Special Report: -Lax testing fuelled wave of cough syrup poisonings

Manali Petrochemicals

13/09/2023 12:00

(Toxic cough syrup made and sold in India may have been the
start of a recent global wave of contamination. Some of the
drugmakers could not prove they even tested their products.
Bereaved parents are still waiting for justice. Click here for
multimedia story)

        * 
      Around 153 children worldwide killed by toxins in
Indian-made
syrups
    

        * 
      Three of the drugmakers did not prove they tested for
toxins
    

        * 
      Indian rules require the tests; multiple sources say tests
are
rare
    

        * 
      Drugmaker involved in supply to India expands, focuses on
export
    

  
    By Krishna N. Das and Jennifer Rigby
       RAMNAGAR, India, Sept 13 (Reuters) - In December 2019,
Jafar Din's two-month-old son Irfan was coughing and feverish.
Din left their single-room home in the Himalayan mountains and
traveled 10 km (6 miles) to the nearest pharmacy, where he
bought a bottle of medicine, COLDBEST-PC.
    He returned and gave the child a dose. 
    Hours later, Irfan started vomiting. He stopped passing
urine. He was admitted to hospital in Jammu city. A week later,
he died.
    Irfan was one of at least 16 children whom authorities in
India's northern region of Jammu and Kashmir found had been
poisoned. Twelve died after their kidneys and other organs
failed, a police charge sheet showed; four others were left with
severe disabilities.
    Investigations by police and state drug inspectors pointed
to medicines made by one manufacturer, Digital Vision Pharma.
The family-owned business is based in the neighbouring state of
Himachal Pradesh, a center for India's pharmaceutical industry
and one of Asia's biggest drug manufacturing hubs.
    Government analyses of the syrups made by Digital Vision
that the children took - as well as samples taken from the
company's factory and its distributor in early 2020 - found they
contained a 34% concentration of the toxin diethylene glycol
(DEG), according to the charge sheet for an ongoing criminal
case against Digital Vision's owners and an investigative report
by Jammu and Kashmir's drugs regulator, both seen by Reuters.
    That concentration is far above safe levels for DEG, an
industrial solvent used in car brake fluid. The World Health
Organization (WHO) says the safe limit, based on internationally
accepted standards, is no more than 0.10%. 
    Digital says there was no DEG in its syrup and its medicines
are not to blame. The company has provided no evidence to
support this.  
    The WHO told Reuters the Jammu deaths may have been the
start of a wave of poisonings, by medicines made in India by
three other companies, that have been linked to the deaths of
141 children in Gambia, Uzbekistan and Cameroon over the last
year. They are part of one of the largest episodes of such
contamination on record.
    In all three cases, the syrups were found to contain high
levels of DEG and a related chemical, ethylene glycol (EG). The
WHO says at least 15 countries may have had tainted syrups on
sale, made by various different companies. 
    The rash of poisonings has led to criminal probes, lawsuits
and a surge in regulatory scrutiny in India and abroad. Indian
regulators have conducted a wave of inspections this year that
found possible violations in nearly nine in 10 of some 160
factories targeted.
    Still, despite intense lobbying on behalf of the families of
the children in Jammu, no one has yet been found guilty in a
court of law for the cough syrup deaths.
    A Reuters examination of court records and regulatory
filings – as well as interviews with two company executives and
two regulators – show that the drugmakers linked to the child
deaths in India, Uzbekistan and Gambia either did not test their
products for known toxins, or could not prove to investigators
that they did so - as required by Indian law.
    India's health ministry, the office of the prime minister
and the federal drugs regulator, the Central Drugs Standard
Control Organisation (CDSCO), did not respond to requests for
comment for this article.
    The three drugmakers - Digital Vision, Marion Biotech and
Maiden Pharmaceuticals - implicated in the cases in India,
Uzbekistan and Gambia said they had purchased pharmaceutical
quality chemical ingredients. But Reuters found these claims
were denied or called into question by the chemicals suppliers
themselves in all three cases.
   Reuters' reporting also showed how two of the companies had
already come under scrutiny for lax manufacturing practices
 urn:newsml:reuters.com:*:nL4N3AO2PE.
   The news agency found that Digital Vision and its unit Orison
Pharmaceuticals had received at least 16 warnings from the drug
regulators of Maharashtra and Gujarat states about substandard
heartburn, antibiotic, anti-fungal and other medicines before
the Jammu deaths. 
    And senior executives at the company linked to cough syrup
deaths in Gambia - Maiden Pharmaceuticals - were on bail on
charges of illegally storing substandard medicines when the
African poisonings occurred.  
    Seven Indian pharmaceutical executives and regulators told
Reuters it is common practice among some manufacturers there to
substitute cheaper, commercial-grade ingredients when making
cough syrups. They declined to identify any companies.
    Police in Jammu and Kashmir in December charged Digital
Vision's founder, Parshottam Goyal, and his sons Manic and Konic
with crimes including culpable homicide not amounting to murder
– comparable to manslaughter – in connection with the
poisonings, according to the charge sheet submitted to a court
in Ramnagar town. 
    The charges carry a possible sentence of up to life in jail.
The Goyals deny any wrongdoing.
    "We will challenge any case against us," Goyal told Reuters
ahead of the next hearing in the case, due on Sept. 15. Asked
about the toxin and the children's deaths, he said someone may
have "planted something" or that medicines may have been
misused. "Who knows what was fed to whom," he said. 
    Konic Goyal declined to comment; Reuters could not contact
his brother, Manic. Police investigators did not respond to
requests for comment about the case. 
    A court in Himachal upheld Digital's appeal in August 2020
against the suspension of its manufacturing license by the state
drugs regulator five months earlier, noting that only one batch
of its COLDBEST syrup had been found to contain toxins - the
consignment that was sold in Jammu. 
    The court barred Digital Vision from making drugs containing
certain ingredients and the case concluded without a definitive
ruling on who was to blame for the Jammu deaths. 
    Asked by Reuters about the impact of the legal cases, Goyal
said Digital Vision's business had "stabilized" and "expanded."
Digital has tripled its capacity to produce other medicines, he
said, and another company he owns that makes medicines,
including antibiotics and eye drops, started exporting them last
year.

