Mike Hennessy Jr. is the President and CEO of 

Mike Hennessy Jr.

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,” 

Articles

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.

How Can We Come Up Short So Often?

As we reach the midpoint of the year, it’s appropriate to reexamine the topics we’re addressing. I’d like to point to a special podcast Pharmaceutical Technology conducted where Editorial Director Chis Spivey talked with the director of FDA’s Office of Pharmaceutical Quality (OPQ ), Dr. Michael Kopcha, and his deputy directors Dr. Sau Lee and Dr. Cindy Buhse about advancing the science of pharmaceutical manufacturing. Discussion encompassed the framework for regulatory advanced manufacturing evaluation (FRAME), quality management maturity ratings (QMM), advanced versus traditional manufacturing, and re-shoring drug manufacturing to the United States. But I particularly want to highlight the emerging technology program (1).

These new technologies initially were brought to FDA by industry and are, therefore, a fascinating window into where the industry believes it is heading. In this respect, Mike Kopcha said on the PharmTech podcast that, “... to address current and potential future innovations ... we worked with NASEM (National Academies of Science, Engineering and Medicine), they held a public workshop, brought in industry experts in this area, to be able to talk with us about what was going on in the industry, what’s on the horizon over the next five to 10 years. ... I can list some of the more significant ones ... end to end manufacturing, distributed manufacturing, point-of-care manufacturing (as the name implies, doing manufacturing right at the point of care where the patient or consumer actually is), and artificial intelligence, in order to understand what the regulatory framework should look like, we needed to know what these technologies were ... so we knew what we were going to be asked to evaluate, and eventually regulate.”

Our new series, “Weighing Up Big Pharma” directly addresses large company performance vis-à-vis their ability to leverage artificial intelligence (AI). With batch values occasionally rising to $3 million dollars, and data streams proliferating both in terms of total amounts but also depth of insight, it is totally logical that pharmaceutical manufacturing has increased the use of AI. Multivariate mechanistic modeling and digital twin strategizing are two areas that leap to mind. But predictive maintenance and advance failure warning systems play an increased role in reducing costs. One example is water purity control. Having to fix a plant’s water system after a problem not only costs in terms of wasted product, but also in terms of lost operating time, until all systems are back online (2). Is AI a panacea for pharma’s productivity gap? As a disruptive force which, “...promises to help speed up drug identification; improve patient selection; creating digital twins; improve manufacturing; tailor marketing material; enhance customer engagement; predict chronic diseases; and support health equity” (3), you can see why the director of FDA OPQ wants to understand more about AI, and why we will all benefit from a better understanding of this increasingly powerful tool.

1. C. Spivey, “FDA Weighs in on Advancing the Science of Pharmaceutical Manufacturing,” Drug Solutions Podcast, 

2. D. Greenfield, “How and Why Pharmaceutical Manufacturers Are Applying Artificial Intelligence,” 

3. C. B. Hartley, “Weighing up Big Pharma,” 

When referring to this article, please cite it as M. Hennessy, “Is AI a Panacea for Pharma’s Productivity Gap?,” 

AI could provide solutions to critical manufacturing inefficiencies.