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

Chris Spivey

Videos

This video is an interview with Jon Brice, Vice President of Business Development at Asymchem at the AAPS Conference in Boston, Massachusetts.

 Asymchem Interview (AAPS 2022)

Content is king in publishing, but interpretation is imperator. Marie Brown, group vice president at RX (organizers of the INTERPHEX conference) recognized this fact when underlining the new relationship between INTERPHEX and the American Association of Pharmaceutical Scientists (AAPS) saying, “We are excited that AAPS will elevate and expand the content to attract and satisfy the educational needs of research scientists and provide that important link between science and commercialization” (1). The skill to knit together coherent and actionable messages from disparate data inputs is what sets a premium on great interpretation over great content alone. As if to embody this very message, Annette Bak, head of drug delivery at AstraZeneca, modeled a splendid T shirt at the 2022 AAPS PharmSci 360 conference that said a researcher is “an expert at identifying, collecting, generating, interpreting, and analyzing data…”

The point being that while its truly wonderful to see, touch, and admire a vast ocean of sophisticated tools, reagents, instruments, and packaging machinery, it is far better to hear and understand why each advance or twist in engineering makes a sizable difference on next process steps, on required resources (including time), and eventually, and on how all this matters to the biology of a patient.

Context and alternative choice matters. In this edition, we have an article on “Process Development and Control for New Modalities” discussing challenges and choices arising from molecular diversity (see page 10). The lack of platform processes is obvious when considering specific modalities. Process and analytical standardization is a challenge for messenger RNA (mRNA) because of the diverse types of mRNA and different encapsulation technologies, according to experts cited in the article.

The task of relating what is happening is simple and useful. But the utility of hearing what is driving choice, and what alternate strategies are effective, is a value beyond reckoning. This is why conference season is so valuable, and why as much as can be crystalized and distilled into print is the mission of the publisher’s role. As always, we hope you will share what you have learned also.

1. J. Davis, AAPS Media Advisory, Oct. 19, 2022.

Chris Spivey is the editorial director of 


Volume 46, Volume 11
November 2022
Page: 10

When referring to this article, please cite it as C. Spivey, "Conference Time Brings Gifts," 

Articles

Content is king in publishing, but interpretation is imperator.

Conference Time Brings Gifts

In business, understanding future key variables ahead of competitors provides a decisive advantage. In highly regulated industries, such as pharmaceuticals, this includes policy and compliance filing changes. Despite an editors’ mission being to educate and inform, I have been conflicted about sharing the following. The reason the first and second rules of fight club are famously “do not talk about fight club” is that productive events often depend on a delicate framework balancing expression, fun, and flexible social mores against a need for certainty and durable authoritative institutions. The annual PDA/FDA Joint Regulatory Conference is, in this way, the same as fight club. I concluded that sharing the fact that there are secrets is entirely different from sharing any of the secrets themselves.

Advertising for the conference says it “is designed to share approaches that facilitate sustainable compliance with CGMPs [current good manufacturing practices] by addressing emerging risks to manufacturing and supply chain reliability [and that] it will provide forums for open discussion between FDA representatives and industry experts, and offer opportunities for the application of approaches that enhance assurance of raw material quality, quality assurance management of contract manufacturing relationships, root cause analysis, and use of current technologies... [and that] key themes will include leveraging the digital and automation revolution, contamination control strategy, latest FDA CGMP trends, how to respond effectively to FDA 483s” and so on (1).

Pivotally, this description left out the secret that “open discussion” extends to a willingness to listen and take into account new information and anecdote, genuine attempts to learn about and resolve short and long-term problems, and heartfelt honest opinion and conjecture. Cumulatively, that makes this event easily the most useful time spent during the year. Details themselves are expressly “off-the-record” and not to be talked about outside of the event. That’s the engine that generates the power of this event, creating more light than heat. Attendance will provide a decisive advantage to anyone attending, and there’s clearly no reason to fight about that.

