[Ip-health] Why Ranbaxy Won't Be the Last Co To Come Under USFDA Scanner

K.M. Gopakumar kumargopakm at gmail.com
Wed Jan 29 05:44:41 PST 2014

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
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Remembering Karl Slym The Writer's Life Post SUC, It's Advantage Reliance Jio
ith 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

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

"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

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.

joecmathew at gmail.com
Twitter: @joecmathew

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