By Louis Garguilo, Chief Editor, Outsourced Pharma
It’s true,” confirms Anders Vinther, chief quality officer at Sanofi Pasteur and a long-time chairman at Parenteral Drug Association (PDA), “global regulatory agencies have only now started to address the subject of harmonizing global post-approval change applications for drugs.”
These post-approval change (PAC) applications are required for the introduction of process or analytical modifications or new manufacturing facilities and advanced technologies to improve and more reliably produce drugs already on the market. It’s hard not to be a little disappointed upon learning that not much progress has been made regarding global harmonizing — or standardizing — of the different PAC requirements for individual countries or regions. It feels like an example of myopic regulatory drug agencies being unable to see the forest through the trees. Vinther, though, is an optimist who views this start as a welcome opportunity. “We are at a tipping point, and we need to work together,” he says. “Our industry has done well not to shoot at global health authorities along the way, because you get nothing out of that.” He adds, “There could be arrows on both sides.”
Drug Shortages: A Tipping Point And Quivered Arrows
The main driver of the tipping point for harmonizing global PAC applications is drug shortages, which have increased in number, severity, and the fear surrounding them. At this point, reproach slung from either side would make drug regulators and biopharma manufacturers combatants instead of companions. Vinther, in his role at PDA, has been a champion of collaboration. He says both camps now realize drug shortages and PAC regulations go hand-in-hand.
For their part, global drug regulators have raised expectations that manufacturers do more to proactively predict and prevent issues that lead to drug shortages. These agencies are also starting to move toward more structured national or regional requirements for notification of changes in facilities and equipment and other supply chain events. On the other side, biopharma has become more direct in explaining to regulators that drug shortages can be caused, in part, by policies set by the regulators themselves. The most egregious of which remains this lack of harmonization of the PAC application processes.
“That’s where we stand right now,” says Vinther. “We agree biopharma manufacturers need to be better at anticipating the risk of a drug shortage from a company perspective. We also need health authorities to find ways to expedite and harmonize the process for introducing changes that improve process variability and the quality of products, in particular when this can enhance drug supply.”
The current situation is indeed an opportunity for both sides to share responsibility and implement measures to improve drug supplies for patients. PDA is one group at the forefront, providing a forum to spur some of these activities. It has 10,000 individuals from all segments of healthcare, including many drug regulators, according to Vinther. PDA recently released a technical report for the biopharma industry that is a “how to” on avoiding drug shortages. A second initiative underway at PDA and led by Vinther, who has passed on the active chairmanship role and now serves as an Immediate Past Chairman, is called the “Global Change Protocols for Comparability Studies.” This is aimed directly at drug regulators to assist in harmonizing PAC applications.
“The technical report first says, ‘Okay, let’s address what we can in our own house,’” explains Vinther. “The Global Change Protocols will then suggest a positive way for biopharma and regulators to work together to define and harmonize PAC requirements. Both documents are based fully on science, not politics.”
The report is officially titled, “Technical Report No. TR 68: Risk-Based Approach for Prevention and Management of Drug Shortages.” Vinther describes it as a fully developed, structured document and practical technical outline for biopharma to go through product portfolios to identify and mitigate the potential for drug shortages.
The upcoming protocols document is a hands-on attempt to jump-start the process of harmonization. “Everybody around the table now says the current situation is not sustainable,” says Vinther. “Shortages are now a global patient-critical issue.”
Vinther says the initial technical report has been well appreciated by both the industry and regulators, who have posted it on their websites to demonstrate their encouragement for biopharma adoption. The European Medicines Agency (EMA) may go further. “They may introduce it as a part of their regulations,” says Vinther. “The dialogue is better now. They see we are answering their call to address concerns.”
Let’s look, then, at what a company like Sanofi Pasteur faces in the current regulatory environment and what global PAC harmonization would actually mean in practice.
Vaccines Made More Difficult
Creating vaccines is akin to trying to hit a moving target; the product has to change as the target does. Sanofi Pasteur, the vaccines division of parent Sanofi, is today the largest company devoted entirely to human vaccines. It produces a range of vaccines, including those for 20 bacterial and viral diseases, and it distributes more than 1 billion doses each year, making it possible to vaccinate more than 500 million people around the world.