1. FDA, 2022 PDA/FDA Joint Regulatory Conference, Events, 

When referring to this article, please cite it as C. Spivey, "Industry’s Best Secret," 

One can only learn the secrets of "fight club" by attending its meetings.

Industry’s Best Secret

Through research collaborations, consortia, licensing, investments, and acquisitions, the emerging science and innovation team at Pfizer seeks to harness external, cutting-edge preclinical assets and novel technologies in emerging therapies. Increasingly, the focus is on true first-in-class mechanisms, if not only in class programs, that would allow real breakthroughs for patients. 

Chris Spivey, editorial director, interviews Uwe Schoenbeck, senior vice president and chief scientific officer for emerging science and innovation at Pfizer. Some of the areas discussed include 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.

 is chief scientific officer, external research and development innovation (ERDI), and senior vice president, worldwide research and development (WRD), for Pfizer. ERDI is responsible for identifying and establishing relationships with key external partners to capitalize on complementary areas of expertise. Through these collaborations, ERDI creates unique opportunities for Pfizer researchers and partners to drive the discovery and development of potential new therapies that address areas of high unmet medical need.

 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

How Pfizer’s external-facing research and development scientists uncover the most promising emerging therapy concepts and ideas in the pharmaceutical landscape. 

Drug Solutions Podcast: How Pfizer Views Partnering and Investing for Emerging Therapies

Laying the foundation stones for creating the right environment to be successful in solid dosage forms can sometimes come down to literally laying down the right brick and mortar building foundations and walls. Pharmaceutical Technology discussed trends and opportunities with experts for good manufacturing practice (GMP) guidance for manufacturing, testing, and quality assurance of products. This built in minimum quality management system is custodial to assure manufactured drug products are safe, both the end user, and also for those working to produce them. In the background it is useful to note that the pharmaceutical community is approaching harmonization, but key differences remain. Pharmaceutical companies must be cognizant of this if they plan to sell their products globally.

From a quality, regulatory, and facilities standpoint, what priorities need to be established to achieve optimal design for a new or existing good manufacturing practice (GMP) facility, and ensure consistent quality of the end product? Richard Anderson cleanroom specialist, of WHP Engineering diplomatically asserts it “depends on a detailed understanding of every stage of the process. WHP’s ‘inside out architecture’ is based on sizing of rooms, room adjacencies, set down areas, warehouse spaces, and packing rooms, in order to achieve the best layout and eliminate bottlenecks. Once we have the layout, we can work out the classification of cleanrooms, air flow patterns, and pressures. We then look to protect the person, product, and environment, and to maximize energy efficiency and sustainability.” So, in the descending order of priorities, at least from an engineering company’s perspective, the space itself, and the structure comes first. This makes even more sense when Anderson continues, “In general, manufacturers will continue to produce their specific product under licence using the same facility and equipment until the licence expires. Only when they need to bring new products to market, will they consider innovative approaches, for example in spray drying, compounding, granulation, or formulation.”

Anderson has seen a lot of trends in facility design come in and out of focus. “Ten to 15 years ago, we used to strip out existing facilities and put in new ones because of cross contamination issues, but we're not seeing that anymore. Instead, even Big Pharma is keeping equipment, carrying out deep cleans, and testing to ensure that there is no trace of possible contaminants, and revamping manufacturing lines. The envelope will change, or the machines might be upgraded, and new packaging lines might be introduced, but they are still able to achieve cost savings by maintaining the same facility. Historically, manufacturers have tended to favor large-scale batch production, and some of our customers choose to maintain this approach. Other manufacturers are switching to smaller batch sizes in higher value products in order to improve the quality of products and speed up the process times. The market is very diverse, and we get different messages depending which customer we talk to.”

Looking at a more global perspective, he continues, “In terms of regulations, [Europe’s] Annex 1 tells us if we need to do anything different as designers. Some fill areas are under Grade A with Grade D background, and we're now seeing Grade A with Grade C background. Open filling is done in Grade A with Grade B background. This shows that some of the classifications and cleanliness regulations are improving, depending on whether or not your process involves open filling, the type of packaging line, and whether it's a tablet or an oral dose.”

