Environment & Regulations

How to avoid icebergs

The world knows all about fake Viagra, but relatively little about the real threat from falsified APIs. We report from the EFCG press conference at CPhI Worldwide

Falsified medicines, said Guy Villax, CEO of Hovione, are like an iceberg. Indeed, the analogy works in more ways than is immediately obvious and this fact needs to be communicated urgently to the legislators of the world. Villax was speaking at a press conference for the European Fine Chemicals Group (EFCG) during CPhI Worldwide 2010 in Paris in early October.

"Falsified drugs are a much bigger business than illegal narcotics, yet supplying them is not even a crime in most countries, the US, the UK and France excepted," he said. "You can make a heap of money in falsified drugs and even if you are caught, you are treated like you had done nothing worse than committing a trademark infringement on a Christian Dior T-shirt."

In many ways, added Villax, making and supplying falsifying drugs is "the perfect crime. The victim swallows the murder weapon, he almost certainly does not know he is a victim and he dies of reasonable causes, so that murder is never even suspected."

The EFCG has had huge trouble explaining all this to politicians, especially in Europe, which does not have a co-ordinated foreign inspection service. Moreover, the picture is actually very complex; there are many shades of grey between those who are fully compliant with legislation and those who are totally, consciously fraudulent.

"Some companies are ahead of compliance, some are just compliant, some are trying their best, some are negligent, some are deliberately non-compliant and some use non-compliance as a strategy to get the terrific competitive advantage of getting to market first," Villax said. These companies are the real problem, not those who fall short in one or two respects.

The proverbial tip of the iceberg - smaller but more visible - when it comes to fake drugs involves falsified drug product in high-profile, patented drugs like Viagra and Epogen that reach consumers along illegal supply chains, mostly via the internet. Those making a loss through it are the innovators, who are relatively high profile companies.

 

Falsified APIs are the hidden but more dangerous and more significant part of the iceberg


The larger, less visible but far more dangerous part comprises falsified APIs in relatively low-profile drugs and ingredients like heparin, glycerine, gentamicin and no doubt many others as yet undetected. They reach the consumer, contained in medicines, via the legal supply chain, so their toxicity is undetected until it actually hurts patients.

The industry loses far less money because of this part of the iceberg than it does via the visible part, though criminals gain more. Far more importantly, whereas falsified drug products are not known to have killed anyone, falsified APIs have caused hundreds of documented deaths and probably far more undocumented ones. "What is not visible presents a far greater risk to the patient population," Villax said.

Attention has so far been focused mainly on the visible part of the iceberg. Legislators and policy makers have not grasped the significance of what lies below, in terms both of the gravity of impact and the difficulty of detection. Only if the toxicity of these falsified APIs is acute will a red flag go up; if it is long-term, it may never be detected. In 2007-8, counterfeit heparin had reached 11 countries before being noticed.

On a more positive note, following years of pressure from the EFCG and others and the scandals that brought the issue to public attention, moves are afoot to address these issues. There is currently legislation coming into place in various regions of the world.

In Europe, a draft proposal for a directive to amend the Falsified Medicines Directive (2001/83/EC) is due to be voted on in a plenary session of the European Parliament this month. The stated aim is "the prevention of the entry into the legal supply chain of medicinal products which are falsified in relation to their identity, history or source". To achieve this, the EFCG regards four things as essential:

  1. Mandatory inspections of API producers in other countries, which has been an EFCG demand for many years
  2. Defining a falsified API to include any medicine that contains one; if not, said Villax, heparin might not even have counted. This is not a given - plenty of lobbying is still going on. Avoiding a repeat of heparin will be the acid test.
  3. A requirement for the API's country of origin to be labelled on the final dosage form, including details of where it was made
  4. Tough enforcement and sanctions as deterrents for deliberate non-compliance; the EU, Villax noted, is all too often "good at making laws but not so good at enforcing them"

 In the US, meanwhile, the FDA has been acting more forcefully of late. Warning letters now go out within four months of an inspection instead of about 18, as before, and letters might go out to sponsors as well as contractors. The agency is increasingly expecting a contractor's other clients to look at audits too, so there is pressure on them to be more demanding of their contractors.

