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

Chris Spivey

While waiting on a freeze-dried long shelf-life vaccine to be developed, the United States let its stockpile of liquid monkeypox vaccine languish and expire. By 2017, all 27,993,370 doses in the national Jynneos stockpile had expired, although the US still had a huge stockpile of its other smallpox vaccines (1). While waste per se is shameful, it’s akin to Greek tragedy when the rise in monkeypox cases internationally is associated with lost opportunities to improve millions of people’s lives in sub-Saharan Africa, where smallpox was eradicated in 1980, and vaccinations halted (2). 

Many countries now face a growing threat. FDA Commissioner Robert Califf has been quick to revisit strategies discussed in the early days of COVID-19 vaccine availability, when production scarcities predominated. This includes widening the spaces between first and second doses. It also includes using an “intradermal injection”—where the vaccine is injected into the skin—rather than injecting into the layer of fat underneath the skin. Officials believe this smaller dose is able to produce an equal immunologic response, which currently seems unclear. But even if true, each vial contains perhaps enough material for around three times the number of patients, certainly not sufficient for the crisis. At least that’s the feedback from frontline healthcare workers. “We are definitely in what we’re still calling ‘The Hunger Games’ phase of this—where there’s nowhere near enough doses for the demand,” said Dr Mark Del Beccaro, assistant deputy chief for Public Health—Seattle & King County (3).

The new administration route requires using a different syringe and a different needle. This has required tapping into a different supply chain network. In addition, administration under the skin requires a new set of onsite training for staff.

Looking ahead, it’s important to remember our fates are interdependent no matter what continent you call home. It is entirely shortsighted to be disconnected from that simple fact.

M. Kozlov, “Monkeypox in Africa: The Science the World Ignored,” 

J. Goldstein, “How the U.S. Let 20 Million Doses of Monkeypox Vaccine Expire,” 

W. Stone and P. Huang, “The New U.S. Monkeypox Vaccine Strategy Offers More Doses–and Uncertainty, 

Chris Spivey is the editorial director of 

When referring to this article, please cite it as C. Spivey, “Vaccine Disconnect,” 

Articles

More than anything else MonkeyPox and COVID-19 have shown that we are interdependent, no matter what continent you call home.

Vaccine Disconnect

In August it feels odd to be speculating what people will find important on the final days of December 2023, but that’s the job when creating next year’s editorial calendar. Sensible navigation typically means maintaining a series of fixed compass headings. But to optimize any journey one must make calculations regarding prevailing weather patterns, current good health, and the indispensability of certain predestined ports of call. As part of a large team, this engenders boatloads of discussion. Ultimately, however, we end up in the same spot and in the same boat.

Writing about the calendar allows me to illustrate how inputs arrive from diverse sources. This includes feedback from articles, discussion at conferences, and mining our own podcasts, video interviews, and symposia presentations. An upcoming September Drug Solutions podcast is a conversation with Dr. Uwe Schoenbeck, chief scientific officer, External Research and Development Innovation (ERDI); and senior vice president, Worldwide Research and Development (WRD), Pfizer. Quite a job title and quite the challenging job. He is also navigating the industries future, albeit with a broader mission than our editorial team. In this dialogue, Uwe covers what’s important to Pfizer when in comes to partnering, by emphasizing areas such as repeat expansion disorders, senescence, DNA damage response and nucleic acid sensing, deubiquitinase pathways, and neuroinflammation. Pfizer feels these hold special promise for new innovative therapies.

And I was struck by a Parthian shot. “An area everyone, including us, is looking into for further improvements,” he fired at me, “is targeted delivery. True not just for RNA but true for small molecules, large molecules, and also oligo-based therapies … there’s a lot of activity for lipid nanoparticles for local delivery, there’s a lot of activity in the capsid space, so any kind of tropism that you can introduce that would really be selective, and could be dialed in and out as desired, would be a very promising platform that we would be very interested in, obviously.”

I can look into the future and it is manifestly obvious targeted delivery will be on next year’s calendar.

When referring to this article, please cite it as C. Spivey, “Navigating the Future,” 

Promising applications for targeted delivery may be cresting the horizon.

Navigating the Future

Of necessity, we are living in a post Lipinksi rule of 5 world. No one expects traditional approaches will meet future needs. Both small and large molecules, having some form of accelerated designation, are proliferating in the pipeline. Small-molecule drugs suffer longstanding issues with bioavailability and solubility, as key development considerations. As we reach further afield in the molecular universe to overcome these issues, we encounter new types of problems to resolve.

Broader molecular diversity inhibits progress in the sense that diverse groups cannot come to agreement on basic questions of biology, patient safety, and manufacturing guidelines. What is an effective but safe total vector genome dose per kilogram, for example? Or does the percentage of empty capsids hurt or help a therapy?

