The challenge of transparency in the global supply chain
In the past year the pharmaceutical industry has witnessed an unprecedented number of drug recalls following the discovery that these products contained impurities, some of which are life threatening.
As recently as January this year the blood pressure medication Irbesartan Hydrochlorothiazide was pulled from shelves across Europe and the US due to contamination issues. This followed a widespread, global recall of Valsartan, a blood-pressure generic, among fears that it contained the carcinogenic, N-Nitrosodimethylamine (NDMA).
These events can no longer be dismissed as one-offs or unfortunate mistakes. The growing number of recalls have thrown the complexities and current challenges of the drug supply chain into the spotlight, exposing the deeper issues arising over the transparency and integrity of pharmaceutical product manufacturing.
The common denominator in these recalls is the active primary ingredients (APIs), now routinely manufactured in newly industrialised countries, and the lack of transparency that exists regarding their manufacture and source. This is a problem that clearly needs to be tackled to prevent further escalation and the onus must be on the pharmaceutical industry to act quickly and work together to pioneer an effective, realistic and durable system that ensures a defined level of product quality and integrity. This solution needs to put the safety of the end users, patients, at the forefront and go beyond addressing just secondary manufacturing as efforts have to date, and go right to the source of the APIs.
A growing problem
The wide-ranging set for recalls began in July 2018 when the US Food and Drug Administration (FDA) issued a recall of the blood-pressure generic drug, Valsartan, following the discovery that a manufacturing change at one factory of the mass medicine producer, China Zhejiang Huhhai Pharmaceutical, had inadvertently contaminated the drugs with unsafe levels of the probable carcinogenic, Nitrosamine.
The case was not a standalone. Subsequent international investigations into the contamination have expanded to include all manufacturers of APIs and finished drugs in the Angiotensin Receptive Blockers (ARB) class. This resulted in additional recalls of Valsartan, and losartan-containing products found to contain NDMA and N-Nitrosodiethylamine (NDEA), known animal and suspected human carcinogens.
In November, the FDA, announced that Indian pharmaceutical firm Aurobindo Pharma had recalled 22 products containing irbesartan amid fears they also had the NDEA impurity, and in January this year, the Medicines and Healthcare Products Regulatory Agency (MHRA) recalled four batches of the Irbesartan/Hydrochlorothiazide made by Actavis, as a 'precautionary measure’ due to possible N nitrosodiethylamine (NDEA) contamination.
This dramatic increase in incidences of drug contamination and the subsequent product recalls are of crucial importance. Many medicines which are administrated parentally, or those with a narrow therapeutic index, such insulin, epilepsy medications, anti-coagulants, and endocrine replacements are especially sensitive to manufacturing issues. With such low thresholds for risk, even the smallest impairments to manufacturing quality or active ingredients can cause serious, even life-threatening adverse reactions. The evidence is clear – a basic standard of safety must now be applied across the industry for APIs.
Getting to the root of the problem
So, what exactly is causing this reduction in the quality and integrity of these drugs?
The answer lies in an ever more complex supply chain which has evolved due to the rapidly growing demand for cheaper and more affordable drugs. Since the 1990s, the pharmaceutical industry has increasingly used factories in lower cost economies to manufacture their products; according to the US Government Accountability Office 40% of finished medications are now made outside of the US.
The same is true for Active Primary Ingredients (APIs). APIs are now almost entirely made in newly industrialised countries, with experts now affirming that up to 80% of APIs originate from China and India – the largest manufacturers of medicines in the world. These APIs then undergo secondary manufacturing in Europe or the USA for onward distribution to wholesalers and pharmacies. Within this process, the transparency about the origin and integrity of the primary pharmaceutical ingredients can be lost, and with it the ability to easily identify potential manufacturing issues including contamination as evidenced by recent cases.
When a manufacturing quality issue such as contamination is discovered, the problem is often already a global one. Generic medicines, such as those involved in the recent blood pressure drug recalls, are derived from the same API source, hence why these recent recalls have spanned multiple Market Authorisation Holders (MAHs).
