Mike Hennessy Jr. is the President and CEO of 

Mike Hennessy Jr.

No matter how busy or complicated life becomes, science news can occasionally stop us in our tracks. Science news can be just so weird, or weirdly useful, that everything else recedes as we ponder whether it is true and what consequences it might bring.

For example, the armadillo is the only known host for the leprosy bacterium other than humans. Unimpressed? What if I told you this bacterium has the power to convert one type of bodily tissue into another? Results from a recent study show that the liver nearly doubles in size in armadillos infected with the leprosy bacterium (1). This kind of growth on the surface looks destined to be defective or even cancerous (inherent to some cell and gene therapy approaches) but the livers in the infected animals were found to be both healthy and functional, including the full complement of blood vessels, enzymes, and bile ducts that would be found in a normal liver. Professor Anura Rambukkana, who led the study, heads a group in regenerative medicine at the University of Edinburgh, that for the last decade has been pioneering an approach around cellular reprogramming. The leprosy causing bacterium hijacks the plasticity of adult tissue niche Schwann cells, reprograming them to modified stem cells, weirdly, to simply have more tissue to feed off.

There may be several practical outcomes from elucidating this mechanism. The leprosy bacterium practices this biomolecular “alchemy” at a relatively slow and natural pace, largely outflanking paths typically understood to also promote cancer growth. Because the bacterium is doing this for reasons of prosecuting its plans to “infect” its host, understanding details here may well lead to new avenues to treat or inhibit infectious disease and related pathologies such as inflammation. On his university webpage, Rambukkana states, “We are also studying how these reprogrammed progenitor/stem cells can be combined with endogenous innate immune cells with natural regenerative properties to promote repair processes in demyelinating neurodegenerative, neuromuscular, and liver diseases in varying model systems” (2).

It feels odd to say it, but I am now genuinely looking forward to hearing more about what leprosy can do for us in the future. Science, or knowledge of how the natural world works, is full of unexpected twists and turns, heroes and villains, saints and sinners. If we can turn the tables and make a villain a hero—how wonderful will that be!


Volume 46, Volume 12
December 2022
Page: 3

When referring to this article, please cite it as M. Hennessy, “Of Mice and Men and Armadillos,” 

Articles

Science news can be just so weird, or weirdly useful, that everything else recedes as we ponder whether it is true and what consequences it might bring.

Of Mice and Men and Armadillos

As a CEO in a well-regulated industry, it is a straightforward path to respect the utility of authority, guidance, standards, laws, and penalties. Complex systems function more crisply when rules and expectations are clear to all, and all are equally clear on what is required of them. It is with great pride I outline our increased coverage of this landscape now, but also extending well into 2023.

A strong series of articles called “FDA Voices” will have a bi-monthly cadence next year. This series will cover core topics FDA staff are prioritizing. This series provides unique input from the front ranks of FDA and is eye catching content and analysis. We plan to start the series with a bonus early installment in our December issue around “distributed and point of care manufacturing” from FDA’s perspective.

Well underway already has been another new series of articles surrounding “Pharmaceutical Quality Systems and Post-Approval Changes”. This series of papers, from One-Voice-of-Quality for Post-Approval Changes (1VQ for PAC), sponsored by the Chief Quality Officers of the largest pharma companies, maintains that manufacturers should be allowed to manage some post-approval changes themselves in their pharmaceutical quality system (PQS) only, and without prior approval when they can demonstrate to regulators product and process knowledge as well as an effective PQS. A perspective from a very different angle and lens.

Most unusually, I’d like to take this opportunity to alert every company to our exclusive Quality Management Maturity (QMM) series. Yet another distinct voice and perspective, this time from Somnath Mishra, president, Shabas Solutions LLC. Somnath and team ran one of two FDA QMM pilot programs. Shabas ran the overseas pilot. In December 2022, the first article will introduce QMM from a practitioner’s standpoint, and educate the industry about its many benefits, and affirm that quality maturity models are nothing new per se. This article will set the tone for subsequent articles where elaboration on practical guidance on QMM adoption at sites, and then on selected topics related to QMM implementation/adoption. Without question this invaluable series will encourage industry to begin plans on how to achieve great grades when it comes to QMM.


Volume 46, Volume 11
November 2022
Page: 8

When referring to this article, please cite it as M. Hennessy, “Voice of Regulators,” 

Next year's "FDA Voices" series will cover core topics FDA staff are prioritizing.

Voice of Regulators

Post-approval changes (PACs) are inextricable sequelae of living in the real world. “They are inevitable and necessary throughout the life of a drug product—to implement new knowledge, maintain a state of control, and drive continual improvement … Many PACs require regulatory agency approval by individual countries before implementation. Because of the global regulatory complexity, individual PACs usually take years for full worldwide approval even when they reduce patient risk, improve compliance, or enhance the manufacturing process or test methods” (1).

