In February, the World Health Organisation raised a medical alert about Indian manufacturer Galentic Pharma over quality defects in several batches of its eye medicine.
The global health body sends out such alerts in rare cases when there is a significant threat to public health and a concern that the risk extends beyond a country.
The alert is sounded only after the WHO carries out an independent inquiry into the product quality. So far this year, the agency has issued three medical alerts. Two out of them concern drugs manufactured in India, including the tetracycline hydrochloride ophthalmic ointment made by Mumbai-headquartered Galentic Pharma.
That’s not all. Two international relief organisations that buy the ointment – the United Nations Children’s Fund and Médecins Sans Frontières – have stopped their purchases from the company and carried out a joint audit of the manufacturing plant. Such an audit is rarely carried out by Médecins Sans Frontières, said an official from the organisation.
“We are currently not buying the ointment from Galentic,” a spokesperson for MSF told Scroll. “As part of our strict and thorough quality assurance policy, together with Unicef, we carried out a good manufacturing practices audit as part of the investigation into this quality complaint, where the root cause was identified.”
Galentic Pharma exports ophthalmic and dermatological products to over 45 countries and is a bulk seller to global organisations. Complaints from at least five international buyers has forced the company to recall all its tetracycline hydrochloride ointment batches from 2020 till February 2023.
In sharp contrast to the action taken by global organsations, Indian authorities have only suspended production of Galentic Pharma’s tetracycline hydrochloride ophthalmic ointment for 25 days.
The suspension will come into force in September, seven months after the WHO issued the medical alert.
Experts have raised questions about the lack of stringent action. The violations flagged “cannot be considered minor”, said KL Sharma, former joint secretary in the Ministry of Health and Family Welfare, who monitored drugs and food safety.
Galentic Pharma and its managing director Bhupendra Sangani did not respond to emails, calls and multiple texts from Scroll about the WHO alert.
In recent months, there has been international scrutiny of made-in-India eye drops. Earlier this year, an eye drop by Global Pharma, a Chennai-based manufacturer, was linked to 68 cases of eye infection in America, including eight cases of vision loss and three deaths. Last month, Sri Lanka complained to the Indian government about eye drops supplied by a Gujarat firm, Indiana Ophthalmics, which allegedly led to eye infections in more than 30 people.
In both cases, the countries immediately stopped further procurement.
The alert
The World Health Organisation was alerted to the problem with Galentic Pharma’s eye ointment when five international buyers flagged a range of quality concerns.
Typically, in such cases, the World Health Organisation contacts the manufacturer and the country where the medicine was manufactured, which then decides whether to take action.
In this case, the WHO informed both Galentic Pharma and the Drug Controller General of India about the concerns.
Eventually, Galentic Pharma was forced to recall all batches of the ointment from 2020 to February 2023.
On February 22, the WHO issued the medical alert.
The ointment is used to treat conjunctivitis, bacterial infection, redness or itchiness in eyes, and trachoma in children. A quality defect or substandard ointment can potentially damage the eyes, more severely in children.
The quality issues, flagged to Galentic Pharma, included particles of different colour and size in the tube, cap and the nozzle, black and brown splotches on the inner foil, and ingredients separating from each other.
The WHO called for “increased surveillance and diligence within the supply chains of countries and regions likely to be affected by the affected batches of this product”.
In an email response to Scroll, WHO said that while it did not carry out an inspection, the supplier of health kits to the organisation found “nonconformities” during a routine inspection at Galentic’s Navi Mumbai site.
According to WHO, there were “quality defects” in 37 batches made in 2022, eight batches from 2021 and four batches from 2020, which suggests that lapses occurred in the plant over at least two years. As many as 55 countries received the defective medicine.
The violations
On March 8 and 9, over a fortnight after the medical alert, the Indian Food and Drug Administration and Central Drugs Standard Control Organisation carried out a joint inspection at the manufacturing plant in Navi Mumbai, and found 24 violations under the Drugs and Cosmetics Act.
A member of the Indian inspection team said that the company had temporarily halted its production of the ophthalmic ointment at the time of inspection. But the Indian authorities “did not object” to their continuing production after the check.
The company received a WHO good manufacturing practices approval in 2005. The inspection report by the FDA and CDSCO, which Scroll has seen, found violations in good manufacturing practices as well.
First, the company was not carrying out random sampling of the product during the beginning, middle and end of batch manufacturing. Random sampling during the manufacturing process helps detect and rectify quality defects immediately.
Second, the manufacturer skipped the bacterial endotoxin test, which checks for any possible bacterial growth in the final product and in the active pharmaceutical ingredient, or the main ingredient, of a drug.
In addition to this, the inspection team found that the manufacturing unit was “not doing purification and filtration during micronisation of API”. Micronisation is a technique used to reduce the size of the active pharmaceutical ingredient, or API, in order to allow it to dissolve better in the drug.
Finally, Galentic Pharma had continued to purchase active pharmaceutical ingredients from a supplier without checking for their audit report. Its Chinese vendor, Ningxia Qiyuan Pharma, was last audited in 2017, five years ago. Though Indian norms demand a mandatory audit of the supplier every three years, Galentic continued to purchase the API.