    "STARTING POINT"
    The risks posed by DEG and EG are well known. The toxins
have killed nearly 1,000 children worldwide over the last 80
years, according to Kalle Hoppu, a Finnish poisons and pediatric
medicines expert, who worked with Gambia's government to
investigate the deaths of children there.
    Cough and cold syrups are made with propylene glycol (PG), a
colorless, viscous liquid that does not react with other
substances, making it an ideal solvent for syrupy medicines. It
is generally sold in two grades: pharmaceutical and industrial. 
    Industrial grade PG - widely used in liquid detergents,
antifreeze, paints or coatings - is always cheaper than the
pharmaceutical version. This is partly because it is not
intended for human consumption, and may contain more DEG or EG.
    Prices for pharmaceutical grade PG in India jumped several
times in recent years due to supply chain disruptions, according
to ChemAnalyst, a Mumbai-based chemicals market tracker.
    A DEG concentration of 34% - the level identified in Digital
Vision's cough syrup - would likely make children sick very
quickly if they took several doses, putting them at risk of
death – particularly if they had poor access to doctors, said
British consultant nephrologist Dr. Graham Lipkin.
    Initial symptoms include nausea and vomiting. Without
treatment, patients may experience acute kidney injury. Then
other organs can become inflamed, start to bleed and fail, he
said.
    The WHO said it learnt of the 2019 poisonings in Jammu and
Kashmir only after it began to help Gambia investigate its
deaths last year. The U.N. health agency has linked the deaths
of at least 70 children in the West African country to cough
syrups made by Maiden Pharmaceuticals.
    Maiden, whose factory is in the northern state of Haryana,
denies any wrongdoing. It did not respond to requests for
comment for this story.
    Rutendo Kuwana, the WHO's team lead for incidents with
substandard and falsified medicines, said such poisonings tend
to cluster together. The agency suspects the contamination
occurred when someone switched in cheaper, toxic ingredients
somewhere along the pharmaceutical supply chain.
    "It is likely that (Jammu) is your starting point" for the
global wave, Kuwana told Reuters. Further testing and paperwork
are required to be sure, he said.  L4N3AO2TE 

