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Diane Langleben BPharm MRPharmS
Pharmaceutical writer and editor
Thanks to a new generation of drugs that are more targeted but also more difficult to make, the medicines manufacturing process is getting progressively more complicated, while drug shortages are at the same time becoming more common.
Manufacturing safe and effective biologics is a complex process, requiring a tremendous amount of effort because – unlike small molecule drugs – biologics are very large and complex molecules manufactured in living cells. This was highlighted by Professor Irene Krämer, Director of Pharmacy at Johannes Gutenberg University Hospital, Mainz. “There is an adage: small children, small problems – big children, big problems,” she said. “It’s the same with molecules. These large molecules present bigger problems in their manufacture and also for biosimilars, in demonstrating their similarity to the innovator biologic.”
The growing biologics market
By way of background, Professor Krämer reminded the audience that the drug market is highly regulated in Europe and drugs require approval from the European Medicines Agency (EMA). While new drugs brought to market are under patent, when the patent expires, other companies can manufacture the same drug as a generic. This is relatively easy for most drugs, she confirmed; they are usually small molecules with a stable and easily characterised structure. However, innovator biologics, many of which are now running out of patent, are large proteins and have to be subjected to special treatment in order to remain stable and are difficult to characterise.
Bringing a generic to market is a relatively easy process because the same active substance as the original, whose patent has expired, can be manufactured and demonstrated to be identical, she said. This can be performed by use of laboratory-based analytical methods and a bioequivalence study in healthy volunteers to ensure the rate and extent of absorption are the same as in the original drug.
The EMA realised early on, however, that new scientific standards and regulations needed to be put in place, with which biosimilars had to comply, before approval could be given. There were several points to consider when evaluating a biosimilars, including the quality, clinical efficacy, safety, tolerability, cost effectiveness and reliability of supply. The latter involves not only the quality of the product but also the quality and commitment of the manufacturer. It is important for the pharmacy to know the company can deliver the product over the long term.
A selection of biosimilars have been approved and are already on the market, including somatropin (Omnitrope and Valtropin), epoetin (Abseamed, Binocrit, Epoetin alfa Hexal, Silapo and Retacrit) and granulocyte colony-stimulating factor (G-CSFs) (Nivestim, Zarzio, Filgrastim Hexal, Tevagrastim and Biograstim).
In many European countries, pharmacists are allowed to substitute a generic for a prescribed drug with the same active substance. This is not the case with biologics and biosimilars. Professor Krämer that emphasised biosimilars are only comparable, not substitutable, and this has been stated by the EMA since 2007. This is because, being such large, complex molecules, biosimilars will not be identical in structure to the innovator biologic.
Pharmacovigilance is especially important for biologics and biosimilars in order to detect unforeseen, rare side effects or differing efficacy that may not be detected in clinical studies before approval or that appear long after approval. This is complicated, as some biosimilars share the same international non-proprietary names (INNs) as the innovator biologic.
At the moment, the market share of biosimilars differs from country to country. In Germany, for example, Professor Krämer reported it stands at 10%. It is also a different situation inside the hospital and outside the hospital. It will be interesting, she added, to see how this changes as more products become available.
Drug shortages
“Hardly a day goes by when you don’t see a headline describing another shortage, especially of those medicines used in patients in oncology,” stressed Rick Lit, Vice President, Regulatory Affairs and Safety at Amgen, in his opening remarks. A recent survey by the British Chemist and Druggist reported 95% of UK pharmacists are spending more than an hour a week trying to locate out-of-stock medicines, instead of focusing on normal pharmacy activities. Mr Lit said he shared concerns about drug shortages and why these shortages occur, including a lack of raw ingredients, manufacturing problems or quality issues due to changes in product formulation and discontinuation of manufacture. For example, several manufacturers may make the same generic drug and individual companies may make a decision to discontinue a particular generic drug from their portfolio. Without co-ordination between the companies, it is quite possible that all manufacturers cease production of the same drug, which then disappears from the market.
A manufacturing problem that compromises the quality of a drug may result in a production facility being closed until the problem is rectified – and that can take some time, particularly if significant changes in the manufacturing process are required. Manufacturing injectable biosimilars, such as those used for cancer treatment or supportive care, are also much more complex than manufacturing traditional pharmaceuticals.
Added to this, hospitals that put a contract out to tender for a particular drug can make the problem worse; the manufacturer offering the best price may attract more demand for their product but be unable to maintain consistent supplies, leading to shortages.
Mr Lit referred to a poster by Andrew Mica and Larry Green, presented at the EAHP Congress, on drug availability. The poster highlighted critical supply chain parameters, which hospital pharmacists should consider when evaluating the ability of a manufacturer to maintain a continuous supply of medicines.