“This is a major violation,” an official, who was a part of the inspection team, told Scroll on condition of anonymity. “It puts a question mark on the API the manufacturer is using.”
The inspection team also noted poor standards in packaging. For example, before the final ointment is filled into tubes, a compatibility test is necessary to check if the inner foil of the tube reacts with the ointment.
But the firm did not have data to show that it had carried out compatibility tests of tetracycline hydrochloride with the primary packaging material used. This may explain the black and brown splotches on the inner foil of tubes.
Most strikingly, during the joint inspection by the Food and Drug Administration and Central Drugs Standard Control Organisation, Galentic refused to share samples from the control batch for testing.
For every batch of medicines made at a plant, the manufacturer has to store a sample so that it could be tested later if there are concerns over quality.
But Galentic Pharma said that the quantity of the control sample preserved was too small to be shared. Neither the Food and Drug Administration nor the Central Drugs Standard Control Organisation seem to have strongly objected to this. “Ideally the company cannot refuse to give a control sample in such a situation,” said Omprakash Sadhwani, who retired as Food and Drug Administration joint commissioner (drugs) and is now a consultant. “It is strange if they did.”
‘Minor violations?’
On March 10, the FDA issued a notice to Galentic Pharma. The company submitted its response and there was a hearing with the licensing authority. The licensing authority in this case was the joint commissioner of drugs office in Thane. “Based on their response, we felt the violations were minor and an administrative action was adequate,” said DM Bhamray, joint commissioner (drugs) of Konkan division in FDA.
The food and drugs department did not take any judicial action – that is, register a case against the company. “Since there were no serious adverse events, there were no deaths, we did not take any judicial action,” Bhamray said.
A judicial action along with administrative action, Sadhwani said, is the normal choice of punishment in such a case. Sadhwani said the final decision, however, is taken by the licensing authority. “CDSCO holds limited power,” he said. “It is the licensing authority, in this case the FDA, that decides what action to take against the manufacturer.”
Experts differ
To many experts, the Food and Drug Administration’s decision appears to be lacking in rigour.
“Whether there was an adverse event or not is insignificant,” said KL Sharma, former joint secretary in the Ministry of Health and Family Welfare. “If the unit fails to comply with good manufacturing practices requirements, they stand to lose their licence.”
He added: “When a medical alert is issued, the matter is no more between just the licensing authority and manufacturers. The public’s health is at stake.”
The quality issues flagged in the inspection report by Indian authorities were not trivial, said Sharma.
“The non-availability of data is a serious concern. It proves that there are issues in quality adherence,” Sharma said, adding that the licensing authority should have taken action beyond an administrative decision.
Shirish Belapure, senior technical advisor at Indian Pharmaceutical Alliance, said if the ophthalmic ointment is a sterile product, it has to comply with stringent quality protocols. “The bacterial endotoxin test may not be necessary if the product is non-sterile,” Belapure said. “But for sterile products it becomes an important requirement.”
A sterile product is manufactured with more vigilance to ensure negligible microorganism contamination. Galentic Pharma lists the tetracycline ophthalmic ointment as a sterile product on its website. Belapure said for sterile products, quality adherence is crucial. “Big pharma companies spend a lot to follow good manufacturing guidelines,” he said. “We see lapses in smaller companies.”
The Food and Drug Administration’s decision to suspend the production licence of the ointment for 25 days shows “a relaxed approach by Indian regulators”, he said. “If the United States Food and Drug Administration had found such non-compliance, they would have declared an import alert and not allowed it in their country.”
Scroll contacted the United States Food and Drug Administration and European Directorate for the Quality of Medicines and HealthCare to ask what action they take about such violations. While US agency declined to comment, the European Directorate did not respond to the email.
The WHO spokesperson said it has not received “a report from Central Drugs Standard Control Organisation regarding an inspection at the manufacturing plant”.
Audit by international agencies
According to records of the Food and Drug Administration, the largest buyers of Galentic Pharma – MSF, Unicef, International Detailing Association Foundation (Netherlands), Medical Export Group (Netherlands) and Mission Pharma – have recalled the ointment.
According to WHO, these agencies will contact all affected recipients to look for cases of adverse reaction.
In a joint response to Scroll, Unicef and MSF said after they carried out an audit, Galentic Pharma has begun to address the concerns.
“We are currently not buying the ointment from Galentic, but once there is sufficient evidence to demonstrate that the problem has been completely resolved, then there should be no reason not to procure from the company in the future,” the spokesperson said.
An MSF spokesperson told Scroll that substandard medicines remain a problem in low- and middle-income countries. “It is critical that the capacity of national drug regulatory authorities to monitor drugs in both the public and private markets is increased.”
The spokesperson added that “financial and political support to achieve this is critical” in India to ensure quality medicines.
Last month, at the eighth Indian Pharmaceutical Alliance meet held in Mumbai, similar concerns were expressed by Sarah McMullen, country director of US Food and Drug administration in India. The lack of data remains a pressing challenge during their inspections, she told a gathering of pharma manufacturers.
This reporting was supported by a grant from the Thakur Family Foundation. Thakur Family Foundation has not exercised any editorial control over the contents of this article.