NEW DELHI: The 8 companies that have been served with Form 483 are Cipla, Torrent, Dr. Reddy’s, Laurus, Eugia Pharma, Zydus, Alkem and Jubilant Generics. All sell their medicines in the US.
In an effort at using the regulatory system to fight competition from Indian pharma companies, eight Indian pharma companies are amongst the 11 global companies that have been served with “Form 483” of United States Food and Drug Administration (USFDA) since the start of this year.
All these eight companies sell their medicines in the US. The eight companies who have been served with Form 483 this year are Cipla Limited (three times), Torrent Pharmaceuticals Limited (once), Dr. Reddy’s Laboratories Ltd CTO Unit 6 (once), Laurus Synthesis Pvt Ltd (once), Eugia Pharma (four times), Zydus Lifesciences Ltd (two times) and Alkem Laboratories Limited and Jubilant Generics (both once). The remaining three companies are from Japan, Iceland and China. In 2023, the USFDA had served this notice 20 times to different Indian companies. These companies are amongst the top manufacturers of drugs and medicines that are sold in India. Big Pharma is very influential in any US administration, which is why pharma prices in the US are often a hundred or more times more than equivalents produced by Indian companies.
The Form 483 notice, on the surface encourages pharma companies to significantly improve the quality standard on their production sites. In those cases where the motivation is not to battle competition, such moves also benefit the local markets and consumers in India by ensuring better quality drugs.
As per latest data, Indian pharma exports to the US climbed to $7.83 billion during the April-February period in 2024, from $6.8 billion in the same period in FY23. India’s total pharmaceutical exports increased by 9.34% at $25.04 billion from $22.9 billion during the period under review. The US contributes to about 30% of India’s total pharma exports.
In recent years, Indian-manufactured drugs have seen a surge in popularity among American consumers, driven by the combination of affordability and quality. Indian-made drugs are significantly cheaper than their American counterparts due to lower manufacturing and labour expenses in India which is achieved, in almost all cases, without compromising with the quality.
Many Indian pharmaceutical companies operate facilities approved by the USFDA ensuring their products meet stringent American standards. This allows them to offer high-quality generic alternatives to expensive brand-name drugs. India’s robust generic drug sector has been bolstered by government support and a knack for reverse engineering, which leads to rapid development of generic versions once patents on brand-name drugs expire.
Industry insiders say that with healthcare costs soaring in the US, demand for affordable Indian medication options has skyrocketed. With India’s established reputation for producing quality drugs positioned well to meet this need, US buyers are seeking to diversify their supply chains away from Chinese products.
This has also led to bilateral cooperation between the two countries on ensuring that only quality medicine is produced.
In February 2020, the US Food and Drug Administration (FDA) conducted its first bilateral enforcement operation with the Government of India, called Operation Broadsword. Under this collaborative effort involving the FDAs, other US agencies and the Central Board of Indirect Taxes, Customs and the Directorate of Revenue Intelligence, the joint team examined more than 800 shipments at an International Mail Facility and successfully intercepted about 500 shipments of illicit and potentially dangerous unapproved prescription drugs and combination medical devices destined for American consumers. The operation identified approximately 50 different FDA-regulated products, including medications for serious diseases like cancer and HIV. This collaboration stemmed from a senior-level FDA delegation’s visit to India in September 2019 that was aimed at strengthening bilateral engagement to combat public health and safety-based crime.
The FDA is responsible for protecting public health in the United States by ensuring the safety, efficacy, and security of human and veterinary drugs, biological products, and medical devices.
Its Form 483 notifies the company’s management of objectionable conditions that the FDA inspectors have found after inspecting the plants and site where the drugs are manufactured. Observations are made when in the investigator’s judgment any food, drug, device or cosmetic has been adulterated or is being prepared, packed, or held under conditions whereby it may become adulterated or rendered injurious to health.
In the case of Cipla, it was served the latest notice last month for apparent issues with its facility at Verna, Goa. The site report prepared by the investigator has pointed out multiple deficiencies including test methods not being validated/verified properly, deficiency in cleaning and disinfecting the room and machines where medicines are produced. The said inspection was carried out from 10 June to 21 June by three FDA drug inspectors.
The Torrent Pharmaceuticals facility at Indrad, Gujarat was served the notice on 12 June. The inspector claimed that there was no testing program designed to assess the stability characteristic of drug products, the evaluation of the historical stability trend of its drugs revealed in the FDA view the potential of the drug decreasing during the product shelf life.
The FDA also alleged that the firm kept manufacturing and releasing tablet batches into the US market using an analytical test method that was both “not fully understood and potentially giving unreliable test results”. The evaluation of the Adverse Drug Events (ADEs) log for 01-Jun-2022 to 02-Apr-2024 revealed that the firm received multiple market complaints relating to lack of efficacy for the unknown batches, but many of these complaints were not logged in the site and investigated as Product Quality Complaints (PQCs).