Ali Rajabi-Siahboomi, Vice President & Chief Innovation Officer from Colorcon outlines a few major trends to be aware of, saying that “new drugs coming to solid dosage formulations are more potent and have chemical sensitivities that require careful handling to ensure safety and overcome the risk of exposure as well as protect from environmental conditions such as moisture, oxygen, and temperature controls. An example is the development and manufacturing of macromolecules for oral drug delivery which require more complex and tightly monitored facilities to ensure safety and quality of the finished product.”

This thread is somewhat picked up and expanded upon by Anderson, who continues, “From an HVAC and containment, airlocks, fire and safety standpoint—everything must be considered in terms of the rising demand for certain types of solid oral dosage manufacturing modalities.”

Dave Di Prospero, associate director, Pharmaceutical Process Technology at CRB Consulting Engineers emphasizes that, “use of airlocks, both material and/or personnel, in concert with HVAC pressurization schemes, provides for the greatest flexibility when looking to future proof an oral solid dosage (OSD) manufacturing operation. Especially when considering high potent compounds. Airlocks, used as a transition between different space classifications (e.g., Controlled not classified (CNC) to Grade D) is a longtime practice that is well accepted by nearly all international regulatory agencies. This facility design configuration offers contained and controlled operations and is often the standard for multi-product facilities.”

Anderson agrees and stipulates that, for “heating, ventilation, and air conditioning (HVAC) designers, the main challenge is containment of powder, as it may be toxic or potentially explosive. Cross contamination is also an issue, and this can be reduced with air handling unit AHU zoning. Humidity control is expensive but a must when dealing with gel products, and new heat recovery systems can help to reduce the high running costs. Reflecting further on a somber tone.” He adds, “In the case of powders, liquids, and any gaseous vapor, it is vital that the substance is contained within the room, to protect both the product and the environment around it. With the clever use of bubbles and sinks, and negative pressure regimes we can minimize the risks while maintaining cGMP [current good manufacturing practice] requirements. An analogy is if you have a birthday cake, no matter how hard you try, you can’t suck the candles out. Similarly, the way to control powders is to push and pull, so you push by blowing and you pull in the right direction, and it's this push-pull approach that helps achieve containment. Due to the risk of explosion, some products require ATEX (explosive)-rated areas in case the ventilation system fails to contain the product. Fire is another potential hazard, and specified fire protection can be achieved through the use of suspended ceilings constructed from white-faced mineral fiber fissured tiles in a lay-in grid, galvanized-finish column casings, and protective fascias.”

Picking the right formulation under expedited commercial timelines

On this score, Di Prospero, with many years of first-hand knowledge, urges anyone to keep it as simple as possible. He states clearly, “whenever possible, direct compression formulations remain the easiest and quickest processing platform for getting new products to market. Direct compression requires the fewest number of unit operations and is the least complex of the typical OSD processing platforms. Ingredients are weigh/dispensed, blended, and compressed. Depending upon the powder properties tablet coating may or may not be needed,” he concludes.

Rajabi-Siahboomi singles out a need for speed, saying “there is more and more emphasis to expedite new product developments and commercialize for not only early access by patients—FDA process supported (e.g., orphan drugs) but also to maximize the commercial exclusivity for the company. A successful and timely formulation development begins with an in-depth understanding of the critical attributes of the API such as its solubility, any structural sensitivities and incompatibilities, dose ranges to be formulated, physical attributes, and target release profile for optimum therapeutic outcome.” He continues to drill down saying, “depending on these parameters, suitable excipients and formulation enablers are selected to ensure the stability of the API in the finished dosage form during storage, as well as its stability post administration and exposure to the biological media. There are various excipients available to bring functionalities like bulking, binding, glidants, and disintegrants, and the suitability of these ingredients for specific API should be tested and understood. Modified release technologies using appropriate polymers are designed to develop different delayed or extended release profiles.”

