Explained:Shortage of black fungus drug

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As cases of mucormycosis fungal infection are rising around the country — over 9,000 have been reported so far — there is a shortage of liposomal Amphotericin B, the primary drug used to treat the condition. Several instances of hoarding and black-marketing have been reported, and the Delhi High Court has asked the central government to explain the reasons for the shortage.

Burden of disease

Mucormycosis is considered a rare fungal infection. However, a 2019 paper in the Journal of Fungi estimated its incidence in India at 140 per million, by far the highest, along with Pakistan, among the countries for which estimates were made.

However, a 2019 paper in the Journal of Fungi estimated its incidence in India at 140 per million, by far the highest, along with Pakistan, among the countries for which estimates were made.

On May 15, Dr Randeep Guleria, director of AIIMS and member of India’s Covid-19 Task Force, said several parts of the country were reporting a surge in a supplementary fungal infection known as Covid-Associated Mucormycosis (CAM), which he linked to the ‘irrational use of steroids’ in Covid treatment. Five days later, the Health Ministry made the infection — popularly known as ‘black fungus‘ — notifiable, making it mandatory for states to report suspected and confirmed cases.

On May 22, Union Minister for Chemicals and Fertilizers Sadananda Gowda said India had 8,848 cases of mucormycosis. Almost half the cases were in Gujarat (2,281) and Maharashtra (2,000), which by Tuesday had added another 245 cases. (See chart)

Treatment for fungus

Doctors say treatment has to be quick and aggressive, and early detection helps. Treatment is with anti-fungals and, in some cases, surgery to scrape off the fungus.

The most commonly used anti-fungal is liposomal Amphotericin B injection. If that is not available, the next choice is Amphotericin B deoxycholate (plain) injection, and a third option is isavuconazole, manufactured by Pfizer in tablet and injectable form. A fourth option is available in posaconazole, a generic medication that comes as tablet and injection.

‘We start with liposomal Amphotericin injection, and switch to other drugs if that is not available. Amphotericin B deoxycholate is also effective, but it can cause kidney damage. We only use it in young patients with no kidney problems,’ Dr Tanu Singhal, infectious diseases expert at Mumbai’s Kokilaben Dhirubhai Ambani Hospital, said.

Treatment with Amphotericin can last 4-6 weeks, require 90-120 injections of the drug, and cost Rs 5 lakh-8 lakh, or even more.

But it is the shortage of the drug that has emerged as the main impediment. Assuming an average requirement of 100 vials per patient, a simple ballpark calculation would suggest India requires 9-10 lakh injections of Amphotericin for the 9,000-odd people currently infected. And numbers are expected to rise significantly.

Amphotericin is manufactured by Bharat Serums & Vaccines, BDR Pharmaceuticals, Sun Pharma, Cipla, and Life Care Innovations. Mylan imports the drug and supplies in India.

Production volumes have always been limited because the number of cases has been small. Following ‘handholding’ by the government, all manufacturers were together estimated to produce 1.63 lakh vials of Amphotericin B in May, the Centre said in a release on May 21. Another 3.63 lakh vials were in the process of being imported, it said.

Data released by the Centre show that only 67,930 injections of Amphotericin B have been allotted to the states for the period May 10-31, much less than their requirement. ‘We need 3 lakh injections per month, but we have got only 21,590 injections from the Centre,’ a senior Maharashtra Food and Drug Administration (FDA) official said.

The Centre has said domestic production will be scaled up to 2.55 lakh vials in June, and another 3.15 lakh vials will be imported, taking total supplies to 5.70 lakh vials.

Five new manufacturers were licensed to produce the drug last week — Natco Pharmaceuticals (Hyderabad), Emcure Pharmaceuticals (Pune), and Alembic Pharmaceuticals, Gufic Biosciences, and Lyka Pharmaceuticals (Gujarat). But they can start production only by July, and together provide only 1.11 lakh vials, so the country is likely to remain dependent upon imports.

Supply bottlenecks

A shortage of two raw materials has hit the production cycle.

The first is the active pharmaceutical ingredient (API) Amphoterecin B, the major supplier of which is Sarabhai Group-owned Synbiotics Limited. ‘Sarabhai can supply 25 kg per month, with that we can manufacture 1.5 lakh-2 lakh injections,’ said Dharmesh Shah, chairman and MD of BDR Pharmaceuticals.

Dr D J Zavar, MD of Kamla Lifesciences, which produces Amphoterecin B on contract for other manufacturers, said the API is the basic ingredient. ‘It is required for both the liposomal form and plain form,’ he said.

Shah said domestic manufacturers are buying this API from North China Pharmaceutical Group (NCPC) . ‘They assured us 40-50 kg by June-end,’ he said. Manufacturers have written to the Drug Controller General of India to provide emergency provisional approval to Zhejiang Pharma to supply Amphoterecin API.

The second raw material in short supply is purified synthetic lipids to produce liposomal Amphoterecin B. Lipids are in high demand globally for the manufacture of mRNA vaccines. Orders placed with Switzerland-based Lipoid in December are being shipped now, manufacturers said. ‘We have reached out to them. The situation should ease in the next 4-6 weeks for all manufacturers,’ Shah said.

In India, the only lipid supplier is Mumbai-based VAV Life Sciences. Its monthly capacity is 21 kg, which the company plans to increase to 65 kg by August, MD Arun Kedia said.

Even when raw materials are available, production of the drug takes around 21 days, besides the time taken for the sterility test.

High Court scanner

A Division Bench of the Delhi High Court headed by Justice Vipin Sanghi, which has been monitoring the Covid-19 situation in Delhi, took note of the shortage of the anti-fungal drug on May 19, after the issue was mentioned verbally by a lawyer.

On May 20, the court stressed the need for immediate imports, since domestic production was ‘far less’ than the requirement across India. On Monday, the court said the Centre’s projected production and imports may well fall short of the needs of patients, and ‘drastic measures’ were required to bridge the gap.

The court will take up the issue again on Thursday. It has asked the Centre to report the latest status on the availability and production of the drug. It has also sought a projection of black fungus cases over the next two weeks.

‘Looking to the substantial shortfall in the requirement, we are afraid that these steps may not suffice to meet the current requirements. It is not clear as to by when the augmented production plans would come into actual production,’ the court said last week.

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