Anders Vinther, despite the long hours and travel dedicated to his work at PDA, and of course his position at Sanofi Pasteur, does have a pastime, one he’s equally passionate about and one not out of character: He’s owner of Flying Suitcase Wines, a vineyard in San Carlos, California. Vinther is Danish by birth, received his Ph.D. in chemical engineering at Danmarks Tekniske Universitet, and started his career at Novo Nordisk. He currently lives in California near his vineyard. There’s certainly an art and science to bottling high quality wines. For one thing, we can be assured he has less paperwork and fewer regulatory bodies to deal with in producing fine reds and whites. And if there ever were shortages, they’d be mostly caused by acts of Mother Nature. In contrast, and in all seriousness, the potential vaccine and other drug shortages facing patients around the world today appear to be mainly man-made and solvable in great measure by industry and regulators harmonizing post-approval change (PAC) applications around the globe. Let’s hope the challenges hampering the efforts of Vinther and so many others are eradicated like some of the diseases they vaccinate us against.
But vaccines have become a low- or no-margin business, and perhaps the best example of how biopharma is hurt financially by the checkerboard of regulations spread across the globe. Just this January, while attending a Gavi Global Vaccine Alliance meeting in Berlin, philanthropist Bill Gates dismissed criticism by health campaigners of the perceived high prices of some vaccines, according to The Guardian. Gates warned it only serves to deter pharmaceutical companies from working on life-saving products for poor countries. (For a look at more factors that have led to this point of increasing risk of drug shortages, please see the inset article.)
In fact, Sanofi Pasteur and other vaccine manufacturers increasingly find themselves the only, or one of few, who produce a certain vaccine for global markets. Others have been driven out of the business by intense price competition and price pressures from healthcare organizations and the complexity of making and getting vaccines approved. For example, each time even a minor change is made to how a vaccine is produced, the company must submit hundreds of PAC applications, all with different requirements, to each country where that product is available. Because of this and other factors, in the worst cases, global supply of some vaccines is down to one or two manufacturing facilities.
Vinther offers the example of a conventional manufacturing — or filling — line currently in a classified cleanroom but with some open operations. Moving from conventional filling to the use of isolators would reduce any risk of contamination and other sterility assurance issues. “This, of course, is a great change,” says Vinther. “However, each country has its own procedure for approval. You can imagine a company operating in a hundred countries and dealing with a hundred applications for the health authorities to look at things differently. While the requirements for each country may make sense, collectively for the company, this complexity of filings can stifle innovation and the introduction of new technologies.”
The unrealistic expectation of this current process is the production of the same product in a variety of different ways. “Companies get bombarded,” says Vinther. “Country A has approved, so now we must manufacture the new way, but Country B has not approved, so we need to continue using the old technology. As a company, you just want to continue to improve. The objectives are the same for patients, health authorities, and companies: safe, high-quality products, everywhere. Right now we have a logistics nightmare.”
Consider the simple example of the common but complicated vaccine DTaP (diphtheria, tetanus, and whooping cough [pertussis]) booster immunization shot. It consists of a variety of strains that have to be kept current, from both a strain and manufacturing point of view. According to Vinther, a DTaP booster might require 15 different manufacturing processes. A change of any kind requires an application to each of the hundreds of health authorities.
For a separate vaccine, Vinther said a company once counted it needed 55 different variations to produce just under 90 batches of product. “Intellectually, let’s all think about it,” he suggests. “If 59 countries have approved a vaccine-manufacturing change, what would country number 60, 61, or 62 add that the others didn’t?”
Finally, we should note that in Europe, for example, it is a legal requirement that manufacturers consider new technologies, like the isolator we mentioned above. On the surface, this sounds like a reasonable and forward-looking policy. And it is, in isolation (forgive the pun). But, if an advancement is made for Europe, this necessitates that PAC applications be submitted around the world to raise all standards. Is this protecting or harming healthcare systems and patients?
Patients Should Know
The magnitude of this challenge with PAC processes is only partially known to patients around the world. The question is how to inform them and bring them into the discussion.
“Every decision I make, I make thinking of what is best for the patients,” says Vinther. “It used to be straightforward for a quality professional to reject a batch, even for a minor violation of procedure that was shown not to affect quality. It’s not good financially, but it’s an easy decision to make. The hard part right now is that if I reject that batch — perhaps an environmental monitoring sample was not properly taken — I know there are patients who will not get their drugs. That is a difficult dilemma to be in today.”
Vinther continues: “Patients don’t necessarily appreciate the full complexity of manufacturing; their concern is their health, and rightly so. But the dialog among regulators, the industry, and patients is important because we really need to understand we all have one common objective — the availability of medicines to all in need.”
However, approaching patients and patient advocacy groups regarding regulatory and manufacturing issues — even related to drug shortages — can be difficult for biopharma. There is the risk of being accused of “politicizing” issues. Patient organizations inherently have a focused agenda. “This is the closest you can get to people not continuing the life that they have because they need medications,” says Vinther. In an era of 24/7 social and traditional media, no organization wants to be seen as trying to manipulate patient opinion.