Interesting new approaches to manufacturing processes

When it comes to what matters most going forward with building designs for drug GMPs, the industry is clearly, from regulators on down,and C suite on down, encouraging , continuous manufacturing (CM) to top the list. CM is fueling rapid adoption of process analytic technologies (PAT) as a process and quality control tool. “Being able to perform real-time quality assurance and real-time release testing is essential to harvest the full benefit of CM,” says Fernando Muzzio, a professor at Rutgers University who has been leading major efforts with the US government and industry in the space. “This requires the integration of highly capable sensing systems into the manufacturing process. Moreover, once this approach becomes well-established for CM, it can be adapted for many batch processes as well,” a benefit he encourages to be more widespread.

Di Prospero, equally well known on this topic concurs. “Continuous OSD manufacturing has now secured a place in many modern manufacturing operations. If not as a stand-alone replacement to batch operations, at least as an additional processing platform in the arsenal. The benefits seen and proven in CM, as related to the elimination of scale up, improved closed and contained systems, product quality improvements via data analytics and

PAT, significant reductions in facility size, and the approaching of real-time release testing makes continuous OSD manufacturing an approach well beyond just an emerging niche.”

Anderson adds some color and crime into the picture. “The industry is changing in terms of in process monitoring and the ability to check products at every stage of the process,” he agrees. “Improvement in raw material APIs has seen an increase in quality with lower wastage and less rejected finished product. Improvements in equipment have also helped to achieve higher quality finished products. Mapping the production process from raw materials to end delivery is essential to highlight weaknesses and the potential for improvement. It may not be possible to achieve the optimum design initially, but this should be built into a strategic plan for the next phase of development following a successful product launch. Many of our customers have put fallow areas into their plants with critical utilities in place to allow future expansion to be carried out quickly and at minimum cost.”

Anderson continues. “Forward planning offers greater flexibility, and we can help to factor in potential changes to the production processes, for example, so that they will be suitable for smaller batch sizes or different end products. This means that the plant might be configured in a specific way to give larger areas, with a number of smaller suites for bespoke products. Understanding how you go through the approval process and demonstrate that a facility is fit for purpose is key. Security may become more of an issue with decentralised facilities and will depend on how attractive the product is to criminals. In the United States, pharma manufacturing facilities are under increasing threat from criminal gangs.” The more elegant of these are also on the rise, through the use cyber attacks. But sadly, Anderson is referring to smash and grab events. Something few executives would have considered only a few years back.

Chris Spivey is the editorial director of Pharmaceutical Technology.

Creating building blocks for good manufacturing practices is essential.

Building GMPs for Solid Dosage

Елена Бутусова - STOCK.ADOBE.COM

True breakthroughs are never in plentiful supply. Recognizing reality, Uwe Schoenbeck, PhD, senior vice president and chief scientific officer for Emerging Science & Innovation (ES&I) at Pfizer, has synthesized and made functional core lessons from two of the past decade’s best business books: 

 (2). His ES&I group, through the power of independent invention and collaboration, applies methods described in these books to the tasks of uncovering, cultivating, and nurturing novel drugs and therapies. No two trees in his orchard are exactly alike, and some bear fruit only when many seasons of doubt, change, and struggle have passed by. But as the COVID-19 vaccine and messenger RNA (mRNA) success stories illustrate, early adoption of new technologies can establish substantial long-term gains—as well as provide emergency solutions when needed. Whatever the season, there is always something taking root and growing at Pfizer.

Each morning, a vast landscape of activity and invention to sift confronts the ES&I team. This team’s X-axis is a challenge that can be described as identifying the right partnering opportunity particularly for less known early science developments and technologies. Pfizer relies on its Emerging Science Leads (ESLs), a team of seasoned PhD/MDs to search for and evaluate opportunities from academia and the biotech industry for Pfizer’s R&D organization. According to Schoenbeck, ESLs are highly experienced in the relevant disease area and embedded within the respective therapeutic areas, resulting in high strategic alignment of the opportunity being sourced and avoiding opportunities that are not a strategic fit (1). Schoenbeck adds, “It’s easier to identify what’s complementary if you have an understanding of the therapeutic area and what’s not on the typical partnering list that might be cutting edge.”

