Releases of API from Pharmaceutical Manufacturing in India

There has been a lot of discussions in Swedish Radio News ”Ekot” (translated into English it would be ”the Echo”), this week regarding releases of active pharmaceutical ingredients (API) from pharmaceutical manufacturing in India. For me it has been a very different week for completely other reasons. My father passed away the day before yesterday after having a stroke last Friday. Hence, I have not taken part in this week’s discussions on API releases. Nevertheless, I would like to give my personal reflections to the ”Ekot-news”. Below follows first a very general comment and then a translation of 6 news articles that have been aired by Ekot this week. After that I give my personal reflections.

The topic as such is not new. We have all been aware of the situation in Patancheru, in the Hyderabad area in India, ever since the first publication on the issue by Cecilia de Pedro (AstraZeneca), Joakim Larsson (Sahlgrenska Akademin, Göteborgs Universitet) and Nicklas Paxeus (Gryaab AB) back in 2007. It has been one of the issues that I have written the most blog posts on during the last 3 years. Read for instance my blog post from Aug 16, 2010, where you will also find links to several of the other blog posts.

The different ”Ekot-news” from the passed few days are summarized below. Translations to English is made by the LIF-office (LIF, the association of the reasearch based pharma industry in Sweden) using ”Google Translation”:

Ekot 1. ”Swedish pharmaceutical producers contribute to environmental disaster”

A growing part of our medicines are manufactured in low cost countries, and India has emerged as a major producer. But pharmaceutical companies have caused an environmental disaster outside India Hyderabad, and “the echo” can now reveal that several of the largest suppliers to the Swedish market is just there.  Anil Dayak from the local environmental organization Gamana says that many companies dump their toxic waste directly into lakes and land and that it is constantly increasing. A few years ago, researchers from Gothenburg found massive release of drugs from the pharmaceutical industry in Hyderabad, India. Massive amounts of eleven different drug substances were found in rivers and drinking water wells – heart medicines, blood pressure medicines, allergy medications and antidepressants. But worst of all was the antibiotics – there were more antibiotics in the rivers than humans have in their blood during an ongoing treatment. In the factories drugs are manufactured which are sold worldwide, also in Sweden. When “the Echo” asked the MPA for data on the origins of Swedish medicines, it emerged that four of the ten largest manufacturers of active ingredient to the Swedish medicines is in Hyderabad, India. But the MPA makes no environmental controls on drugs sold in Sweden. “It would be against the rules of EU”, says environmental director Charlotte Unger.

- We have low requirements concerning the production. There are no limits saying this much is OK to emit, antibiotics for example, and that is why the government has given us a mission to see how we can change the laws of EU to include also that, ”says Charlotte Unger.

According to “the Echo”, it is likely that the companies that supply medicines to Sweden also contributes to environmental disaster in India. The local environmental authority in Hyderabad confirmed that at least two of the major Swedish suppliers send their wastewater to the widely criticized general treatment plant in the area. Every day, the waste-water treatment plant let out 44 kilograms of antibiotics in nature, according to Swedish researchers who carried out measurements on site. There have been no studies of how drugs emissions affect human health. But a Greenpeace report speaks of a greatly increased risk of cancer and heart disease in the villages around the medicine factories. Anil Dayak from Gamana environmental organization says that the problems were big already five years ago, but now it’s worse because of the high demand for drugs.

Ekot 2. ”We export our environmental problems”

New figures from the MPA shows that nearly half of the cheap generic pharmaceuticals that Swedes consume are produced in factories in India. Medicine becomes less expensive, but at the cost of severe environmental problems abroad, ”says Charlotte Unger, environmental manager at the MPA.

- The biggest problems are that we do something that is not acceptable, that we export our environmental problems to another country, ”says Charlotte Unger, environmental manager at the MPA.

Anil Dayak on the Indian environmental organization Gamana in Hyderabad, confirms the picture of a gigantic environmental problem. Pharmaceutical companies dump waste straight into the wild.

- The factories dump their waste in lakes and in the wild, and that procedure is now increasing.

It is mainly the cheap drug copies, produced in low cost countries. Nearly half, or 46 percent, of the active ingredients in the substituted medicines we get in the pharmacies are manufactured in India showed the MPA databases that echo requested. There are currently no environmental requirements for pharmaceuticals. Karin Johansson, State Secretary at the Ministry of Health agrees that there needs to be changed.