 

Villax - Legislators are slowly realising the danger


Meanwhile, there are various bills going through Congress with a view to tightening up safety. These include the draft FDA Globalisation Act, also known as the Drug Safety Act, and Senator Michael Bennet's proposed Drug Safety & Accountability Act (S.3690).

Among other things, Villax said, the proposed legislation would expand the definition of 'adulteration' to include anything made in a plant without a good quality system or control of the supply chain. It also aims to give the FDA mandatory recall authority. New criteria are envisaged for civil penalties and the protection of whistleblowers.

In addition, foreign manufacturers whose products are imported into the US will be required to identify 'registered agents' with the responsibility to serve as points of contact for the communication of legal proceedings and actions and to consent to the jurisdiction of the state and federal courts where they are located for judicial purposes. This, according to Villax, will facilitate taking action against such manufacturers in the US.

It is also envisaged that the FDA will establish and maintain a corps of inspectors dedicated to inspecting facilities abroad that are engaged in producing both APIs and finished products. These are to be inspected at least as frequently as domestic facilities - every two years or, if a good track record exists, every four.

(Clearly, though, despite an increase in foreign inspections, there is a long way to go. Since CPhI, the US Government Accountability Office reported that the FDA may never have inspected 64% of the 3,765 foreign sites and 88% of the Chinese sites that were in its inventory in fiscal 2009; it inspected 52 of them in that year. These figures also suggest that the inventory itself is seriously out of date...!)

Japan's Pharmaceutical & Medical Devices Agency (PMDA) is one agency "that we will hear a lot from," in Villax's view. Established only in 2005, it now has a new GMP law fully translated into English and an excellent website in English, albeit that communication and translation issues persist.

Indeed, 2010 has seen the PMDA begin to show its teeth. International inspections of API producers have begun and inspectors are checking the real state of production at facilities in detail against what is stated in the DMFs. Sanctions will be taken immediately against pharmaceuticals companies whose suppliers are non-compliant.

Another symptom of how seriously world legislators are taking the issues comes from Brazil, which revised its GMP requirements in April 2010, incorporating GMPs for pharmaceutical products from the whole Mercosur region. The Brazilian agency, Anvisa, actually inspected more API plants abroad in 2009 than the FDA. It is also more stringent in some ways, for instance in not allowing veterinary APIs to be made in the same facility as APIs for human therapeutics.

So, when does non-compliance shade into fraud? Villax cited the case of a maker of generic blood-thinning drug clopidogrel (Plavix) that was inspected earlier this year. Although he did not name the company involved, it was clearly Glochem Industries of Hyderabad, which had been supplying generic clopidogrel to the Swiss drugs company Acino for some years.

 

Clopidogrel, like heparin, is used in blood thinning


In March, the European Medicines Agency (EMA) was made aware of a GMP inspection at the site by the Germany supervisory authority in February. As well as eight major GMP deficiencies, this identified a critical one related to the discovery of at least 70 completed batch manufacturing records that were found in the waste yard, which had been re-written and some original entries changed. The supervisory authority consequently issued a certificate of non-compliance.

(The EMA's Committee for Medicinal Products for Human Use subsequently recommended the recall of all batches of generic clopidogrel made at the site. Since these failings did not represent a health hazard, patients could continue to use medicine they already had.)

As Villax observed, "the sanction was the same as it would have been if the manufacturer had inadvertently closed a vessel incorrectly. The pattern here was deliberate falsification of documents. Does the EMA not have other sanctions to apply?"

Thus, he concluded, there are gaps in terms of legislation and enforcement still. Fortunately, "the cavalry has come to the rescue" in the form of Rx-360, the international pharmaceutical supply chain consortium that was also present at CPhI Worldwide in its own right for the first time. This is "by far the most significant initiative to secure the pharma supply chain".

As already discussed in a previous issue, Rx-360 has made significant strides in recent months. The Federal Trade Commission, by a letter sent in September, has removed any anti-trust concerns, thus enabling the sharing of data to begin and removing any worry that whistleblowers might not be protected. A joint audit pilot programme is now under way

At the time, Rx-360 had 22 pharmaceuticals companies and 18 suppliers as members, with 14 observers, including the EFCG. Villax said that he expected thousands of new audit reports to be added every year to the database of 163. As well as this, he said, Rx-360 is the best source of intelligence and the fastest review of on regulatory and legislative issues in the world.
 

From Online Issue: December 2010