Each afternoon that same team takes what they’ve uncovered, turns it sideways, and overlays this onto their Y-axis—an $80 billion dollar a year enterprise already populated with 80,000 competitive busy staff (3, 4). The ES&I team, in conjunction with colleagues working in Business Development, has stood out for bringing genuinely creative partnership ideas and innovations into an already creative and crowded environment. “They’re not just the typical corporate venture type of series A, B, or C,” continues Schoenbeck from a 

Pharmaceutical Technology Drug Solutions 

podcast (5). “Increasingly, we’re doing more seed investments, new company formations, really trying to enable cutting-edge, emerging science areas that we see on one hand strong strategic fit to Pfizer. On the other hand, [areas] also holding a lot of potential—but really early, needing more work before you could fully implement them.” A long, successful track record has cleared the decks for Pfizer to go earlier than most, to uncover exciting advances as they happen, before first bloom.

To augment integration capability on the Y-axis, Pfizer brings internal expertise, capabilities, and resources. Discussing Pfizer’s Centers for Therapeutic Innovation (CTI), for example—a collaboration model that helps translate early scientific concepts into potential drugs—Schoenbeck says, “We do have a number of wet bench capabilities, our own labs through which we run a portfolio of about 25 or so projects, and these projects are partnered with academic or very early stage biotech companies, which focus on cutting edge new projects.”

Using its many flexible partnering and collaboration vehicles, Pfizer has been identifying strong partners in both the academic world and in the biotech industry to help its scientific engine and company at large make changes it needs in the gene therapy, mRNA, and degrader spaces. The most recent and most notable example would be the multi-year partnership Pfizer established with German biotech company, BioNTech, to deliver the world’s first COVID-19 vaccine in 2020. But before the pandemic arrived, the two companies had been in discussions since the early 2010s, first about the use of mRNA for oncology and later establishing an agreement for influenza.

While COVID has been on the frontlines of the company both in headlines and scientific delivery, Schoenbeck’s team has continued to plant and grow its roots in other areas. For example, in early 2022 Pfizer announced several collaborations designed to augment its leadership in mRNA. Their agreement with Beam Therapeutics will leverage Beam’s base editing platform in support of potential therapies for rare diseases. A collaboration with Acuitas will allow Pfizer to explore the use of their lipid nanoparticles (LNPs) to deliver a variety of vaccines or therapeutics. Finally, a collaboration with Codex DNA will potentially streamline the mRNA production process by facilitating synthetic DNA assembly, another notable fruit of the team’s labor to bring forth a competitive pipeline in gene therapy. Through gene therapy partnerships, such as 2019’s deal with Vivet Therapeutics to advance a treatment for Wilson disease, Pfizer now has one of the most competitive pipelines in gene therapy in the industry.

Increasingly, Pfizer’s focus is on a “true first-in-class mechanism, if not only in class kind of programs, that would allow us to bring real breakthroughs to patients.” Schoenbeck continues, “So these are by definition a higher-risk approach, a higher-risk kind of biology, but they hold a lot of promise and could provide a very strong fit to the Pfizer R&D organization, if we can then build a pipeline and portfolio around those areas … So, you really need to start thinking early and clearly about where do you want to focus your search? Where do you want to place your bets? And what’s important to us is actually that when we partner, we really partner in the true sense of doing things jointly … not just to bring in the intellectual property in-house or anything like that. It’s really about identifying an academic or biotech partner, that can bring something to the table that would be very complementary … allowing us to do something to benefit patients that neither of us could do alone.”

