Why Ranbaxy Won't Be the Last Co To Come Under USFDA Scanner

28 Jan, 2014 06:59 IST

Why Ranbaxy Won't Be the Last Co To Come Under USFDA Scanner

Even the best Indian drug making facilities will fail to satisfy the increasingly sophisticated standards

Joe C. Mathew


With the latest ban imposed by the United States Food and Drug Administration (FDA) on export of medicines from its Toansa plant in Punjab, drug maker Ranbaxy laboratories is facing one of its biggest crisis ever. All its four Indian production facilities have now failed to match the regulatory compliance levels of the FDA. The company will now have to find alternate ways to serve the world’s largest medicine market to keep a third of its global revenues intact.

A somewhat similar story is unveiling at the production facility of Mumbai based Wockhardt where FDA inspections have resulted in bans and import alerts over medicines shipped from India by the company.

However, experts believe that these companies will not be the only ones to face the FDA heat in near future. Though, the reason for their skepticism is not rooted in some gravely wrong compliance issues, as have been alleged in the case of Ranbaxy or Wockhardt, but the ever increasing vigour of the FDA to ascertain the interests of the US consumer and the US industry through its continuous modernisation programmes.

FDA has made it very clear why its overseas drug suppliers are coming under intense scrutiny.
FDA states that the future of drug manufacturing lies in high-technology, computer-controlled production facilities that can rapidly respond to changes in demand and are capable of seamlessly producing a variety of dosages and dosage forms - a level of competence, which, even the best of the current Indian drug manufacturing facilities, will fail to qualify.

In a submission before the Subcommittee on Energy Policy, Health Care and Entitlements of the US Congress on 12 December 2013, the FDA representative makes it very clear why its overseas drug suppliers are coming under intense scrutiny. Stating that FDA’s inspection and compliance focus has changed in recent years, the agency points out that is has enhanced its inspectorate capability and increased familiarity with the quality systems model (based on a quality systems guidance published in 2006). “Some of these inspections have found operations with antiquated or obsolete facility or process elements, and operations with high defect rates in violation of cGMP (current good manufacturing practices). These operations are receiving higher focus, while manufacturing operations that have been upgraded and are more dependable have been de-emphasised”, Janet Woodcock, Director, Center for Drug Evaluation and Research, FDA notes.

With 40 per cent of the finished drugs taken by US patients and 80 per cent of the raw materials (active ingredients) coming from other countries (India accounts for 10 per cent of the US generic drug market by value), it is only natural that FDA should enhance its oversight to ensure safety and quality throughout the supply chain.

But that’s not all that FDA intends to do.

It believes that use of foreign-sourced materials creates vulnerabilities in the US drug supply and, as a long term measure, wants to reduce its dependence on imported medicines. It states that advances in pharmaceutical manufacturing technology today provide new opportunities to reinvigorate pharmaceutical manufacturing sector in the US. The agency is all set to encourage a new type of manufacturing that is on the verge of entering commercial production.

“The new technologies enable forms of ‘continuous manufacturing,’ wherein the finished drug product is produced in a continuous stream, as opposed to traditional methods (which drug companies in India follow today) that involve a series of so-called ‘unit operations,’ such as milling, mixing, granulation, and so forth”, FDA states. The agency believes that this type of advanced novel manufacturing, where production is continuous from chemical synthesis of the active ingredient through production of the tablets or other dosage form, has a multitude of advantages over the current global manufacturing practices.

“Product quality can be precisely controlled, production scale-up issues, which frequently bedevil drug development, will likely be much less of an issue”, FDA representative informs the House of Representatives of the US Congress Committee. Ease in capacity addition and preparation of varied strengths and doses is another advantage, though, more importantly, FDA notes that “continuous manufacturing plants require a smaller footprint and can be located closer to markets, thus reducing the need for transcontinental shipping of components”.

Ever Increasing Sophistication
The Pharmaceutical Current Good Manufacturing Practice (cGMP) was announced by FDA in 2002 to enhance and modernize the regulation of pharmaceutical manufacturing and product quality.  Four years later, it issued a final guidance, “Quality Systems Approach to Pharmaceutical cGMP Regulations” which provided information to help in implementing quality systems and risk management approaches, but also provides the framework for integrating these approaches into existing programmes with the goal of encouraging industry to adopt modern and innovative manufacturing technologies.  In 2011, came a final version of the process validation guidance, which modernised recommendations and expectations of how pharmaceutical manufacturers should ensure a state of control of their commercial manufacturing processes over the life cycle of the product.

The QbR serves a dual purpose
Implementation of a Question-based Review (QbR) process - a general framework for the assessment of the chemistry, manufacturing, and quality control information submitted in generic drug approval applications – was the next step. This incorporates the most important scientific and regulatory review questions that focus on critical pharmaceutical attributes essential for ensuring generic product quality, the submission to US House of Representatives of the US Congress committee states. “The QbR serves a dual purpose.  First, it provides a guide to reviewers in preparing consistent and comprehensive evaluations of whether a product is of high quality and in the determination of the level of risk associated with the manufacture and design of the product.  Second, it provides industry with transparency about the logic that reviewers invoke in their reviews”.

Quality By Design
The latest among FDA’s plan is the Quality by Design (QbD) project which offers an opportunity to reduce manufacturing costs while ensuring that consumers receive high-quality drug products.  “QbD utilises a systematic approach to product design and development. Instead of being in a reactive mode and taking corrective actions once failures occur, QbD causes manufacturers to focus on developing process understanding and supporting proactive actions to avoid failures through vigilant lifecycle quality risk management.  It can enhance development capability, speed, manufacturing robustness, as well as the manufacturer’s ability to identify the root cause of manufacturing failures”, the submission states.

FDA says that QbD and quality systems are beginning to gain ground in the pharmaceutical sector.
“ While QbD is catching on in development, manufacturers have been reluctant to modernise manufacturing methods by taking advantage of advances in modern facility and process design, such as replacing manually-intensive processes with automation, using closed systems, integrating process analytical technologies into operations for better process control, and adopting continuous manufacturing platforms”, the agency notes.

FDA states that it has been working diligently for over a decade, in collaboration with the pharmaceutical industry, to improve drug manufacturing. “Building on this foundation, and utilising new technologies, groundbreaking new manufacturing methods are within reach.  These new ways of making drugs could, with the proper strategies, revitalize pharmaceutical manufacturing in the US”.

While the move will certainly auger well for the US public and the US drug industry, Indian government and the domestic drug industry should turn more pro-active in understanding the long term implications of these developments for Indian patient and its industry.

Twitter: @joecmathew

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