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Phase out of CFC-12 propellants in Metered Dose Inhalers (MDI)

In a joint project with the UN Industrial Development Organization (UNIDO), the Islamic Republic of Iran, a signatory to Montreal Protocol, managed to eliminate the ozone depleting Chlorofluorocarbons (CFC) propellant from the locally manufactured Metered Dose Inhalers (MDIs) consumed by asthmatic and Chronic obstructive pulmonary disease (COPD) patients, and the CFC-free products were successfully launched in the Iranian Market in January 2011.

“It was a great experience working with UNIDO; we were in very close contact in every step of the way and the whole process moved very smoothly,” says Dr. Mazhari, executive deputy of Sina Darou Laboratories Company, the sole domestic manufacturer of MDIs in Iran. “The new products have been well received by physicians and patients so far.

CFC inhalers have been recognized as taste accepted and convenient medicine for asthma and COPD patients during decades. After conversion of the project and CFC free products realization, in few cases; patients and physicians questioned the change due to difference in taste of the new products. They were satisfied when the ecological reasons and global commitments for elimination of ozone depleting substances including CFCs were explained for them.”

Background

It is estimated that about 500 million MDIs were used annually worldwide, resulting in the use and emission of around 10,000 tons of CFCs into atmosphere every year and eventually find their way to stratosphere, which by chemical reaction destroy the ozone layer.

The international community agreed in the 1980s to gradually reduce and eventually ban the production and consumption of ozone depleting substances (ODS) by accepting the Vienna Convention to Protect the Ozone Layer (1985) and the Montreal Protocol on Substances that Deplete the Ozone Layer (1987).
The Multilateral Fund for the Implementation of the Montreal Protocol was established to assist developing countries in phasing out their production and consumption of ODS in accordance with globally agreed phase-out schedules, the first key milestone being the total elimination of CFCs by 1st January 2010.
In 2010, total of 2400 tones of CFCs have been authorized by the Montreal Protocol to be used as essential uses for MDIs. This is reduced to about 880 tones (nomination) for 2011. Two parties i.e. Russia and China shall phase out their use of CFCs in 2013 and 2016 respectively. (Draft 2011 Report of MTOC of UNEP)

Although Iran is not a producer of CFCs, it is a consumer of this substance. Accordingly, most of Iran’s efforts under the Montreal Protocol have been to eliminate the use of CFC in the country.


Extensive Research

The transition Project for Sina Darou Laboratories Co. started in March 2006, with the company making extensive research on different aspects of the transition. In April 2007 a National Transition Strategy for elimination of CFC in manufacturing and sales of MDIs in Iran was prepared by the Iranian Ministry of Health (MoH) with the cooperation of the National Ozone Unit (NOU) of the Department of Environment (DoE) and the technical assistance of UNIDO.

Mr Viktar Shatrauka, UNIDO’s project manager, coordinated the joint effort of Sina Darou, MoH and DoE and UNIDO, to design the project document that was finally approved at the 52nd meeting of Executive committee of the Multilateral Fund for the Montreal Protocol, July 2007.

The National Transition Strategy introduced a few alternatives for CFC MDIs, such as DPIs (Dried Powder Inhalers), and concluded that the best alternative for the Iranian Market is conversion to HFA (hydrofloroalkanes) MDIs, which required less development and commercialization time and would be a more “Patient friendly” transition, as use, operation, etc. of the two types of MDIs (CFC vs. HFA) are very similar. Hence, the company decided to convert three of their four CFC-based MDIs (Salbutamol, Bechlomethasone and Salmeterol); the production of Cromolyn Sodium, which formed a very small percentage of the company's MDI production, was decided to be stopped at that time.

Manufacturing Adjustments

The project required installation of new machinery and technology transfer from an established enterprise that had experience in the formulation and manufacturing of non-CFC MDIs as well as modification of production area. Accordingly in a joint effort with UNIDO, suppliers for machinery and technology were identified and by December 2009, installation of HFA machinery, test run and training of the operators were completed. The transition, which took 36 months to complete, cost about US $4.5 million, which was mainly covered by UNIDO. Sina Darou Labs. Co. bore around 20% of the expenses for the adjustment of the production area and running the clinical tests.

The manufacturing line was closed for 6 months. A long period for which the company had built up enough stock to supply the market. During this period of time the 15 staff members who were working on MDI line were used in other sections of the lab. Besides inhalers, Sina Darou with almost 350 personnel produces ophthalmic and nasal drops and ointments, nasal sprays, syrups and ampoules.

As per the contract signed with UNIDO, Sina Darou committed to never revert to the use of CFCs, hence the machinery from CFC manufacturing line had been demolished.

Manufacturing License

“Ministry of Health was very supportive in terms of issuing the official manufacturing licenses” said Dr. Mazhari. “The manufacturing licenses were issued in December 2010 and Clinical tests are to be executed after the product meets its deadline to enter the market. “Clinical trial was not a crucial part of the process, as the formulation is not new and is already available in various countries however, clinical test will be carried out in Iran, for each of the products, in due course.” said Dr. Mazhari. “All parts of the inhalers are being imported: The HFA, the active ingredients, excipients and the valves and only a part of the plastic actuators are being produced in Sina Darou Labs” he continued.

Awareness Campaign

CFC-MDI Phase-out Awareness campaigns and workshops have been on the agenda of the Ozone Unit of the Department of Environment. On 8 March 2009, one awareness seminar was held in Tehran with the participation of physicians and Health Ministry officials and more communications and campaigns are programmed to be rolled out in order to raise awareness among all stakeholders, from officials to physicians to patients.

“The new CFC-free MDIs were supplied to us accompanied by awareness brochures and CDs,” said a pharmacist in north Tehran. “The packaging looks exactly the same as the old product except a line stating that Ozone Friendly HFA Propellants are used in this product,” he added and emphasized that the transition took place very smoothly.

However, work is ongoing and more needs to be done in terms of awareness. Another pharmacist was unaware of the transition when asked for the “New” Salbutamol inhaler. “Is there a new one?!” he asked in a surprised manner, and it suddenly dawned on him: “So that’s why some patients have reported about the different taste of the medicine!; We of course advise them to contact the manufacturer if they have a problem.” he emphasized.

In the near future, UNIDO will be organizing the second official awareness seminar ever since the start of the project with the presence of different relevant stakeholders, and the Ozone Unit of the Department of Environment has more programs at hand.

Iranian market size for MDI inhalers is around 4.5 million, 65-75% of which is currently produced by Sina Darou as Dr. Mazhari stated and the remaining is produced by another local manufacturer and imported from Europe and India. According to Montreal protocol, Iran is obliged to phase out CFC by 2010. However, almost all products available in the market are already CFC-free as the Islamic Republic of Iran banned the importation of CFC in early 2008.

As expressed by UNIDO representative, Alessandro Amadio, Iran’s case of CFC conversion can be used as a best practice for other countries that are going through the same process. Not only was it successful in terms of the processes and quality of the finished good but it also happened in a timely fashion.