How to manage risk without risking innovation

Many approaches sound great on paper, or even anecdotally, so how does ES&I manage risk? “I think each company might take a different approach, but the way we have thought about it is that you want to have a balance in your portfolio when it comes to risk. Risk can be defined as risk in biology, risk in development, risk in therapeutic modality. If you have a mature modality, but you go for a new target, that’s one level of risk. If you go for a novel target and a new therapeutic modality and invention in your development direction, then you’re really multiplying your risk. Obviously, the COVID-19 vaccine was one of these examples that fortunately has been quite successful but really was a high-risk approach. You can do this where you really see the need for patients, where you really see the potential for breakthrough, but you can’t do it for every single program in your pipeline obviously. Now on top of that, as I said earlier, you want to make sure you get a good feel for the cutting edge for anything that’s emerging, really promising on the horizon. And for that we have for example this ES&I team here at Pfizer. Some of the areas that we’re focusing in on include 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.”

All of the fields mentioned previously are newly emerging and require technical bravery and alongside special care. The book 

 mainspring metaphor borrows from material science concerning phase transition as applied to both creative (artistic) and execution (soldier) teams (2). Within that framework, the author, by examining a multitude of examples, asserts that structure may matter more than culture. Transplanting this to Pfizer’s orchard, Schoenbeck has successfully practiced a version of companion planting, where seedlings of different crops are carefully placed in proximity to lower certain technical or resource barriers, while simultaneously raising pollination and nutrient availability. Reduced footprint along these guidelines is seen as a feature, not a bug. The concept itself sprouted within the garden walls of the Mesopotamian proto palaces, where, “The oldest written evidence of medicinal plants’ usage for preparation of drugs has been found on a Sumerian clay slab from Nagpur, approximately 5000 years old. It comprised 12 recipes for drug preparation referring to over 250 various plants, some of them alkaloid such as poppy, henbane, and mandrake” (6). These alkaloid drugs were far from mild, and great care was taken not only in their application, but also in raising their yield, by careful germination and cultivation techniques.

So, the essential oil for the ES&I group stems from the orchard structure itself, enabling them to identify and nurture pharmaceutical creativity well before first florescence. These orchard rules follow a pattern laid out in the book 

, by Ed Catmull, who founded Pixar in 1986 with John Lasseter and Steve Jobs (1). Their philosophies, or planting scheme, defied convention and protected the creative process by institutionalizing concepts such as “the cost of preventing errors is often far greater than the cost of fixing them” and, “It’s not the manager’s job to prevent risk, it’s the manager’s job to make it safe for others to take them.”

This is a pragmatic view of what enhances the creative process, in line with that practiced by Schoenbeck. One of the strongest but subtle suggestions, being “don’t assume that general agreement will lead to change it takes substantial energy to move a group, even when all are on board” (1). This is certainly a precept worth following up on when dealing with large organizations such as big pharmaceutical companies. Catmull, however, is not above advice on pruning to promote optimal health.

His sections on recognizing “you are not your idea” point to the constant need for reality checks, and his postmortems are as important as any other section in the book. Pfizer’s ES&I team, who by their outward facing role interact with anyone performing interesting material, pharmaceutical, or manufacturing science, have perhaps taken to heart the inner core message of this book, that, “The companies communication structure should not mirror its organizational structure; everybody should be able to talk with anybody.” Last year by any measure was a bumper crop for the ES&I team, and indeed they currently top a patient group survey (7) for best reputation. Even amidst a widespread drought, Pfizer’s orchard remains well irrigated.

Creativity, Inc: Overcoming the Unseen Forces That Stand in the Way of True Inspiration

Loonshots: Nurture the Crazy Ideas That Win Wars, Cure Diseases, and and Transform Industries

Pfizer, “Pfizer Reports Fourth-Quarter and Full-Year 2021 Results,” Press Release, Feb. 8, 2022.

M. Matej, “Pfizer’s Total Number of Employees 2006–2021,” 

C. Spivey, “How Pfizer Views Partnering and Investing for Emerging Therapies,” 

Pharmaceutical Technology Drug Solutions Podcast,

Datawrapper, Respondent Cancer Patient Groups, 2021: Familiarity, and Partnerships, witih Pharm Companies.


Vol. 46, No. 9
September 2022
Pages: 16-19

When referring to this article, please cite it as C. Spivey, “Pfizer’s Idea Orchard,” 

The flow of capital and scientific acuity irrigates this pharm system.