- We’ve asked the MPA to submit concrete proposals on the amendments on the regulations that exist regarding drug production, to be more demanding.

Today one cannot impose environmental requirements, is that a problem?
- Yes, of course, ”said Karin Johansson.

Most operators, industry, authorities and politicians, agree that we have to change the global rules for the manufacture of pharmaceuticals, so they not only ensure human health, but, also the environment in the manufacturing countries. But the changing global regulatory framework takes time, ”says Charlotte Unger at the MPA.

- The vast majority of the work is to put the issue on the table, it is important and then it takes less time to change the laws.
And approximately how long?
- I think one can expect between five to ten years.

Ekot 3. ”The state saves billions on environmental scandal in India”

The Swedish exchange system for pharmaceuticals, forcing pharmacies to dispatch the cheapest medicines, may contribute to serious environmental damage from production in India for example. The extremely cheap production and poor treatment of wastewater from factories makes drinking water polluted and people ill. But at the “Dental and Pharmaceutical Reimbursement Agency (TLV)” Magnus Thyberg said that they hitherto have not been allowed to take environmental considerations.

- The state subsidy system does not account for the environmental aspects of generics, but in essence there is no knowledge of which medicines are environmentally friendly, said Magnus Thyberg, TLV.

The Swedish system of generic replacement, which means that the expensive original drugs are replaced by cheap copies in the pharmacy, entail high economic contribution to the state. More than seven billion per year, according to the calculations, and according to recent studies, Sweden has the lowest prices on generic versions when comparing 18 European countries. But the production of the cheap medicines causes severe damage to the environment around the factories outside the Indian city of Hyderabad, and people in the area are sick. Several of those factories produce substances for drugs sold in Sweden. And it is the low price that is most important when the authority TLV select between different medications. In the case of new medicines, TLV may consider environmental issues, but it has not been done, ”said Magnus Thyberg.

- If a company could argue that it received a higher benefit and lower cost if you had a minor impact on the environment, we can take that into account under the legislation we have. But it requires companies to demonstrate this connection for us and argue for it, and it has not yet been done by any company.

When you created the generics system without regard to the environment, was it so very successful?

- All countries in the world actually have tried systems that, when a patent has expired, attempt to use market competition, and environmental issues were not something that was discussed and not in any country that I know of, ”said Magnus Thyberg, TLV.

Ekot 4. “Cheap drugs cause resistant bacteria“

In India, soaring levels of resistant bacteria have been found in the environment around the drug factories supplying cheap drugs to countries such as Sweden. A new Swedish study now shows that the bacteria in soil and water are becoming more resistant to antibiotics.

- We have shown that the major release of antibiotics that we have previously seen is at production sites in India, also leads to much greater resistance, says Dr. Joakim Larsson, Göteborg University.

Joakim Larsson and his colleagues took samples of the environment around the Indian pharmaceutical factories outside Hyderabad. Here are substances manufactured for drugs that are sold worldwide, also in Sweden. Four of the ten largest suppliers to the Swedish market is here. But production causes serious environmental problems. The treatment plant receives wastewater factories and emits 44 kg of antibiotics every day. The new study, published in the scientific journal PLoS One, shows that the suspicions of an increased antibiotic resistance in bacteria in the environment is confirmed.

The bacteria’s resistance genes are at least 100 times as common in the area around the Indian Hyderabad as in Sweden, ”said Joakim Larsson, Göteborg University.
- It means that there is a risk that the genes conferring resistance of the bacteria might be spread to bacteria that cause diseases.

The researchers findings around the factories are not the type of resistant bacteria we have problems with in hospitals today. Instead, it’s bacteria that occurs naturally in the environment, which has become significantly resistant. No one knows how easily the resistance genes detected in India could spread to bacteria that provide human diseases, but the risk exists and is worrying, ”said Joakim Larsson.

- If it happens it is very serious. We have a big problem of antibiotic resistance today and the World Health Organization classifies it as one of the three greatest threats to public health.

Ekot 5. “Swedish treatment plants cannot handle all the antibiotics”

Indian pharmaceutical emissions worries scientists, but not even Swedish sewage treatment plants reach a high standard. Swedish treatment plant is not able to clean synthetic antibiotics, ”says Professor Otto Cars, chairman of the network ReAct.

