Ranbaxy and USA FDA regulation

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What is the issue ?
The US Food and Drug Administration (FDA) has banned many medical products from Ranbaxy Laborataries (a popular pharmaceutical company) to enter into the USA market. FDA has issued Form 483 to Ranbaxy.
 
What is FDA ?
The Food and Drug Administration (FDA or USFDA) is an agency of the United States Department of Health and Human Services, one of theUnited States federal executive departments. The FDA is responsible for protecting and promoting public health through the regulation and supervision of food safety, tobacco products, dietary supplements, prescription and over-the-counter pharmaceutical drugs (medications),vaccines, biopharmaceuticals, blood transfusions, medical devices, electromagnetic radiation,cosmetics, emitting devices (ERED), and veterinary products.
 
How come FDA, a firm based in USA got interested in Ranbaxy, a firm located in India ?
The whole case against the firm brought by the U.S. Department of Justice was built on a large trove of evidence collected by whistleblower and former Ranbaxy Director Dinesh Thakur.
 
How come FDA was able to inspect Ranbaxy in India ?
FDA said it exercised its authority under a provision in the consent decree which permits the agency to extend the decree's terms to any Ranbaxy-owned or operated facility if an FDA inspection finds the facility in violation of the Federal Food, Drug, and Cosmetic Act or FDA regulations.
 
Why the name Daiichi Sankyo comming in the news ?
Daiichi Sankyo is a global pharmaceutical company & is located in Japan. This particular company is the parent company of Ranbaxy laborataries of India. That is in short, Daiichi Sankyo owns the Ranbaxy & hence is in news.

Why the name Toansa comming in the news?
There is a factory of Ranbaxy in Toansa where the inspection of this facility was undertaken by the FDA which proved that there were serious violations going on in the company.
This particular factory at Toansa was catering to the company’s 70% of the raw material requirement for medicines.
 
Why is Ranbaxy so famous ?
Ranbaxy is a big player in pharmaceutical sector to manugacture generic drug. (A generic drug is a drug defined as "a drug product that is comparable to brand/reference listed drug product in dosage form, strength, route of administration, quality and performance characteristics, and intended use.)
 
What was being manufactured in the Ranbaxy’s Toansa Factory ?
This particular factory manufactured active pharmaceutical ingredient (API).
 
What is API ?
API (Active Pharmaceutical Ingredient) refers to a substance or substance combination used in manufacturing a drug product. API also refers to the active or central ingredient in the product which causes the direct effect on the disease diagnosis, prevention, treatment or cure. While API is the active component of a drug, excipients are the inactive or inert substances present in a drug.
 
What is Form 483 ?
The U.S. Food and Drug Administration (FDA) is authorized to perform inspections under the Federal Food, Drug, and Cosmetic Act, SEC. 704 of “Factory Inspection" (USA).
Form FDA 483, “Inspectional Observations,” is a form used by the FDA to document and communicate concerns discovered during these inspections. Also referred to as "Form 483" or merely "483".

What are the issues cited by FDA?
The US FDA Form 483 highlighted eight serious deviations in Ranbaxy’s Toansa factory. These included presence of flies through broken windows, building up of melting ice in refrigerator where drug samples were stored, non-maintenance of analytical instruments, etc.
 
Too Numerous To Count (TNTC) flies were found in a sample storage room, and there was inadequate control over samples and non-adherence of procedures in sample analysis.
 
Following is the list of issues cited:
  • Deliberate falsification of data made by the employees in the test results of the medicines
  • Samples were not analysed according to established laboratory test method procedures
  • Numerous results not reported
  • A lack of written procedures and documentation of test results.
  • Appropriate controls are not established over computerised systems
  • Records are not completed contemporaneously, suggesting that Ranbaxy analysts and other personnel were “back-dating” testing records or log books.
  • Laboratory samples are not adequately controlled to prevent mix-ups
  • Deliberate attempts made to avoid detection of any drug or test quality issues.
  • Inadequate laboratory facilities
  • Incomplete records on the maintenance of manufacturing equipment
  • Inappropriately calibrated analytical instruments.
What is DCGI ?
Drug Controller General of India is responsible for approval of licenses of specified categories of drugs such as blood and blood products, IV fluids, vaccines and sera in India.
 