    "JUST ADD IT IN"
    Reuters' examination of the children's deaths in Jammu shows
the difficulties of tracing chemicals within India's $42
billion-a-year pharmaceutical industry.
    Digital told Reuters it produced the suspected batch of
COLDBEST in September 2019 using pharmaceutical-grade PG from a
supplier, Thakur Enterprises, based in Haryana state.
    Thakur confirmed it sold PG to Digital, but said it only
supplies industrial grade chemicals.
    "All my bills say, in red letters, that all my products are
for industrial use only," said Vibhor Chitkara, who runs Thakur.
Neither he nor Digital Vision's Goyal would provide any
documentation to Reuters to support their assertions.
    Chitkara said he had bought the PG from another company,
Manali Petrochemicals, which is India's sole PG manufacturer and
sells both pharma and industrial grades, according to a
spokesperson. 
    But Manali told Reuters it had not done business with either
Thakur or Digital, and called such a claim "entirely incorrect
and misleading." Thakur declined to provide proof of having done
business with Manali.
    In the case of Marion Biotech, whose cough syrups have been
blamed by authorities in Uzbekistan for the wave of poisonings
there, Reuters reported in June that its PG supplier Maya
Chemtech did not have a license to sell pharmaceutical-grade
materials and dealt only in industrial-grade chemicals. 
    Marion did not respond to requests for comment for this
story.
    Maiden, meanwhile, told Indian authorities that its PG was
made by South Korea's SKC. But SKC told Reuters it never
supplied PG to either Maiden or its stated chemicals supplier,
Delhi-based Goel Pharma Chem, the agency reported in May. 
    Digital Vision told the High Court of Himachal Pradesh in
August 2020 – when it was appealing to reopen its factory there
– that it had requested tests of its syrup for DEG and EG at a
laboratory in New Delhi. But it provided no proof.
    The laboratory, Shree Sai Test House, did not respond to
Reuters inquiries.
     Indian regulations require drug manufacturers to test each
batch of raw materials and products for strength, quality and
purity. They explicitly require tests for DEG and EG. Violations
carry fines or jail sentences up to life if a product is found
to cause grievous harm or death. However, there is no nationwide
record of punishments for selling or failing to test toxic
medicines.
    The Himachal High Court ruled in August 2020 that Digital
had not proven it bought the PG from a licensed dealer, nor
tested it for DEG.
    The court nevertheless allowed Digital to resume production
of medicines – as long as these do not contain PG. 
    Though Goyal insisted that his ingredients met
pharmaceutical-grade standards – known as pharmacopoeia – he
said others' may not. 
    "Many pharma companies buy non-pharmacopoeia PG," he told
Reuters, without providing evidence. "Many people don't even
test PG. They think, 'It's in a big drum, just add it in.'" 
    
    "NOBODY'S RESPONSIBILITY"
     Consumer advocates and lawmakers have lobbied India's
government for more than two decades for improved oversight of
its pharmaceuticals industry, one of the world's largest. 
    They say supervision remains ineffective partly due to a
patchwork of understaffed regulators with no overarching
authority, and an array of vague production standards.
    There are 37 local-level regulators across India as well as
the federal body, CDSCO. Different states often have
jurisdiction over different companies in the supply chain.
     Although CDSCO is responsible for laying down standards and
coordinating state drug control organizations, its role is
curtailed by India's constitution, which allows individual
states to have their own laws on drugs.
    "So, everybody's responsibility becomes nobody's
responsibility," said Kundan Lal Sharma, a former senior Indian
health ministry official.
    In the Jammu and Kashmir poisonings, the local government
said the onus of investigating the products was on the state
where Digital Vision's operations are based – Himachal Pradesh.
    But Himachal says finding out how the cough syrups were
contaminated is mainly the responsibility of yet another state,
Haryana, because that's where the PG supplier, Thakur
Enterprises, is based.
    Haryana's drug regulator did not respond to requests for
comment.
    A Jammu and Kashmir court ruled in March 2021 that the
regional government's Drugs and Food Control Department should
be held accountable because it could have kept the syrups off
shelves if it had tested them vigilantly.
    The government appealed but India's highest court upheld the
ruling, saying last November that drugs officers had been found
"negligent."
    The Supreme Court ordered Jammu and Kashmir to pay the
families of the 12 dead children 300,000 rupees ($3,668) each in
compensation. But again, it did not rule on who was responsible
or order help for those left disabled. 
    Jammu and Kashmir has paid the compensation. Its drugs
controller, Lotika Khajuria, told Reuters that before the deaths
it did not inspect medicines or medicine-makers thoroughly, but
it will open a new laboratory in September to double its annual
testing capacity to 10,000 samples.
     "We're hoping that we will do some justice to the kids,"
she said. "Small and medium-scale industries, they never used to
test."