So whilst the globalisation of drug supply keeps prices down, with cheaper medicine helping emerging markets and the developing world access affordable medicines, it comes at a safety cost. The current complexity of the supply-chain has reduced the transparency, monitoring efforts, accountability and ultimately the current quality, of our medicines.
Searching for a solution
To increase transparency, bringing the manufacturing of medicines back to domestic markets and in-house seems a pragmatic solution. However, the current cost-driven climate is likely to prohibit this being a viable option. Reducing medicine costs is a global priority, and the outsourcing of manufacturing to lower cost markets has become somewhat institutionalised in the pharmaceutical industry due to its short term, huge financial benefits.
In November 2018, faced with significant resource pressure the NHS announced its commitment to saving costs on medicines, by moving towards generic, and therefore cheaper, versions of well-known brand names, which it claimed saved them than £200 million in 2017-18.
The US also remains entirely focused on ensuring low drug prices. The outgoing FDA commissioner, Scott Gottlieb, announced when taking on the role in 2017 that he would be prioritising getting more generics to market.
If localising pharmaceutical manufacturing is not viable in the current climate, then regulatory oversight would seem the next most obvious solution to increasing transparency and accountability in the drug supply chain.
Regulators and inspectors are clearly currently failing to meet the demands of the market and are falling short of adequate monitoring to prevent these contamination occurrences. According to Bloomberg, US surveillance inspections of overseas factories actually fell 10% to 778 inspections between 2017-2018. This marked a second year-on-year decline for the country, after surveillance inspections of pharmaceutical manufacturing facilities overseas dropped nine per cent between 2016 and 2017. So while the levels of outsourced and overseas manufacturing is increasing, inspection levels in these countries is decreasing, seriously affecting regulators’ ability to maintain a regulated, safe production environment.
Yet while clearly an increase in regulatory oversight is required, as an isolated mechanism for increasing transparency and mitigating the risks of a complex supply chain it is not sufficient.
Irrespective of oversight, there is a further problem with regards to the manipulation in the recording and presenting of data in the medical supply chain as the desire for drug approval often comes before safety concerns. In 2017 Zhejiang Huahai was found to have omitted from official records quality-test results that showed a number of drugs had failed to meet US standards, and instead it recorded a passing grade. In a similar case, Mylan’s largest manufacturing plant in India came under recent scrutiny for allegations that poor factory processes meant data was incomplete and of poor quality, and there were even accusations that employees were deliberately circumventing and manipulating data to accelerate drug approval.
It is evident that an innovative new approach is needed for the pharmaceutical industry if it is to improve the quality of drugs manufactured outside its domestic markets, and increase transparency in the supply chain.
The serialisation of medicines through the EU Falsified Medicine Directive in 2018 was a good first step, as it enabled the identification and source of medicines. However, it only addressed secondary manufacturing. Adulterated or defective APIs, as evidenced by the recent recalls represent the much broader challenge that is currently being inadequately served by existing practises.
Where similar issues have persisted across other industries, technology has come to the fore in providing an independent, secure means of ensuring compliance, accountability and transparency and improving how data is shared. The industry needs the right technology to provide robust, quality data at source. It must be tamper-proof and user-independent – mitigating the risks of human and deliberate error. It is only by working together to establish this that the industry will effectively be able to ensure traceability, transparency and accuracy.
The airline industry illustrates perfectly how this can be done. Flight data recorders, otherwise known as ‘Black Boxes’ are virtually indestructible. The devices give an accurate testimony, narrating the aircraft's flight history, the cockpit crew's voices, engine sounds, instrumentation warnings and other audio recording during the flight – allowing investigators uncover all the details, and get to the bottom of what went wrong in the case of any incidents or foul-play.
Call it the 'black box recorder' for the safety of primary active primary ingredient (API) – if the airline industry has pioneered independent monitoring though technology, why not pharmaceuticals?
About the author
Dr Andrew Rut is chief executive and co-founder of MyMeds&Me, the developer and provider of Reportum, a SaaS solution for the digital capture of adverse event and product quality reports across the life sciences industry.