What is CDSCO ?
  • The Central Drugs Standard Control Organization is the national regulatory body for Indian pharmaceuticals and medical devices, and serves parallel function to the European Medicines Agency of the European Union, the PMDA of Japan and the Food and Drug Administration of the United States.
  • Within the CDSCO, the Drug Controller General of India (DCGI) regulates pharmaceutical and medical devices. This is comming under the ministry of health and family welfare India.
  • The DCGI is advised by the Drug Technical Advisory Board (DTAB) and the Drug Consultative Committee (DCC). It is divided into zonal offices which do pre-licensing and post-licensing inspections, post-market surveillance, and recalls when needed.
What has DCGI said to Ranbaxy ?
The company has been given strict warning by DCGI to comply with the standards and norms, failing which it can even face a ban in the domestic market. The company’s Toansa factory is also expected to be inspected by domestic regulatory authorities soon.

What is Daiichi Sankyo going to do for this issue ?
The Japanese company (Daiichi Sankyo) is also likely to bring in more of its people in the Indian factory to clean up the process and procedures on the ground. Many Japanese executives have already been inducted in Ranbaxy over the past one year. However, it appears Daiichi Sankyo now plans to induce more foreign faces not only in the top management of the Indian company but also in the middle and bottom level.
 
Where according to Daiichi Sankyo the problem lies?
Daiichi Sankyo said that the real problem lies with the culture of the company in India & that definately needs to be changed.
 
What Ranbaxy has to say ?
Ranbaxy has recently informed the Drugs Controller General of India (DCGI) that the recent violations at the company’s Toansa factory are suspected to be a sabotage by some of its disgruntled employees who were offered VRS (voluntary retirement scheme).

Are any other facilities also banned ?
Three other formulation manufacturing facilities of Ranbaxy – at Mohali, Poanta Sahib and Dewas are also barred from supplying to the US.
 
What experts have to say about the situation ?
The plant is not in a very good shape and employees should not be blamed for sabotage, as many of the observations made by US Food and Drug Administration (US FDA) are related to lack of documentation over several months, lack of specifications, inadequate laboratory facilities, etc. “How can a set of employees who are offered VRS (voluntary retirement scheme) be given charge during an inspection process? What was the plant in charge doing if these employees were playing mischief?” asks an industry representative.

What are CGMPs ?
CGMP refers to the Current Good Manufacturing Practice regulations enforced by the US Food and Drug Administration (FDA). cGMPs provide for systems that assure proper design, monitoring, and control of manufacturing processes and facilities. Adherence to the CGMP regulations assures the identity, strength, quality, and purity of drug products by requiring that manufacturers of medications adequately control manufacturing operations. This includes establishing strong quality management systems, obtaining appropriate quality raw materials, establishing robust operating procedures, detecting and investigating product quality deviations, and maintaining reliable testing laboratories. This formal system of controls at a pharmaceutical company, if adequately put into practice, helps to prevent instances of contamination, mix-ups, deviations, failures, and errors. This assures that drug products meet their quality standards.
 
Why are CGMPs so important?
A consumer usually cannot detect (through smell, touch, or sight) that a drug product is safe or if it will work. While cGMPs require testing, testing alone is not adequate to ensure quality. In most instances testing is done on a small sample of a batch (for example, a drug manufacturer may test 100 tablets from a batch that contains 2 million tablets), so that most of the batch can be used for patients rather than destroyed by testing. Therefore, it is important that drugs are manufactured under conditions and practices required by the CGMP regulations to assure that quality is built into the design and manufacturing process at every step. Facilities that are in good condition, equipment that is properly maintained and calibrated, employees who are qualified and fully trained, and processes that are reliable and reproducible, are a few examples of how CGMP requirements help to assure the safety and efficacy of drug products.

If a manufacturer is not following CGMPs, are drug products safe for use?
If a company is not complying with cGMP regulations, any drug it makes is considered “adulterated” under the US law. This kind of adulteration means that the drug was not manufactured under conditions that comply with cGMP. It does not mean that there is necessarily something wrong with the drug.

What Ranbaxy is supposed to do according to FDA ?
Ranbaxy is required to hire a third-party expert to thoroughly inspect the Toansa facility and certify to the FDA that the facility and its methods and controls are adequate to ensure continuous compliance with CGMP.
Ranbaxy will not be permitted to resume manufacturing and distributing API for FDAregulated drugs from the Toansa facility until the agency is satisfied that Ranbaxy has addressed its manufacturing quality issues at that facility.

What if Ranbaxy gets or does not get a clean chit from FDA authorities ?
If Ranbaxy manages a clean chit from FDA authorities, it may enable the company to confidently use inhouse APIs instead of outsourcing it.
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