The FDA further claimed that equipment and utensils were not cleaned and maintained at appropriate intervals to prevent contamination that could alter the safety, identity, strength, quality or purity of the drug product. The FDA alleged that the company also failed to establish written procedures for the testing of materials as well as recording or storage of laboratory data.
Dr Reddy’s laboratories plant at Srikakulam District, Andhra Pradesh was inspected in May-June. In the inspection the inspectors claimed that analytical methods were not validated or verified under the actual conditions of use, that there was a failure to ensure that manufacturing processes were maintained in a validated state; there was a failure to thoroughly review any unexplained discrepancy and the failure of a batch or any of its components to meet any of its specifications whether or not the batch had been already distributed and there was a “failure to ensure that materials are not released before the satisfactory completion of evaluation by the quality unit”.
The Hyderabad-based Laurus labs, which has a drug manufacturing plant at Parawada, Andhra Pradesh and was inspected in the first week of December 2023, was found to allow critical deviations in manufacturing which were not resolved and its APIs were found to be “unadulterated”. It allegedly also failed to clean equipment and utensils to prevent contaminations.
Eugia Pharma Specialities Limited, which operates a plant in Ricco industrial area, Rajasthan, was inspected in March-April and the FDA in its 14-page exhaustive report alleged that procedures designed to prevent microbiological contamination of products purporting to be sterile were not established and followed. The company allegedly also failed to check the accuracy of input to and output from the computer and records or data.
There was also a failure to thoroughly review any unexplained discrepancy and the failure of a batch or any of its components to meet any of its specifications whether or not the batch has been already distributed. The FDA inspectors found that separate or defined areas to prevent contamination or mix-ups are deficient regarding the manufacturing and processing operations. The firm also failed in establishing adequate written procedures for production and process controls designed to assure that the drug products have the identity, strength, purity, and quality that they are purported or represented to possess. The site was deficient regarding the system for cleaning and disinfecting the equipment to produce aseptic conditions for manufacturing the drugs.
The inspection of Zydus Lifesciences Limited drug facility site at Waghodia, Gujarat was carried out in April and the FDA inspectors said that there was a failure to thoroughly review any unexplained discrepancy and the failure of a batch or any of its components to meet any of its specifications whether or not the batch has been already distributed.
Procedures designed to prevent microbiological contamination of drug products purporting to be sterile were not being followed. The firm also failed to establish adequate written procedures for production and process controls designed to assure that the drug products have the identity, strength, purity, and quality that they are purported or represented to possess.
Cipla’s Raigad, Maharashtra drug manufacturing site too was marked for failure to clean and maintain equipment and utensils to prevent contamination or carry-over of a material that would alter the quality of the API beyond the official or other established specifications. The inspectors found that equipment and utensils were not cleaned and maintained at appropriate intervals to prevent contamination that would alter the safety, identity, strength, quality or purity of the drug product.
Zydus Lifesciences Limited Matoda, Gujarat facility was served the notice after inspectors found deficiency regarding the system for monitoring environmental conditions, procedures designed to prevent microbiological contamination of drug products are not written and followed. Buildings used in the manufacturing, processing, packing and holding of drugs are not maintained in a good state of repair, equipment and utensils are not cleaned and maintained at appropriate intervals to prevent contamination that would alter the safety, identity, strength, quality or purity of the drug product.
Alkem Laboratories Limited’s plant in Baddi, Himachal Pradesh was found to have no system to thoroughly review any unexplained discrepancy and the failure of a batch or any of its components to meet any of its specifications whether or not the batch has been already distributed.
Jubilant Generics Limited’s Roorkee, Uttarakhand-based plant, which was investigated between January-February was found to employ deficient and unreliable cleaning validation and verification systems. Also no time limits were established for the completion of each production phase to assure the quality of the drug product. There were no control procedures established which validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product.
The standards set by the US and FDA regarding the checks on the quality of medicine that can be sold in the US are amongst the toughest which ensures that manufacturers send only the best quality of medicine to the states. Hence the danger of this being misused.
The FDA’s observations in Form 483 are “inspectional observations, and do not represent a final agency determination regarding compliance of the manufacturer. If the firm has an objection regarding an observation, or has implemented, or plan to implement, corrective action in response to an observation, they can discuss the objection or action with the FDA representative(s).”
All the said companies were approached for a response on these developments.
Cipla, in its response, said that it has notified the share exchanges about the USFDA inspection and the six inspectional observations that it received in Form 483 on which it will work closely with the USFDA to address them comprehensively within stipulated time
Similarly, Dr Reddy’s too has informed the stock exchanges about the four observations that it received in Form 483 which the company will address within the stipulated timeline.
None of the other companies shared a response within the deadline. It appears Big Pharma in the US is using every way it can to avoid competing with cheap, high-quality Indian medicines.