Generic drug safety: US regulators struggle to keep up with a global market
While foreign manufacturing inspections have increased, the challenges of properly regulating generics from non-US drugmakers remain. Darcy Jimenez finds out more.
Generic drugs – cheaper copies of once-patented, brand-name medicines – are quite literally life-savers in the US, where prescription drug prices are 2.5 times higher than other nations of comparable wealth. According to the Association for Accessible Medicines, generic and biosimilar drugs saved the US health system a whopping $338bn in 2020.
A generic drug is, ostensibly, interchangeable with the original product. As long as a generic drugmaker can prove its product has the same active ingredient and strength, and uses the same dosage form and route of administration, the company does not have to go through the same trial process the original manufacturer did to prove that the drug has the desired therapeutic effect – that much is assumed from its chemical composition.
The problem is that not all generic drugs are made equal. Some can be more or less potent than the medicine they’re mimicking (as digital pharmacy Valisure found after testing batches of a common blood pressure drug), release doses into the bloodstream incorrectly, or contain impurities – sometimes to dangerous effect.
Take heparin, a commonly used generic anticoagulant. In 2008, the blood thinning drug was subject to a worldwide recall after scientists concluded that a contaminant, known as oversulfated chondroitin sulfate, was responsible for around 350 adverse events and 150 deaths in the US. The adulterated heparin was traced back to Chinese chemical manufacturer Scientific Protein Laboratories–Changzhou, where an investigation conducted after the scandal revealed a number of manufacturing quality issues.
Regulatory oversight and reliance on non-US manufacturers
Having very little manufacturing capacity of its own, the US relies heavily on drugmakers in countries like India and China for its supply of crucial generic drugs and active pharmaceutical ingredients (APIs). In fact, Chinese and Indian manufacturers supply an estimated 75% to 80% of all active pharmaceutical ingredients used in the US, while around 54% of drugmakers supplying generics to the US are located overseas.
Not only do overseas facilities offer lower labour costs and looser environmental regulations, but less monitoring and regulatory oversight. In 2010, 64% of foreign manufacturing plants had never been inspected by the FDA – and in 2015, 33% were still yet to receive a visit from regulators.
While inspectors can, and do, turn up at US factories unannounced, it’s far trickier to perform surprise inspections at facilities located on the other side of the world, particularly amid a global pandemic – making it easier for rules to be flouted and improper practices to be covered up.
Michael White is chair of the Department of Pharmacy Practice at the University of Connecticut School of Pharmacy and has written extensively about the drug quality issues associated with generics manufactured outside of the US.
“Overseas, they usually have several weeks’ worth of lead time, where they know that on these dates, the inspectors are going to be coming,” White explains. “It remains to be seen whether or not the inspections that are occurring overseas are of the same quality of the ones inside the US – because if you know what those issues are, you have time to get all your paperwork in order and make sure your facility is sparkling clean.”
Overseas, they usually have several weeks’ worth of lead time, where they know that on these dates, the inspectors are going to be coming.
A prime example of foreign manufacturing oversight is Ranbaxy, the Indian drug manufacturer that had plants banned from supplying drugs to the US after it was revealed the company had fabricated drug test reports and knowingly distributed substandard generic medicines. The malfeasance only came to light after two of the facility’s employees blew the whistle in 2004 – six years after the company had first begun making drugs for the US market.
The FDA’s monitoring of overseas manufacturers improved in the wake of the Ranbaxy scandal – foreign inspections have increased from 333 in 2007 to 966 in 2019 – but the challenges of properly regulating non-US generic drugmakers, and ensuring the medicines they make are of consistently high quality, remain.
White says that while the number of inspections done overseas is now close to those conducted domestically, that doesn’t necessarily mean better regulation is taking place.
“A lot of that parity is because they’re dropping the number of inspections for manufacturers inside the United States, to be able to have enough inspectors to be able to do the inspection elsewhere,” White explains.
A spokesperson for the FDA told Pharmaceutical Technology: “The FDA’s global inspection and facility evaluation efforts focus on higher-risk facilities to prevent, uncover and correct data integrity issues and manufacturing problems.
“We also monitor reports from industry, patients and healthcare providers to identify and to resolve quality problems and concerns.”
US health regulators have been implementing small-batch tests of imported drugs more regularly in recent years. White says this is “a good start”, but that the number of tests carried out must increase to serve as a “stopgap” until more in-person foreign inspections can take place.
Competition and cutting corners
The appeal of generics, for patients and health insurance companies alike, is their affordability; the most successful generic drug on the market will usually be the cheapest. The goal for any generics manufacturer, therefore, is to undercut the competition by offering the drug for the lowest price possible.
This race to the bottom between competitors means drugmakers producing cheap generics will be looking to spare costs elsewhere – and sometimes, that means cutting corners when it comes to manufacturing operations and quality control.
Manufacturing quality is something that’s hidden from the consumers, it’s hidden from the pharmacies that are purchasing the products.
“The financial pressures in the generic market are such that it’s very hard for people to be able to raise prices, even if they needed to raise prices for quality,” White says. “[Drug companies’] financial solvency is contingent upon meeting certain price points. Their competitor ends up coming out at a lower price point, and then they’re under pressure to be able to go down and meet it.
“Manufacturing quality is something that’s hidden from the consumers, it’s hidden from the pharmacies that are purchasing the products,” he explains. “When you have the financial pressure on one side, with lower levels of accountability on the other, just based on how the regulatory oversight is occurring, you end up creating a recipe for issues.”