    "WE NEVER TESTED"
     Marion Biotech, based in the Indian state of Uttar Pradesh,
produced cough syrups that the health ministry in Uzbekistan
linked to the deaths of 65 children there last year. 
    The syrups shipped to Uzbekistan last year by Marion were
made with a toxic industrial-grade ingredient, rather than the
legitimate pharmaceutical version, Reuters reported in June. 
     Tests by an Indian government laboratory in January found
22 samples of Marion-made syrups were "adulterated and
spurious," the country's drug controller said in March.
    The company's then-head of operations, Tuhin Bhattacharya,
told Reuters it had exported cough syrups for more than a decade
without testing the PG for impurities like DEG or EG.
    "No exporter in India used to test for DEG and EG," he said.
"No one does it." 
    Reuters reported in April that government inspectors had
found that Maiden Pharmaceuticals also did not test the PG
before use. 
    Authorities in Uttar Pradesh canceled Marion's license in
March and arrested Bhattacharya and two of its chemists. They
were released on bail a few days later. 
    A court barred police from arresting Marion's owners, Jaya
Jain and Sachin Jain, saying police should not have investigated
the matter without first bringing it to court. But it allowed
drug officials to continue their enquiries.
    Drug inspectors from the federal regulator CDSCO are
pursuing their investigation into Marion, according to two
sources with knowledge of the matter, who declined to be named
as they were not authorized to talk to the media. 
    A lawyer for Marion's owners declined to comment, and the
owners themselves could not be reached.
    Bhattacharya said the standards Marion followed were set by
the British Pharmacopoeia, or drug standards guidelines, as
requested by authorities in Uzbekistan and approved by drug
regulators such as CDSCO. Uzbek authorities did not reply to
requests for comment. 
    Bhattacharya said British standards do not explicitly call
for propylene glycol to be tested for DEG or EG. "If something
has happened, it's because of the regulation," he said. "It is
not the fault of our technicians."
     A spokesperson for Britain's Medicines and Healthcare
Regulatory Products Agency, which oversees the standard, said
that was "not a fair statement." She cited wider British and
international manufacturing guidelines requiring tests that
should uncover any toxins and spark further inquiry. However,
she added that the agency is working with global regulators to
make its requirements more explicit.

    "WOULD HAVE KILLED 100 KIDS" 
    Digital's Goyal told Reuters COLDBEST-PC could not have
killed the children in Jammu, because the deaths were
concentrated in one region, while his companies supplied 5,575
bottles to eight regions in total.
     "Had something been wrong with our product, kids would have
died elsewhere too," said Goyal, 60.
     "I am not saying that all those who consumed the medicine
would have died, but had it been toxic, it would have killed at
least 100 kids."
    Half a dozen experts interviewed by Reuters said Goyal's
argument was not convincing. Several variables could explain the
pattern of deaths, they said: For example, any single batch may
have used different barrels of the same ingredient. And smaller
patients are more vulnerable to DEG poisoning.
    "The toxicity depends on the dose and the size of the
child," said Hoppu, the poisons and pediatric medicines expert.
"The more doses a child gets, the more likely they are to get
kidney damage."
     The seven other regions recalled COLDBEST in February 2020.
Federal authorities found toxins in samples sold in four states,
according to court and government documents. In Haryana, a
sample had 35.87% DEG – the highest of all. 
     One of the states, Tamil Nadu, told Reuters no deaths had
been linked to the syrup but said it was seeking legal action
against the company and its owners for selling adulterated
drugs.
     The others did not respond. Reuters could not determine how
many medicines had been sold outside Jammu or if anyone was
harmed.