This is where Vinther sees the PDA as playing a vital role in bringing all sides together to harmonize PAC requirements and lessen drug shortages. He says that to the extent possible, PDA members check their business or organization affiliations at the door and focus on science and nonpolitical solutions. “We are made up of individuals; we also just happen to be the best experts in the world in a variety of areas in the pharma industry. This is a venue for all people to gain perspective and forge solutions based on rock-solid science.”
How Did We Get Here? Four Errant Steps To Drug Shortages
Anders Vinther, chief quality officer at Sanofi Pasteur, and long-time (immediate-past) chairman at Parenteral Drug Association (PDA), points to four factors leading the world down the path to drug shortages.
In some ways, the first is the most difficult to understand. Free markets and competition are the very stuff of capitalism and should lead to innovation, more supply, and yes, lower prices. But hyper-price competition has now even reached generic/biosimilar players, who are partly based on win-on-price business models. “Go to your local pharmacy,” suggests Vinther. “Over-the-counter drugs are sometimes cheaper than a 6-pack of bottled water.” He says for drug manufacturers today, selling into healthcare organizations can leave little – or no – profit. This drives companies out of the market and leaves patients with one or two manufacturers, and at times one facility, manufacturing drugs they need.
“The industry has changed,” says Vinther. Pharma finds itself manufacturing many drugs with little or no margins and no supply elasticity. What else has changed has to do with our initial premise of free markets. With increasingly socialized healthcare systems, powerful intermediaries, and government intervention that brings with it concern for political outcomes, the healthcare industry is far from any status of free-market principles.
Another reason for drug shortages is that while both demand and requirements for production are increasing globally, funds for investing in infrastructure at manufacturers is decreasing (see directly above). Drug manufacturers can fall behind in meeting requirements, and making the upgrades that in turn lessen supply pressures. “Equipment gets outdated, new facilities are needed, and you might see skilled-employee turnover in a certain area; many reasons directly related to manufacturing quality lead to drug shortages,” says Vinther.
This prompts authorities – already scrutinizing manufacturers – to place even more attention here. “Government regulators say to manufacturers, ‘You need to do everything you can to predict supply issues,’” says Vinther. As we documented in our main article, the industry is serious about the need for a greater level of risk management to avoid drug shortages. Manufacturers, though, know fewer problems would occur if there were an understanding of the impact of the constraints they are put under in the first place, both requirement- and market-wise.
A third cause, of what can be identified as “isolated” shortages, and perhaps the least known or understood, is “parallel trading.” The World Health Organization (WHO) describes the phenomenon of parallel importing this way:
Parallel imports are imports of a patented or trademarked product from a country where it is already marketed. For example, in Mozambique 100 units of Bayer’s ciprofloxacin (500mg) costs US$740, but in India Bayer sells the same drug for US$15 (owing to local generic competition). Mozambique can import the product from India without Bayer’s consent.
According to the theory of exhaustion of intellectual property rights, the exclusive right of the patent holder to import the protected product is exhausted and thus ends when the product is first launched on the market. When a state or group of states applies this principle of exhaustion of intellectual property rights in a given territory, parallel importation is authorized to all residents of the state in question. In a state that does not recognize this principle, however, only the patent holder who has been registered has the right to import the protected product.
“I’ve experienced this with my work in the European Union,” explains Vinther. “One country has plenty of supply for pharmacists for a certain drug. But a second country in Europe starts buying up the supply because it can actually purchase it cheaper by a parallel import. Suddenly the first country, which had all the drugs it needed, doesn’t anymore.”
Parallel imports are also referred to as the “grey market.” Remarkably, the Trade-Related Aspects of Intellectual Property Rights (TRIPS) agreement specifies this practice cannot be challenged under the World Trade Organization (WTO) dispute settlement system. This allows the practice to continue, and according to Vinther, adds to unnecessary drug shortages.
Our fourth reason for drug shortages is the topic of our feature article, the inadequate harmonization for post-approval changes. These are not the only four. However, the common thread of these we’ve outlined is pricing pressures on BioPharma to discover, develop, manufacture and distribute more drugs anywhere in the world ever more cheaply. This seemingly incessant demand for lower prices comes from legitimate market forces – although normal supply-and-demand mechanics seem no longer to operate in healthcare – and less legitimate non-market, outside forces and manipulation.
Perhaps here’s the bottom line: There is no free ride to improved healthcare and medicines. No industry — providers of home-heating oil, assisted-living facilities, transportation companies — can operate at no profit and continue to provide products and services.
Time will tell if we are demanding that some drugs cost so little we’ll end up paying a much dearer price later. Drug shortages are a first and troubling sign we are getting there already.