The discussion in India following the resolution of my case against Ranbaxy has been primarily focused on violations of processes that the U.S. Food and Drug Administration (U.S. FDA) requires pharmaceutical companies to follow. The general theme of the discussion is that, while the U.S. FDA requires compliance with detailed processes for manufacturing drugs and establishing drug stability, Indian regulators do not have such strict requirements. Others have stated that violations of detailed processes do not necessarily result in poor quality drugs.
In response to this discussion, the Indian Health Ministry offered an assurance to the public that it considers products manufactured by Ranbaxy – and other generic manufacturers – to be of high quality. This response from the Ministry of Health (and others in the medical field) is understandable. Any statement to the contrary would have created a panic in the delivery of healthcare in India. Indeed, one incident with Ranbaxy should not be used to paint the entire Indian generic industry with a broad brush.
Having said that, there are two important aspects of this discussion that need closer attention.
- How do we establish quality when the processes by which drugs are manufactured are not sufficiently described and documented?
- What kind of data do regulators need in order guarantee drug quality to the public?
Comparing Indian and U.S. Standards
The U. S. FDA has a Quality Systems Model that represents a framework for compliance with the Current Good Manufacturing Practices (cGMPs) (21 CFR Parts 210 and 211). Its prime directive is: “Quality should be built into the product; testing alone cannot be relied [upon] to ensure product quality.” This is the U. S. FDA’s stated approach to compliance and is available online.
In India, however, there is no such policy to define what constitutes “standard quality.” Drug The Controller General of India (DCGI) tests commercial samples following complaints, known as an adverse events, from consumers. The Central Drugs Standard Control Organization (CDSCO) publishes a list of products that are tested by the central laboratories, which are found to be “not of standard quality.”
It also is instructive to compare how regulations are framed in both countries to understand minimum expectations of high-quality products. In India, cGMP standards are described in Schedule M; in the U.S., the Code of Federal Regulations, Title 21, Volume 4 governs these standards. For example, in the area of training and skill of personnel employed in the manufacturing facilities, India’s Section 6 of Schedule M describes the role of the management, operators, staffing and training in general terms. There are more stringent and defined requirements in the U.S. Subpart B of Part 211 of the CFR, which governs organizational and personnel standards, states that:
There shall be a quality control unit that shall have the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging material, labeling, and drug products, and the authority to review production records to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated. The quality control unit shall be responsible for approving or rejecting drug products manufactured, processed, packed, or held under contract by another company.
Such detailed expectations are missing in the Indian regulations. Although there are additional clauses elsewhere in Schedule M that govern the rejection of products that fail tests, there is nothing as explicit as what is the law in the U.S. on how the process ought to work. There are many such examples in Indian regulations.
Why Processes and Standards Matter
Why is this important? Inspectors generally check compliance with stated regulations to establish variance from standard processes. If there is no explicit expectation of independence of the personnel and management in the quality-control unit, why should anyone be surprised if records, documents, and final products released to the public haven’t gone through rigorous checks for quality?
Violations of such processes result in significant penalties in the U.S. Historically, the same cannot be said about India.
Rigorous compliance with detailed and established processes and systems is a key determinant of the quality of the product. Business process excellence requires definition of the process in detailed steps, its dependencies and associated decision criteria so that the process can be executed consistently by a trained operator.
By way of comparison, the Indian information technology (IT) industry has used this approach as a key differentiator in its growth. SEI CMM is a standard that most Indian IT companies adhere to. ISO 9001 and other certifications require clear definition and adherence to detailed process. The reason these frameworks and certifications require adherence to a well-defined, detailed process is because consistency and repeatability across each step of the process leads to a better quality of the overall product. I believe this adherence to detailed process is why the IT industry from India is proving so globally competitive.
Improving Adverse Event Reporting
In safeguarding drug safety, compliance with processes and standards is particularly important when it comes to adverse event reporting—which is how regulators learn of problems with drugs already in the market. The U.S. has a well-established system to collect and analyze adverse event data. It is easily accessible to the consumer, and regulations require compliance with reporting both individual cases and annual aggregate reports that provide an analysis of trends for a particular drug product. The systems and processes needed to collect such data are still nascent in India.
Historically, reporting of adverse events for generic products lags behind that for branded products in the U.S. This needs to change. The U. S. FDA continues to educate consumers of the need to report adverse events. However, the frequency of reporting adverse events for the same products (generic formulations) in India is significantly lower compared to the U.S. Although the Indian regulator requires submission of periodic aggregate safety data, it is not clear what actions result from the analyses of such data. Regulatory actions seem to be driven more by international incidents (recalls, judgments etc.) than the results of analysis of aggregate safety data.
It’s worth noting that safety is a good surrogate for product quality, a case that I have made before on this blog. There are many such sources of data that are key to a sound scientific decision-making process used by the U. S. FDA. Unless the regulatory framework makes it a priority to collect and analyze such safety and adverse event data, assertions to the superior quality of products dispensed in the Indian market will remain subjective.
FDA Has Approved Only a Fraction of India’s Drug Manufacturers
According to the DCGI, there are 169 manufacturing facilities in India approved by the U.S. FDA, 160 facilities approved by European regulators, and approximately 1,300 certified by the World Health Organization. Overall, the DCGI estimates there to be about 8,000 manufacturing units across the country. Industry estimates put that number as high as 20,000.
The facilities that are inspected by the U.S. FDA and European Regulators have to comply with detailed processes and standards that govern the manufacture of medical products sold in those countries. Can we say the same about the other manufacturing facilities that cater primarily to the local market? Do we really have the confidence that the drugs manufactured in these facilities are in-fact of high quality?