A modification to a vaccine, sold in a dozen different countries, can require more than 100 new approvals. If successfully handled by a robust internal (and already well proven) pharmaceutical quality system (PQS) to manage these modifications, time, energy, and money—for both the manufacturer and also the regulators—would be saved. Both 

 have published a series of position papers on this topic. They cover “Change of Lot or Extension of Shelf-life of Reference Standard”, “Change in Size of Thermal Shipping Solution Used for Transport of Product”, and “Addition of a Testing Lab to an Existing Testing Site,” among other facets.

The 2022 Parenteral Drug Association (PDA)-FDA Joint Regulatory Conference in Washington, DC truly showcased how well industry stakeholders can communicate and cooperate. Sufficient trust has been established, one would think, such that some of these product modifications can be managed in a streamlined and expedited fashion. Particularly since these positions are proposed by senior quality leaders (chief quality officers and heads of quality) from more than 20 global pharmaceutical companies, and “are speaking with “One-Voice-Of-Quality” (1VQ) to advocate for an effective management of specific PACs that currently are handled as a prior-approval change in some countries, but where a standard science and risk-based approach concludes that these should be downgraded to a notification or handled only in the PQS (2).

Special mention should be given to Emma Ramnarine, Global Head, External Development Collaborations at Genentech/Roche, and Anders Vinther, VP Quality at Kronos Bio, for galvanizing action in this field.

Pharmaceutical Regulatory Science Team, Industry One-Voice-of Quality (1VQ) for Post-Approval Changes (PAC), accessed Sept. 26, 2022. 

When referring to this article, please cite it as M. Hennessy, "Optimizing Quality," 

The 1VQ papers advocate for the idea that certain post-approval changes should be streamlined and expedited.

Optimizing Quality

The recent passing of the Inflation Reduction Act expands the Affordable Care Act and allows Medicare to negotiate for the price of prescription drugs, in a limited and phased introduction. This introduces direct government influence on drug prices, albeit in a phased and small-scale initial deployment. The median launch price of a new drug in the United States in 2021 was $180,000 for a year’s supply [fewer than 8% of drugs introduced cost this much in 2008] (1). While drug makers aren’t hiking prices of existing products quite as aggressively as they did prior to 2019, they continue to rise approximately 5% a year, according to 46brooklyn Research, a nonprofit drug pricing research firm (1). Patients’ out-of-pocket costs are only 13.3% of total costs. But these “are ultimately passed on to members of the public through the premiums they pay to keep their insurance policies active (40.4%) and the taxes they pay to the government,” Medicare 31.5%, Medicaid 9.9%, others 4.8% (1).

On August 17, 2022, bluebird bio’s one-time treatment, Zynteglo, for Beta-thalassemia (liver and heart malfunctions caused by oxygen deprivation) was approved by FDA and priced at a record $2.8 million (2). Not only sticker shock, but trendline increases for median prices are hard to ignore. To defend its cost structure, bluebird bio’s Chief Operating Officer Tom Klima pointed out that traditional transfusion intervention can cost around $6.4 million per patient, and the company will reimburse 80% of the fees if transfusion independence is not achieved after one treatment with Zynteglo. “We feel the prices we are considering still bring a significant value to patients,”
Klima stated (2).

While it is unclear how the cards will play out for bluebird and Zynteglo, it is instructive to look back to what happened to the previous most expensive drug, Novartis’ Zolgensma, which in 2019 offered discounts and outcome-based installment payments, after insurers demurred (3).

While high-priced genetic disorder treatments are here to stay, I would argue the cost of poor diet, lack of pandemic planning, poor general infectious disease control, and sporadic exercise, are a far higher cost to society, and a much more obtainable fix, than overreacting to either legislative change or wildly expensive niche treatment options. The cost of overlooking simple public health overhauls, and behavior change, is far more expensive.

R. Langreth, “Why Prescription Drug Prices in the US Are So High,” 

M. Roy, “Bluebird’s $2.8 Million Gene Therapy Becomes Most Expensive Drug after US Approval,” 

M. Nuijten, “Pricing Zolgensma–The World’s Most Expensive Drug,


When referring to this article, please cite it as M. Hennessy, “What Does Cost Mean?,” 

While the cost of certain medicines are alarmingly high, they can be considered a bargain measured against a lifetime of traditional costs. 

What Does Cost Mean?