There is an absorbing observation in a podcast by Nicole Paulk, a professor at the University of California San Francisco, who reflects that one can argue opposite cases from the literature (1), … “empty capsids might be a good thing because they can sop up like a sponge these preexisting neutralizing antibodies against that particular capsid serotype, so that more, full packaged capsids can get to the target tissue to transduce. But then there is also literature that says the more empty capsids that you have, the less potent your vector is, and that these also might be immunogenic, because they might not be perfectly formed capsids, etc. … and they might have their own modifications on them, or be packaging non-desired genomes, such as host cell genomes in which these viruses were made in.” Disagreement on basic biology is going to cause differences in industrial process design decisions. Eventually guidelines will be produced, but until then, their lack will act as a drag on progress in manufacturing. And that is true for all the new molecular chemistries we now confront.

The industry may want to establish a sort of chemical diversity and inclusion training program for process development departments. In sport, the Olympics exhorts us to go “faster, higher, further”. Pharmaceutical sciences may want to consider operating on a “faster, smarter, broader, and more digital” footing.

Phacilitate, Does AAV Have a Long Term Future? With Nicole Paulk, Phacilitate Talks, Podcast, 

Chris Spivey is the Editorial Director of 

When referring to this article, please cite it as C. Spivey, “Process Development Struggles with Molecular Diversity,” 

As we reach further afield in the molecular universe, we encounter new types of problems to resolve.

Process Development Struggles with Molecular Diversity

Authorities and governing bodies have lost the public’s trust when it comes to pandemic response. I won’t discuss the how or why of that here, suffice to say front line nurses using garbage bags as personal protective gear and a lack of ventilator and intubation equipment (and in some cases oxygen), or diagnostic tests are components. But I hadn’t anticipated saying that the United States has begun releasing a monkeypox vaccine from the Strategic National Stockpile to protect high-risk people.

In 2013 when researching pandemic threats, Peter Daszak, president of the EcoHealth Alliance, collected 1897 samples from flying fox in the wild. He identified 55 viruses in nine viral families. Of these, only five were previously known, including two human bocaviruses, an avian adenovirus, a human/bovine betacoronavirus, and an avian gammacoronavirus. Another 50 were newly discovered. This brought the estimate of viruses in wild flying fox to 58. Extrapolating for all 5486 known mammals, we yield a total of 320,000 viruses which interact with humans—in unknown ways—both good and bad (1). But we have a messy and varied microbial soup beyond mammals and viruses who harbor potential pathogenic virulence. Bacteria, Fungi, Protozoa (causing such things as malaria and amebic dysentery), helminths, and prions all engage and interact with us.

We dodged a bullet with the coronavirus dubbed COVID-19. In early 2017, Graham and McLellan at Vanderbilt worked with Moderna on a plan to combine their precision antigen design with Moderna’s rapid and potent messenger RNA (mRNA) delivery (2). They focused on two virus families: coronaviruses (represented by MERS-CoV) and paramyxoviruses, for which Nipah virus had caused periodic outbreaks in Asia, as the prototype. By early 2020, they had designed the vaccine, and Moderna was ready to manufacture the Nipah mRNA vaccine and take it into a human clinical trial. But on Jan. 6, 2020, word came that Chinese scientists had isolated the virus that had caused a problem in Wuhan. So, they pivoted to create a potential vaccine to test within weeks.

I suggest we create a new foundation to win back the trust the public lost in recent years. What signifies most is that it is independent of the traditional ways of handling pandemics, with strong leadership led by the United States Pharmacopeia, The International Society for Pharmaceutical Engineering, and the research universities of Vanderbilt, Emory, and perhaps the Karolinska Institute. These are all serious people who perhaps don’t want to lead and game plan pandemic organizing, but who because of that reticence I contend may well be best suited to do so.

1. S.J. Anthony, et al., mBio 4 (5) ASM Journals (Sept. 3, 2013).
2. M. Blanding, “A Dose of Hope,” Research News, Vanderbilt University, May 17, 2021.

When referring to this article, please cite it as C. Spivey, “The Next Pandemic,” 

The Next Pandemic

Pharmaceutical Quality/Manufacturing Standards (CGMP) Data Integrity and Compliance With CGMP

, FDA began discussing its remit with a foreboding introduction stating that, “In recent years, FDA has increasingly observed CGMP [current good manufacturing practice] violations involving data integrity during CGMP inspections. This is troubling because ensuring data integrity is an important component of industry’s responsibility to ensure the safety, efficacy, and quality of drugs, and of FDA’s ability to protect the public health. These data integrity-related CGMP violations have led to numerous regulatory actions, including warning letters, import alerts, and consent decrees” (1). The context and consequences of those warning letters was made clear in com- mentary by Peter Zipfell, product marketing manager at Thermo Fisher Scientific, who spelled out that “... based on findings from a 2019 report on drug shortages, of 163 drug shortages in the US between 2013 and 2017, 62% of supply disruptions were associated with manufacturing or product quality problems” (2).

