutics in which not only are better drug choices made, but the administration regimens—how frequently the drug is administered, by what route, and at what dose—may be optimized as well.”

Tissue Dynamic, an emerging organoid company, estimates (in a dramatic claim) that the company could cut drug development costs by 40–80%, and time required by 30–50% overall. Their approach is to ab initio embed sensors into the organoid while its being grown, which allows AI-driven computation to directly interrogate biology every step along the development process. “This allows the robot to start screening drugs against different models of disease. It can perform, by itself, safety assessments in the microtissues and identify the drug that works best and causes the least damage to human organs, and it does this extremely fast. We can do it in 19,000 tissue samples at once. It is the equivalent of [testing on] 5000 patients,” said Yaakov Nahmias, founder and chief scientific officer of Tissue Dynamics LTS (2).

Artificial intelligence (AI) and machine learning (ML)

In a presentation at the 2022 PDA-FDA Joint Regulatory conference, Martin Van Trieste spoke about quality 4:0, six sigma, and the date deluge, saying, “We’re now using machine learning and AI, and that will really help eliminate failures, eliminate deviations, eliminate non conformances, and get past what I call blind compliance.”

At the conference, Van Trieste spoke about saving an in-process batch of protein product at Amgen as a case example, before proclaiming that because of AI, “the future looks really bright for patients with improved safety, reliability, and quality, and all at a lower cost, some of which will be passed on to the consumer. Now if the future is bright for this group of people, it must be bleak for somebody else. And it’s going to be bleak for the dinosaurs of the industry, for the large quality organization that have been built around testing and inspecting the product, because if you are doing AI, you don’t need large testing organizations. The computer will not allow a mistake to happen, and it will safety check everything at the end … It’s really good for the patients. It’s not good for the quality unit, so I suggest that you really learn data analytics, you really learn AI‚ become that resource in the company, because that’s how you’re going to keep your job in the future.”

In concrete terms, Nicholas A. Geisse, CSO of Curi Bio, explains, “Where we’ve been using AI at Curi is to unbias the observer. We routinely use AI/ML routines to analyze our imaging data in an unbiased way and use it to find the unquantifiable subtle idiosyncrasies that are within the data. One thing that always frustrated me was that for certain procedures, for example stem cell differentiation, we’d have to grab one specific expert to look down the microscope and give a thumbs up or a thumbs down for our go/no go criteria.” That was the past.

According to a press release, PictorLabs (3) uses deep learning algorithms to stain tissues 

, producing near-instantaneous virtual stains, claiming, “From a single unstained tissue sample, PictorLabs’ proprietary platform can produce an unlimited number of virtual stains that are indistinguishable from analogous chemical stains.” To even imagine this requires a robust adjustment of our preconceptions.

Drug recalls, warning letters, and persistent repeated drug shortages have been a drag on both the bottom line and the perception of the pharmaceutical industry for many years. FDA has now moved ahead in its plans to push for higher corporate quality culture through its QMM assessment program. In an article published in 

 (4), the authors state their experiences running the overseas pilot program. The program assessed eight overseas excipient companies’ quality culture and business process performances. “While FDA provides oversight of the site quality management processes and product quality via CGMP [current good manufacturing practice] inspections, and other surveillance methods, there are currently no comparable regulatory tools that examine a site’s business processes and how well they are integrated with quality objectives. QMM fills that much needed gap.”

, Somnath Mishra of Shabas Solutions pointed to senior management’s role in controlling aspects of quality (5). “They’re the ones that control the purse strings and the decisions that are made that actually breathe life into a quality system ... Those people can better solve some of the pernicious intractable problems that exist … Pharmaceuticals are simply recognizing the initiatives and successes that these other industries have achieved, and realizing these only so much that can be done at the technical level, …. you can train technicians, provide SOPs [standard operating procedures], specifications … You can oversee with managers, supervisors, even director level personnel, and still there are problems. So, it was these other industries that solved that. They illuminated the source of some of the pernicious problems, and it pointed back to senior management … [who] had underappreciated the quality aspects of corporate culture.”

To clarify the reasoning to include QMM in this list of trends, QMM won’t promote pharmaceuticals to make a bigger impact on patients directly, but it will make a very big impact on how the industry conducts itself internally, in particular, at C suite levels, and how better outcomes and efficiencies cascade outwards.

Improving yield and standardizing manufacturing for viral vectors

One of the constraints to cell and gene technology (CGT) growth is to scale vector production. “By its very nature, transient transfection is an inconsistent process and really limits the ability of the field to make significant yield improvements,” says Clive Glover, general manager, gene therapy, Pall Corporation. Comparatively monoclonal antibodies (mAbs), “are three to five orders of magnitude greater than when the field started out. We are aiming to reproduce this in the viral vector field, but it turns out to be significantly more difficult to make a stable producer cell line for viral vectors due to the inherent toxicity of some of the proteins to the producing cell,” Glover observes.