    "ABSENCE OF TESTING"
    Amid mounting international outcry, Prime Minister Narendra
Modi's government doubled down on testing requirements in June,
introducing a new rule that all cough syrups for export must be
checked in government laboratories. Health Minister Mansukh
Mandaviya said more than 900 cough syrup samples have since been
cleared.
     Mandaviya told parliament in August that authorities had
inspected 162 drug factories since the overseas cough syrup
deaths and found possible violations in 143 of them – nearly
nine in 10.
    The health ministry said in August the inspections of drug
factories found an "absence of testing of incoming raw
materials." It gave all companies up to a year to fix that
shortcoming and comply with international manufacturing
standards set by the WHO. The ministry said fewer than a quarter
of India's 8,500 small drug factories currently meet these. 
    But India did not increase testing requirements for the
domestic market.
    Industry executives have complained about the cost of extra
tests for exports and asked the government to cover this,
according to communications viewed by Reuters.
    In June, a national association of small businesses close to
Modi's Bharatiya Janata Party (BJP), called Laghu Udyog Bharati,
wrote to the health ministry that inspecting drug factories
whose products had been found substandard was a "death sentence"
for small companies.
    The group later retracted the letter, which the president of
its pharmaceutical wing, Rajesh Gupta, told Reuters was
inadvertently issued by an official on "emotional grounds." He
declined to identify the official.
    "We are not against the government on quality inspections,"
Gupta said. "It is the regulator's right to inspect but it
should be done in a friendly way and not in the manner of a
raid, which creates fear."
    He also said the deadline for small factories to meet WHO
manufacturing standards would lead to the closure of nearly half
of them, because they are already heavily indebted. The health
ministry did not respond to a request for comment. The WHO
declined to comment. 
    Digital Vision's Goyal said his company's sales have now
returned to levels seen before 2020, to up to 400 million rupees
annually, and he is ramping up exports.     
    A Goyal-owned company called Vellinton Healthcare is
registering to sell drugs in eight countries including Ghana,
Ethiopia and Afghanistan. It has exported to countries including
Turkmenistan since last year, he said.
    "Our vision is mainly export now. There is barely any money
in the domestic market," Goyal said. "Competition is fierce and
unhealthy. Quality is not maintained."
    In Jammu, Reuters spoke to the families of six of the dead
children. Din took a reporter to the hilly graveyard strewn with
boulders where Irfan, his firstborn, is buried. Like the parents
of the other five, he said he wants the manufacturers punished.
    "I demand strict action against them," said the 27-year-old
father. "It's been too long already."

    <^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^
As African children died, doctors fought to get toxic Indian
cough syrup banned    https://www.reuters.com/investigates/special-report/health-coughsyrup/
Indian cough syrup: mystery middleman may be new clue    https://www.reuters.com/business/healthcare-pharmaceuticals/indian-cough-syrup-mystery-middleman-may-be-new-clue-2023-04-29/
Indian firm used toxic industrial-grade ingredient in syrup    https://www.reuters.com/business/healthcare-pharmaceuticals/indian-firm-used-toxic-industrial-grade-ingredient-syrup-sources-2023-06-28/
India probes bribery claim in toxic syrup tests    https://www.reuters.com/world/india/india-probes-bribery-claim-toxic-syrup-tests-2023-06-13/
WHO says toxic syrup risk 'ongoing', more countries hit    https://www.reuters.com/business/healthcare-pharmaceuticals/who-says-toxic-syrup-risk-ongoing-more-countries-hit-2023-06-16/
Indian firms linked to cough syrup deaths had received warnings 
    urn:newsml:reuters.com:*:nL4N3AO2PE
India's contaminated cough syrup cases     urn:newsml:reuters.com:*:nL4N3AO2TE
    ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^>
 (Additional reporting by Saurabh Sharma and Shivam Patel in New
Delhi;
Edited by Sara Ledwith, Michele Gershberg and Daniel Flynn)
 ((krishna.das@thomsonreuters.com))