In the pharmaceutical industry, the Venn diagram intersection between shortages and quality manufacturing issues occupies more space than anyone wants. There has long been discussion about the best way to reduce this. Recently, FDA formed a “multidisciplinary, multi-Center working group to facilitate the development of a Quality Management Maturity (QMM) rating program. This working group is developing a framework to objectively assess and rate the QMM of manufacturing sites through the integration of interactive site assessments and relevant intelligence pertaining to the site’s state of quality.” To some degree this framework has been borrowed and modified from similar manufacturing industries. In discussions, FDA is “...considering standardized assessment tools, policy approaches, industry incentives, transparency, and communications” (1).

 Drug Solutions podcast, Cindy Buhse, Deputy Director of Operations, Office of Pharmaceutical Quality at FDA, made a relevant insightful business observation saying, “I think the key words here are business processes and continual improvement. It’s not about the product. We already know the product is of high quality because its being made under current good manufacturing practices (CGMPs) with inspections and assessments and everything FDA does, so QMM is really about the busines processes, and rewarding those manufacturers who have robust processes … because if you have robust business processes and really understand your supply chain, you have risk management plans, you have continuous improvement plans in place, … you end up making sure your particular product does not end up in shortage” (2).

A paper by the Brookings Institution discusses the ongoing baby formula shortage, but also calls out excipients such as Microcrystalline cellulose and Magnesium Stearate, as of special consideration given the number of drug products affected were there to be a disruption in supply (3). It continues, saying the baby formula shortage falls into the national Academy of Science “A Framework for Resilient Medical Product Supply Chains” recommendations (4), and so should include those excipients also. Given what we now know, it’s hard to disagree.

1.	FDA, CDER Quality Management Maturity, 

2.	PharmTech Editors, “FDA Weighs in on Advancing the Science of Pharmaceutical Manufacturing,” Drug Solutions Podcast, May 17, 2022.

3. M. E. Wosinska and R. G. Frank, “To Prevent Public Health Crises, We Need to Update the Essential Medical Product List,” 

4. National Academies of Sciences, Engineering, and Medicine, 

Building Resilience into the National Medical Product Supply Chains

 (Washington, DC: The National Academies Press, 2022).

When referring to this article, please cite it as M. Hennessy, “The Stick and Carrot of Quality Management,” 

How can we fix the quality manufacturing issues that come with product shortages?

The Stick and Carrot of Quality Management

As infant formula shortages force parents to be creative in finding new types of supply, the post-pandemic world forces us all to be more aware of what products we need, and what systems we rely on to get them. Pharmaceutical companies, already focused heavily on implementing serialization tools for the US Drug Supply Chain Security Act (DSCSA) requirements, could “... link serialization data with temperature data collected along the supply chain (such as storage, transportation, last mile, and more) to gain better end-to-end visibility and leverage stability budgets across the supply chain,” conjectures an Elpro representative in an article in this issue on cold chain advances by Suzanne Shelley (1). Vaccine access and efficacy conversation has had a spillover effect placing food and drug supply more into mainstream conversation.

Inside that conversation, one of the largest (missed?) opportunities and unmet needs, continues to be neurological health. The second installment of 

 new series “Weighing Up Big Pharma” looks with a Sophoclean steady gaze at industry performance. One major conclusion is that, “Pharma should expand on successful cell therapies in oncology by applying these development and manufacturing methods to neuronal cell therapies,” asserts author Marina Necdina (2). She also contends that products have resorted to dealing with effects (such as beta amyloid plaques) rather than their root causes. Memory enhancing drugs—both in business performance and private pursuits—would be on most people’s wish list as welcome additions. But ending or mitigating neurodegenerative diseases are a holy grail, worth any effort.

And as a parting thought, more than 25% of drugs on the market worldwide and candidates in the pharmaceutical pipeline are considered to be formulated with highly potent APIs (HPAPIs) in 2020. More than 115 contract manufacturing organizations had the capability to produce highly potent drugs, and many had recently invested or were in the process of implementing capacity expansions to meet growing demand for HPAPIs and products formulated with them. “But in addition to specialized facilities, equipment and highly trained personnel,” writes Cynthia Challener. “Organizations developing and manufacturing highly potent drugs must have the requisite expertise to overcome numerous formulating challenges ranging from lack of sufficient toxicity data to managing poor solubility and bioavailability to ensuring uniform dosing of low concentrations of HPAPIs” (3). How to manage manufacture and deployment of these strong drugs, remains a challenge.

3. C. Challener, PharmTech 46 (7) (2022).

When referring to this article, please cite it as M. Hennessy, “How Can We Come Up Short So Often?,” 

Systemic inefficiencies in the pharmaceutical industry undermine problem-solving efforts.