Optimally, we might have producer cell lines that can produce vectors without the need of transient transfection, but creating high-titer stable producer cell lines is difficult. “In time, researchers rediscovered the potential for gammaretrovirus in CGT, focusing where oncogene promoter-adjacent insertion is less of a concern, including CAR-T therapies—and this is where the industry stands now, at an exciting nexus point where potential is becoming reality,” Bill Vincent, founder and executive chairman, Genezen remarked (6).

Glover elaborates on his earlier point saying, “CEVEC, a Germany company, recently acquired by Cytiva, has figured out how to solve this problem by putting the genes required for viral vector production behind an inducible switch that can be turned on once the producer cells have been grown up to their final production volume.”

Adam Fisher, director, Science Staff, Office of Pharmaceutical Quality, Center of Drug Evaluation and Research (CDER), FDA, rhetorically asked (7), “If a future with distributed and point-of-care manufacturing doesn’t look like traditional brick-and-mortar manufacturing, what might it look like? Prefabricated, mobile, modular manufacturing units might move frequently between different geographical locations. Manufacturing units at multiple locations, perhaps even 3D [three-dimensional] printers at patients’ bedsides may operate under a single remote quality management system. This is no longer science fiction. FDA has seen some of these technologies from developers of distributed manufacturing processes.” While FDA’s CDER does not have any approved drugs in its current purview made with distributed or point-of-care technology, experts know they are coming.

CDER’s outreach is asking input by Dec 13, 2022 to: “How can manufacturers ensure location changes do not impact product quality?” The article ends by quoting FDA’s Larry Lee, “I think pharmaceutical manufacturing is on the verge of reconstruction; we have reached the point where change is necessary to improve quality and access” (7). A sentiment echoed by the 

(8), “…cryopreservation has become a critical area of interest in cell-therapy manufacturing, as issues of cell viability, functionality, and patient safety become increasingly important to resolve as more therapies reach the market. For autologous cell-based applications, many have argued that the best place for cell production is the ‘bedside’.”

1. Ewart. L.; Apostolou, A. et al. Performance Assessment and Economic Analysis of a Human Liver-Chip for Predictive Toxicology. 

2. Nahmias Y. Biologic Drug Development and Manufacturing.

3. PictoriLabs. PictorLabs Launches with More Than $18.8 Million to Advance Transformative Virtual Staining. Press Release. Dec 1. 2022.

4. Mishra, S.; Hauck, W.; Royal Z.; and Michalik R., Introduction to Pharmaceutical QMM Model: QMM Assessment to Promote Pharmaceutical Operational Excellence, 

5. FDA Quality Management Maturity (QMM) Overseas Pilot Progran Findings: Going Beyond the Regulations, 

6. Mirasol F. Driving Manufacturing Improvements Through Viral Vector Advances. 

7. Fisher, A. Nurturing Manufacturing Agility,

8. Kaiser A.; Assenmacher, M. Towards a Commercial Process for the Manufacture of Genetically Modified T Cells for Therapy. 

When referring to this article, please cite it as C. Spivey. Six Approaches Making the Most Significant Impact in the Future. 

This compilation allows readers to adjust their thinking to appreciate the full impact certain select technologies will make on the industry by 2026.

Six Approaches Making  the Most Significant  Impact in the Future

It’s easy to get excited about flamboyant paradigm breaking inventions. As editors, we don’t hesitate. Coverage of COVID-19 vaccines, alongside the business and regulatory innovations that allowed their warp speed passage, was surprisingly displaced by this year’s astounding oncology and iconoclastic gene therapy “cures.” Without taking shine off these mercurial performances, the background workhorse approaches and tools to these atypical advances have generated consistent growth, performance, and adaption to increasingly complex demands.

By sheer readership percentages, the most absorbing content in 2022 was ALCOA+ (attributable, legible, contemporaneous, original, and accurate—with complete, consistent, enduring, and available components added). As Industry 4.0 demands spread, there is increasing need for more layers of deeper equipment integration and coordination as digital data acquisition and transfer ramps up; hence, the need for aligning processes to ALCOA+. In close second place came perspective and context on various international pharmacopoeias and regulatory requirements, monographs, reference standards, and protocols. This is no surprise, and we’ve allocated many spots for these topics on the 2023 editorial calendars.

A fair way behind, but well ahead of all others, we see topics such as chewable tablet formulation, chromatography development and validation, tablet disintegration, dissolution testing, statistical understanding, and updating supply chains. Next are perennial primers like assessing shelf life through stability tests, establishing acceptance criteria for analytical methods, and closure design and test controls. If I were an advertiser seeking to speak directly to any of our 2 million annual website users, I would circle any of the above that my clients were active in or in some fashion, supported.

But I would also target staff recruitment and training. For ordinary roles, but also for advanced therapy medicinal products, one of the most pedestrian needs you can conjure is the experienced staff to execute these activities. Alongside digital transformation, I see trained staff (even pedestrian team members) as being a requirement no winning pharmaceutical company can avoid placing at the top of the priority list.

When referring to this article, please cite it as C. Spivey. Pedestrians as Priority. 

Coverage of COVID-19 vaccines was surprisingly displaced by this year’s astounding oncology and iconoclastic gene therapy “cures.”

Pedestrians as Priority

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