 (updated February 2020), the second recommendation was to “create a rating system to incentivize drug manufacturers to invest in achieving quality management system maturity... as the market does not recognize and reward mature quality management systems. This recommendation aims to rectify this failure by suggesting the development of a system to measure and rate the quality management maturity (QMM) of individual manufacturing facilities based on specific objective indicators” (3). This new framework appears near introduction as FDA issued a white paper last month (March 2022) on the QMM program and will be holding two workshops in May to gain further input from stakeholders.

The drug shortages report goes on to say that, “A rating system could be used to inform purchasers, Group Purchasing Organizations (GPO) and even consumers about the state of, and commitment to, the quality management system maturity of the facility making the drugs they are buying. Pharmaceutical companies could, at their discretion, disclose the rating of the facilities where their drugs are manufactured. GPOs and purchasers could require disclosure of the rating in their contracts with manufacturers. This effort would introduce transparency into the market, and provide firms committed to quality management maturity with a competitive advantage, potentially enabling them to obtain sustainable prices as well as grow market share” (3). So, change is coming, and with it the requirement to tighten up on how data are collected, collated, and shared.

Because past is prologue, BioPharm International asked Edita Botonjic-Sehic, director, Global Analytics, Pall Life Sciences if the original push by FDA to promote process analytical technology (PAT) adoption was helpful in setting expectations and in creating a new tools and services ecosystem. “Yes,” Botonjic-Sehic says, “advanced technologies and computation modeling has contributed significantly to making this capability come to life. By utilizing PAT into integrated bioprocessing, better process understanding is gained, production cycle time is reduced, improvement of yield is achieved, efficiency is improved, and cost reduction is achieved by the reduction of waste and energy consumption resulting from the real-time release of a batch with improved quality.” She goes on to explain, “Biotech processes consist of several unit operations, with each unit operation serving a defined purpose. The need for appropriate control of each step and continuous evaluation of its performance is critical. To date, there are still gaps in the area of advanced analytics for the process; however, computational modeling has slowly started to contribute towards process characterization. The goal is to have both process technologies and advanced computing used in real-time for process control.” So along with the rest of the world, pharmaceutical manufacturing is becoming a digital undertaking.

When asked if increasing compliance and validation requirements lead to more processes and documentation burden, Botonjic-Sehic responded that, “Data driven frameworks and transformation to digitalization will lead to a new future state. There are still many challenges in bringing technological innovation and advancement due to lack of adoption and change in processes ... FDA has been very much involved with the industry to support the adoption of the advancements in the process. It may seem as if it is complex at this given moment; however, the ultimate goal is to make the process and filing seamless and putting in the effort upfront is a necessity in order to make the future of manufacturing much easier.”

Measuring complex product quality attributes

For the future of the industry, does biological complexity require a more diverse set of scientists and wider array of team members? Botonjic-Sehic consid- ers a “lack of advanced process analytical technologies capable of measuring product quality attributes in real-time [as] a change today; however, Pall Life Sciences and many other companies have been investing in making these technologies available to customers that support biotherapeutics manufacturing. Computational techniques supporting predictive outputs of the process are also at the early stages; however, we have seen a much larger uptake of such innovations being utilized in the bioprocess. Integration of process technologies and advanced analytics will support Industry 4.0 and provide bioprocessing manufacturing with real-time process monitoring and control. As far as scientific experts— many of the process analytical scientist and chemometricians (data scientist) come from small molecules manufacturing industry and there is a growing need for these skills sets to move forward faster as we progress in providing advanced technologies for biomanufacturing processes,” concludes Botonjic-Sehic.

This coincides nicely with comments from Dr. Natalia Vtyurina, senior quality assurance officer at HALIX B.V., who, in a blog post for the International Society for Pharmaceutical Engineering (ISPE) emphasized that in every highly regulated industry there are specific rules and regulations that when embedded in guidelines, help shape both culture and data collection while streamlining future planning and optimization. Dr. Vtyurina points out that “a data integrity (DI) maturity program uses standard rules and procedures that will take the organization through all aspects of DI. It will support your organization towards a safe environment and a strong culture by properly managing data, ensuring high-quality standards, and improving efficiency. On top of ensuring a high-quality product, your business’s core processes’ costs will be significantly reduced. A DI program will also help you to identify, remediate, and manage potential risks to DI” (4).