The Echo has reported on the major problems of emissions from the Indian pharmaceutical manufacturing. The countryside around the Indian plant outside Hyderabad contain not only antibiotics but also environmental bacteria that become resistant. The companies have not managed to clean up their emissions sufficiently. But neither Swedish sewage treatment plants are able to clean off synthetic antibiotics, it says Professor Otto Cars, chairman of the network ReAct.

- Some of these antibiotics which are synthetic cannot be eliminated with our methods either, although of course here in Sweden it is a much less quantitative problem, ”says Otto Cars.

The Swedish researchers report presented today shows that the bacteria in soil and water around the Indian plant has become resistant. That as a result of high concentrations of drugs in wastewater from pharmaceutical factories in the area. Researchers have investigated the bacteria that occurs naturally in the environment, but they may be able transfer their resistance to pathogenic bacteria. The researcher Joakim Larsson is concerned.

- If it happens it is very serious. We have a big problem of antibiotic resistance in day and the World Health Organization classifies it as one of the three greatest threats to public health, ”said Joakim Larsson.

Professor Otto Cars, who has worked on issues of antibiotic resistance, sees the emissions from the manufacturing of medicines as yet another threat to the antibiotics that are still effective. – It’s hard to say, in quantitative terms, how big the problem is in relation to the massive misuse of antibiotics in both human and veterinary medicine appearing everywhere.

- All emissions and all misuse of antibiotics is necessary to try to reduce. The risk is that what is emitted this way will come back in the cycle through the water, soil, animals, people and food, ”says Otto Cars.

Ekot 6. “They choose cheap production despite environmental problems”

More and more pharmaceutical companies outsource their manufacturing to contract for low cost countries. AstraZeneca and Pfizer are among those who have signed an agreement in Indian Hyderabad, despite the fact that pharmaceutical plants emit very large quantities of drugs into the environment. For Pfizer’s part a low price was an important factor, and we were well aware of environmental problems in the area when signing up for a few years ago, says John Walde, Senior Director at Pfizer in Sweden.

- Yes, we did. We knew them and had our eyes fully open to it. We reasoned that it is better to be in place and try to influence from within, in cooperation with our suppliers than to refuse them.

The Echo has just told you about how pharmaceutical manufacturers in India Hyderabad emit very large quantities of pharmaceuticals in the environment. Swedish researchers have measured sky-high levels of antidepressants, allergy medications and antibiotics in lakes and drinking water wells.

The land and water has also a sharp increase in antibiotic-resistant bacteria, and people in the area have health problems, ”says Joakim Larsson of the University of Gothenburg, which was the first to reveal the emissions.

- I had pain in my chest by walking along such a lake after a few minutes, and it stayed all day because of the chemical vapors that came up from the surface. It is an extremely polluted environment, ”he says.

From the company Aurobindo Pharma in this area, Pfizer is buying antidepressant drugs and diabetes drugs. Also AstraZeneca has contracts for more than 20 medicines with the same company, and also with Divis Laboratories to manufacture the active ingredient. Both Aurobindo and Divis is connected to the criticized treatment plant in Hyderabad, which emits the drugs in the environment.

AstraZeneca sais that a thorough environmental review was conducted before the Indian contracts were written. In the same time you cannot promise that the environment is not affected, says the company responsible for contracting out the active ingredient, Nicklas Westerholm.

- We cannot guarantee it 100 percent because some 90 plants is treated in the same treatment plant. However, we are working very closely to the suppliers we have chosen and ensure that they continuously improve their processes and have an eye on their emissions.

If you cannot guarantee it 100 percent, why have you chosen this vendor?
- We have done the same control of this provider as of all others, and they meet our internal requirements, ”said Nicklas Westerholm.

 

The discussion at Ekot has of course resulted in attention also from other media representatives. One of my favourite news letters, MiljöRapporten Direkt, from MiljöRapporten had the following comment today (in Swedish), based on an interview with Richard Bergström, Managing Director of LIF:

”Fortsatt uppmärksamhet kring indiska utsläpp av läkemedelsrester

Sveriges Radio Ekot fortsätter att uppmärksamma de sedan några år kända problemen vid tillverkning av aktiva läkemedelsrester i Indien. Ekot tar upp det faktum att både Pfizer och AstraZeneca använder sig av leverantörer som kan kopplas till utsläppen till reningsverk i Hyderabad. Frågan uppmärksammades första gången av den svenska forskaren Joakim Larsson.