Mica and Green’s research found that good manufacturing practice of biotech products includes: linking biotech production to patient demand through integrated manufacturing and distribution systems; obtaining raw supplies from more than one source so that there is always a back-up; using certified suppliers; maintaining adequate stock levels to offset potential manufacturing delays or interruptions; strategic capacity management and provision of redundant manufacturing capabilities to counteract any delay in production; and active management of robust and secure distribution networks.
Their conclusion is that, before including a drug in the hospital formulary, hospital pharmacists must understand and consider such factors in the supply chain, as they can have a bearing on a manufacturer’s ability to manage its supply.
In Europe, according to material provided by Amgen at the meeting, there have been multiple drug shortages, including biotech drugs, and, in recent years, the drug shortages have escalated, putting vulnerable patients at risk. In some cases, problems with manufacture have become so severe that plants have been shut down because the products failed to comply with quality assurance.
Recently, biosimilar and cancer drug shortages have been reported in Germany, The Netherlands, Hungary and the UK. In Hungary, for example, the chemotherapy treatment 5FU has been in short supply since November 2011. These shortages may result in either drug rationing, delay in critical treatments, or the substitution of less efficacious medicines.
Maintaining patient care
Teresa Petrangolini, Secretary General at the Italian consumer rights group Cittadinanzattiva, acknowledged that the cost of biosimilars present a problem. In Italy, it mainly concerns hospital pharmacists, because hospital budgets are unable to meet patient needs, but one also has to consider patients’ rights, she said. Citizens are now very knowledgeable about drugs; they know in which countries these drugs are available and where they are not.
She spoke of a situation akin to a ‘postcode lottery’: one region acknowledges the rights of patients and allows these life-saving products drugs to be prescribed, another region does not. “Patients believe they have an entitlement to innovation and problems with drug access and supply can compromise this right.”
Rick Lit discussed the effect drug shortages have on patients, which include drug rationing, delays in initiating critical treatments; use of less efficacious medicines and cessation or delays to clinical trials, threatening progress on new treatments. In the US alone, hundreds of thousands of patients could be at risk of disruption to their treatment because of drug shortages. Inevitably, patients are subjected to further anxiety at a time when they are already under stress. Mr Lit commented: “Denied on-demand access to the drug of choice, hospital pharmacists and physicians are forced to compromise by using different drugs, rationing and even postponing critical treatments. It is unacceptable that patients are deprived of proven or chosen treatments because of avoidable supply chain issues.”
“Shortages have effects on innovator drugs as well as biosimilars,” he said, “and trying to source drugs when they are in short supply takes time away from the pharmacist’s regular role and commitments.” Professor Krämer also emphasised that trying to source drugs when they are in short supply can impact on hospital pharmacy budgets, be time-consuming for the pharmacist and ultimately pose a threat to patients.
The problems associated with shortages have not gone unnoticed by the industry and the regulators. One problem is that drug shortages are often not reported soon enough by manufacturers. In the EU, Mr Lit explained, a directive requires manufacturers to give two months’ notice of expected shortages. In the UK, there is now a parliamentary inquiry into continuing drug shortages; in the US, manufacturers are not required by law to report shortages to the FDA, but this is being addressed.
Discussion between industry and regulators is continuing to look for ways of safeguarding drug supplies. This includes the authorities being encouraged to or requiring manufacturers to report shortages early, to have back-up manufacturing plans in place and to find alternative sources for raw materials. Shortage warning systems, an ability to manage and adapt manufacturing capabilities and strong governance were also essential.
An industry leader in manufacturing
“Amgen is currently in the fortunate position of never having had a drug supply problem,” stated Rick Lit. “That’s not because we have not been close, it is because it is in the very fabric of our culture that we define how we operate to ensure that reliable product supply is at the top of our agenda.” Amgen has now had 30 years’ experience in manufacturing biotech products. Integrated global manufacturing and distribution systems, dual sources of suppliers and the availability of alternative manufacturing facilities all have enabled the company to deal with supply issues promptly.
Amgen, he said, has the experience and expertise to ensure consistent supply of medicine. “We will continue to innovate to ensure that all our future medicines remain safe and effective by keeping our focus on manufacturing processes and product quality features that are most important to patient safety.” This approach does require a large financial investment.
Robust manufacturing processes and quality systems designed to detect and react early to potential problems can help alleviate the situation and ensure that these complex medicines will be there for pharmacists and doctors to use in their fight against disease.
The Amgen satellite symposium ‘A collaborative approach to drug shortages’ was held at the European Association of Hospital Pharmacists Congress in Milan, Italy on 21 March 2012.