To round out the discussion, BioPharm International asked Stefan Holzner, vice president R&D, Pall Life Sciences, if momentum toward modular manufacturing with continuous adjustments and improvements creates a premium for real-time feedback, and has the industry hit a rate limiting bottleneck or bottlenecks. Stefan’s position is that there is a need to get real-time data and make it actionable. “This requires state-of-the-art sensors to cover a wide array of parameters (including different types of metabolites etc.). The data needs to be transferred into insights to make them actionable. Multivariate data analysis could be a tool to achieve this. However, it does (seem) like we have reached a bottleneck as new sensors are required that enable better real time data as well as the proper ecosystem to process this data in real time and allow insights to act accordingly,” Holzner says. Some growing pains allows us some room to grow into, it seems. Data are now how business performance is officially measured and recorded. The sooner DI is controlled for, and firmly established, the earlier organizations will reap its rewards.

Guidance to Industry, Data Integrity and Compliance With cGMP

2. P. Zipfell, “Strengthening Data Integrity and Traceability,” 

Drug Shortages–Root Causes and Potential Solutions

, 2019, updated Feb. 21, 2020 (FDA, 2019). 

4. N. N. Vtyurina, “Why is Data Integrity Critical in the Pharma Industry,” iSpeak Blog, 

FDA continues efforts to incentivize drug manufacturers to follow higher data integrity requirements.

Ensuring CGMP Standards for Data Integrity

Quality will forever be a topic of discussion for the pharmaceutical industry, and who better to share their insight than FDA? Director of FDA’s Office of Pharmaceutical Quality, Michael Kopcha,deputy director of science, Sau Lee, anddeputy director of operations, Cindy Buhse, join Chris Spivey, editorial director, for a discussion about:

The framework for regulatory advanced manufacturing evaluation (FRAME)

Quality as a co-dependent variable of economic outcome

Advanced versus traditional manufacturing

Pandemic pressures and improved communication

Keeping up with biotech and emerging therapies

Re-shoring drug manufacturing to the United States

What manufacturers need to understand about advancing pharmaceutical science


Michael Kopcha, PhD, R.Ph., Director of the FDA’s Office of Pharmaceutical Quality (OPQ)

, PhD, R.Ph., is the director of FDA’s Office of Pharmaceutical Quality (OPQ). This office has more than 1,300 staff responsible for assuring the availability of quality medicines for the American public through assessment, inspection, surveillance, research, and policy. OPQ contributes to the assessment of nearly every type of human drug marketing application including new drug applications (NDAs), abbreviated new drug applications (ANDAs), and biologics license applications (BLAs), including 351(k) applications (i.e., biosimilars). OPQ also performs the quality assessment of investigational new drug applications (INDs) and establishes quality standards for over-the-counter drug products and facilities. Dr. Kopcha earned his doctorate and master’s degrees in pharmaceutical science and a bachelor’s degree in pharmacy from Rutgers University. He served as an adjunct assistant professor in the Department of Pharmaceutics at Ernest Mario School of Pharmacy at Rutgers.

Sau Lee, PhD, Deputy Director of Science, Office of Pharmaceutical Quality, CDER at FDA

, PhD, is the deputy super office director of science in the Office of Pharmaceutical Quality. He directs the activities of staff members in OPQ sub-offices responsible for the quality assessment of regulatory submissions (OBP, OLDP, ONDP, and OPMA). He represents OPQ in programs and activities that impact quality assessments by coordinating with OPQ, the Center of Drug Evaluation and Research (CDER), and ORA. He also serves as the point person for the pharmaceutical industry and scientific/academic groups in developing programs to support science- and risk-based application assessment and approval. Prior to joining FDA, Dr. Lee received a bachelor of science degree in chemical engineering from the University of Virginia with a minor in materials science and a PhD in chemical engineering from Princeton University.

Lucinda (Cindy) Buhse, PhD, Deputy Director of Operations, Office of Pharmaceutical Quality, CDER at FDA

is currently the acting senior advisor for scientific operations in the OPQ in the CDER in the FDA. Dr. Buhse joined FDA in 2001 in OPQ’s office of testing and research. She was the director of the office of testing and research from 2013 to 2017 and the director for the office of quality surveillance (OQS) from 2017 to 2019. Before joining FDA, Dr. Buhse worked in management positions in production, validation, and analytical services at Sigma Aldrich Corporation and as a senior research scientist for Rohm and Haas Company. Dr. Buhse received a B.A. in chemistry from Grinnell College and a PhD in physical chemistry from the University of California, Berkeley. OQS assures that quality medicines are available through signal detection, data analysis, review of the state of quality, and proactive stakeholder engagement.

 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.

Podcasts

In this episode of the Drug Solutions Podcast, Chris Spivey, editorial director, interviews Michael Kopcha, Sau Lee, and Cindy Buhse of FDA about not being afraid to try new approaches and how they invite fresh ideas and abundant communication.