Richard Bergström, vd på branschorganisationen Lif, de forskande läkemedelsföretagen, hoppas på en miljöcertifiering av läkemedel för att förbättra utsläppsreningen och säger att det är svårt för läkemedelsföretagen att byta leverantörer.

– Vi känner till problemen men i dag finns inga drivkrafter för underleverantörerna att investera i grön teknologi. Läkemedelsbolagen kan inte bara starta upp en ny anläggning heller eftersom det tar lång tid att få alla tillstånd och godkännande. Det som behövs nu är bland annat ett miljöcertifieringssystem som gör det ekonomiskt lönsamt att satsa på hållbart tillverkade läkemedel, säger han till MiljöRapporten Direkt.”

So what are my reflections on all this?

First of all, I would say that all stakeholders are aware of and worried by the situation. Everyone understands that actions are needed. Some stakeholders have a preference for regulatory initiatives, others for market driven initiatives. Probably we will see some kind of a mix of both types of initiatives. The Swedish MPA continue their work to evaluate the possibility to include environmental requirements into GMP (Good Manufacturing Practice) as proposed in their report on the issue from Dec 2009. As you know if you have followed my blog, I however believe market driven initiatives such as ”green incentives” will give faster results and should therefore be evaluated in parallel to regulatory initiatives. Read my blog post from Feb 8 called ”4 steps to a sustainable use of pharmaceuticals” and focus upon ”step 4″.

It is a good thing that the pharmaceutical industry is present in countries such as India and China. These markets grow rapidly and there are several unmet medical needs. With the industry presence, patients will benefit. However, it is of course of extremely important that the operations in these countries are up to acceptable standards. Industry should continue to work closely with the vendors. Both in collaboration to solve issues and improve performance, but also from more strict auditing protocols. For instance, during 2009, Pfizer conducted more than 100 environmental audits on third party manufacturers. You can read about Pfizer EHS External Supply program via this link. Read also this stakeholder commentary from Pfizer’s 2009 Corporate Responsibility Report regarding our work with our 3rd party manufacturers. Mr Ramaprasad Reddy (Chairman at Aurobindo which is the vendor being discussed under item Ekot 6 above) says the following:

”Corporate responsibility at Pfizer must be the work of every department on every day, and is what has attracted Aurobindo most as being one of the latest entrants into the Pfizer family of stakeholders. Pfizer has not only selected us as one of the stakeholders this year, but really proved it to us by collaborating and working with our teams in supply chain. Pfizer performed an audit to determine supply chain capability, and diagnosed certain deficiencies giving us 2.5 points on a scale of 4 and suggested Advanced Planning Scheduling (APS) and Vendor Management Interface. These inputs have been taken very positively by Aurobindo and are now reaping benefits. With the implementation of the above inputs, we should be moving to a 3+ on a scale of 4. Aurobindo is keen to understand ”technology and innovation strategy” for manufacturing facilities to reduce costs. Right first time strategy, green purchasing and responsible contracting are the strategies equally innovative. We will certainly look at Pfizer results in the months to come to learn and adopt wherever we can!”

As you probably understand, I think companies such as Pfizer and AstraZeneca take responsibility for their supply chain. We could probably do things even better, and I am convinced that our programs will keep on improving over time. But I also strongly believe that governments need to take their part of the responsibility as well. As pointed out under item Ekot 3 above (”The state saves billions on environmental scandal in India”) the pressure on costs from systems such as the Swedish ”generic reform” is also part of the problem, and hence most likely could also be part of the solution. I strongly recommend you to read the article from fall 2010 in Veckans Affärer where the situation in India is discussed in relation to the generic reform.

I like to come back to Richard Bergström’s comment from MiljöRapporten Direkt. It is important that it becomes economically viable to take sustainability initiatives. Then there must be some kind of ”green incentives” within the pricing and reimbursement systems and not only a focus on ”lowest, lowest, lowest possible price”…

2 comments on “Releases of API from Pharmaceutical Manufacturing in India

  1. tony skriver:

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    9666166667

  2. budget skriver:

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