Patient trust and traceability
When drugs are manufactured overseas, transparency about their origin and the conditions under which they were produced can be compromised. Supply chain traceability is even more opaque for the patients consuming the medicines, who are kept relatively out of the loop when it comes to safety and quality issues of some generic manufacturing plants.
“When a manufacturing facility ends up having issues with an inspection, it’s not really communicated well outside of the FDA – to purchasers, to clinicians or to patients – what the implications of that manufacturing facility’s issues are,” White says.
“It’s difficult for a patient to come in and be able to ask the pharmacist at the counter, ‘this didn’t come out of one of those manufacturing facilities that had quality issues, did it?’ It’s really, really hard for anybody to be able to ask those questions.”
Most patients likely won’t become aware that the drug they’re taking is substandard or dangerous until something catastrophic happens, and the FDA is forced to announce a recall – but poorly made generics don’t have to be poisonous to have serious implications for patients. A person whose blood pressure medicine doesn’t work properly risks a heart attack or stroke; low-quality insulin will see a patient’s diabetes go unchecked; an improperly treated infection could turn fatal.
There are a lot of different levers that people can be pulling to have greater transparency and a greater level of oversight for drugs.
For White, an official list of drugmakers that have been found to have breached regulatory requirements, published by the FDA, would go a long way towards encouraging good manufacturing practice and ensuring public trust in generic medicines.
“I do think that public shaming is something that can help to put pressure on manufacturers; there are a lot of different levers that people can be pulling to have greater transparency and a greater level of oversight for drugs,” he says.
“To some extent, though, I think the FDA was very worried that if they pulled too many of those levers simultaneously, they could end up in a scenario where they didn’t have an adequate number of drugs for everyone to have them.
“They’re trying to move into greater enforcement for some of those quality standards, but in a way that gives the manufacturers time to be able to build up to that.”
Drug supply shortage risks
Low-quality drugs aren’t the only threat the US’s fragile supply chain poses to public health. Heavy reliance on foreign manufacturers means the country’s access to crucial and widely used drugs is precarious, and shortages could result in crisis. In fact, at the time of writing, over 100 different drugs are currently in short supply in the US.
Drug shortages can occur for many reasons, including widespread recalls – such as that of generic blood pressure drug valsartan – manufacturing and quality problems, or geopolitical issues. White says that due to its limited domestic manufacturing capabilities, the US is particularly vulnerable to shortages of vital medicines like antibiotics.
The US now has virtually no capacity to make the active ingredients in many antibiotics.
“The US now has virtually no capacity to make the active ingredients in many antibiotics; you need special fermentation plants,” he says. “So, what if something horrible happens between the United States and China, or other regions, where virtually all of this capacity exists?
“We could have zero antibiotics and [shortages of] many, many different categories [of drugs] here in the United States – that’s the horrible vulnerability.”
Fixing a broken system
It’s clear that something must be done to secure the US’s supply of high-quality generic drugs – but as an FDA spokesperson told Pharmaceutical Technology, simply transferring all manufacturing facilities back home is not an option.
“It is not realistic to envision a future where all of American patients’ drugs are produced domestically,” the spokesperson said. “Other strategies include targeted investments in global resiliency throughout the drug supply chain, establishing emergency stocks of critical drug substances and drug products, as well as capacity expansion in allied countries to aid in the response to future crises.”
It is not realistic to envision a future where all of American patients’ drugs are produced domestically.
Further measures to ensure a secure, safe generics supply, White says, should include a rating system for drugmakers based on manufacturing or product quality; better international collaboration between drug regulators; and employing continuous manufacturing methods in the US to increase domestic production of critical medicines.
The introduction of affordable generic medicines and the globalisation of drug production has saved countless lives and dollars in the US, but flaws in this fragile system have also allowed bad actors to profit and cause harm.
Ensuring safe, effective drugs should be of the utmost priority to the US government and its health officials – because the very least patients should be able to expect is that their medicine is exactly what it says it is.
Preparing for the challenge ahead
To a large extent then, preparing for vaccine distribution will mean learning from what’s been achieved so far.
“I think some of it has to do with modelling – you can do a lot of simulation around production and distribution logistics,” says Boyle. “You can plan some ‘what if’ scenarios, at least identifying where the weaknesses are in the system and what kind of stressors would bring down parts of it. Then when you start to see the stressor, you already know it’ll cause a breakdown in the system and you already have a contingency plan.”
In practice, this might mean implementing a regional strategy with some redundancy in the supply chain, giving back-up if a certain country ends up in lockdown.
Delivering billions of doses of vaccine to the entire world efficiently will involve hugely complex logistical and programmatic obstacles.
“Everybody wants to operate at minimum inventory levels and maximum cost efficiency levels, but we’re asking now ‘where does lean become too lean?’” says Boyle. “The risk profile of that position has changed and people are going to be re-examining some of their goals. It’s about ensuring resilience of the supply chain and working out what level of risk you’re willing to take.”
With the first vaccines in sight, it is time for logistics providers, governments, airlines, and many more to begin their preparations in earnest. As the speakers emphasised at the IATA teleconference, this is an enormous undertaking that requires careful planning from every stakeholder.
“Delivering billions of doses of vaccine to the entire world efficiently will involve hugely complex logistical and programmatic obstacles all the way along the supply chain,” said Dr Seth Berkley, CEO of Gavi, the Vaccine Alliance. “We look forward to working together with government, vaccine manufacturers and logistical partners to ensure an efficient global roll-out of a safe and affordable Covid-19 vaccine.”