When the story about Ranbaxy pleading guilty to seven counts of criminal felony broke in May 2013, the standard response across the Indian pharma industry and the Indian drug regulator CDSCO was that there was nothing wrong with products manufactured by Indian companies and somehow the US regulator was out to get Indian industry because it was under the influence of large Pharma and therefore acting maliciously. Events of the last four years, which have included detailed Warning Letters documenting outright fraud and Import Alerts have categorically shown what the reality is when it comes to compliance with good manufacturing standards in the Indian pharmaceutical industry when supplying to the US market. Faced with real evidence of actual behavior within the industry when it comes to compliance, the industry seems to have finally accepted the truth. Finally, earlier this year, the Industry Lobby in India, the Indian Pharmaceutical Alliance (IPA) acknowledged that 85% of the drug supply in India has no data supporting therapeutic efficacy. So much for the “foreign-hand conspiracy” theory!
A second, more insidious reason, now being propagated by the Indian pharmaceutical industry is that the US regulator is somehow capricious; that its standards for compliance are evolving when it comes to how the US regulator assesses compliance for Indian manufacturing facilities. The underlying insinuation is that somehow the goal posts are being moved, thereby intentionally making it hard for the industry to comply. Nothing can be farther from the truth.
It is true that standards do evolve over time, but the process of adopting new standards is very detailed, thorough and transparent. Unlike in India, in the US, new proposed standards get a lot of attention in trade publications and discussions at meetings such as PDA and ISPE. Take the case of Quality Metrics for Manufacturing. It has been over two and half years of discussions with the industry to get a final draft of the proposed metrics. The argument advanced by the Indian industry is that somehow the standards to which the industry is held change overnight, or every few months making them hard to comply and therefore be cited for lack of compliance.
The question therefore is, why do those representing industry indulge in such false propaganda? It seems to me that there is a disconnect between what the Indian pharmaceutical industry sees in inspections from what they are designed to do.
An “audit” or an “inspection” is NEVER intended to identify all the deficiencies at any manufacturing location. If you read the standard text in all Warning Letters, it includes the following: ‘Deviations cited in this letter are not intended as an all-inclusive list. You are responsible for investigating these deviations, for determining the causes, for preventing their recurrence, and for preventing other deviations.’
Inspections are a snapshot in time, and it is unreasonable to expect that even the most experienced inspectors can identify ALL deficiencies in one or two at the site. On a Pre-Approval Inspection (PAI), the investigators generally look to see that the facility and the batch records are consistent with the NDA/BLA/ANDA submission, and that the laboratory data (particularly lot release and stability) are traceable to raw data. On a routine, periodic cGMP inspection, they have more leeway, the scope is broader and inspectors generally look for areas where other inspections have identified common problems. An example is “test” or “sample” injections in chromatography weren’t even on the inspection radar a decade or so ago; they are now a standard inspection item because they have become more knowledgeable and sophisticated in detecting fraud and many have been trained in forensic procedures recently. If the inspection is “for-cause”, it’s a whole different ball-game. These type of inspections are triggered by a specific concern, and therefore are more focussed on specific aspects of the manufacturing process.
Pre-inspection audits are routinely used by pharmaceutical companies to get an “independent-assessment” of their processes and systems. Many a time, such audits identify areas of concern which are flagged to the management’s attention. What becomes of such notifications is largely driven by the prevailing culture within the company. As the saying goes, “you can fool some people most of the time …”
So, now, let us understand what makes the industry say that the goal-posts are being moved? Indian pharma industry has always seen inspections as the qualifying gate, an event at a point in time, that gives us the ticket to sell our product in the US market. The entire focus is on “passing the inspection”, not necessarily making a quality product. A cursory Google of news about the industry will throw up umpteen articles focussing on the number of observations on Form 483, or whether an EIR has been issued; keep looking for articles that talk about “continuous improvement”, CAPA and Statistical Quality Control within these companies. Yes, you will find them, but they will be few and far between.
Gone are the days when the US FDA gave the industry a month’s notice to “prepare” for the inspection; the days when someone from the company tagged along with the inspectors because they did not know the local language, and because the facilities were located in remote areas. These factors gave the company’s ability to “control” what they wanted the inspectors to “see”. Plus, the fact that these were overseas trips for the inspectors from the US, in a new country and the inspectors were afflicted with common travel phenomenon “jet-lag” all played into the ability of the company to “direct” the inspection. Post Ranbaxy, the game has changed. The US FDA has permanent inspectorate staff stationed in its office in India. The sooner the Indian pharma industry understands this, the better.
The fact that inspectors have now gotten smarter, come prepared with knowledge and forensic training in detecting fraud appears to the honchos at these companies as “moving the goal post”. Just because during the last visit, inspectors did not look in the trash-bin where the shredded raw data was discarded or at the entry log which showed that people who signed off on the cleaning validation never actually present on that day the document was signed doesn’t mean that this time they wont. Requirements for “Data Integrity” were always in the “Predicate-Rules” of Code of Federal Regulations, it’s just that the inspection team last time did not pay attention to these fraudulent behavior because they assumed the integrity of scientific process, something which is taken for granted across the world. Now they know better. The investigation led by Office of Criminal Investigations (OCI) at the US FDA as a part of the investigation into Ranbaxy’s fraudulent practices educated the inspectorate on the “reality” of how inspections are managed by the Indian pharma industry.
We are so focussed on managing the inspection to ensure a “successful” outcome that we have lost sight of what the inspection is intended to do in the first place. Ask those who are responsible for these inspections and how large a bonus is tied to their objective of successfully “passing” a US FDA inspection. This is the reason why, even after three and sometimes four years from the time were first inspected, some of these companies continue to face punitive regulatory actions even today. And this, is what is meant by the industry when they claim that the US FDA is changing regulations and that is the reason why the Indian industry fails to comply.
A significant contributor to the industry’s nonchalant attitude toward inspections is the dysfunction at our own regulator, the CDSCO. If our regulator had its act together, and played a constructive role in ensuring the industry was held to proper standards to begin with, pharma companies would have never gotten away with doing the kind of things that we find in almost all the warning letters issued. Lab supervisors would have never “encouraged” scientists to “test-samples-into-compliance”, destroy raw data if the results did not match their expectations, make-up Certificates of Analysis or run a second set of samples to produce “desirable” results. These were acceptable actions during most CDSCO inspections. Inspections from CDSCO were more about “managing” the inspector than ensuring compliance with Schedule M. More importantly, the same Lab Managers and Directors would have stood-up to the C-Suite and told them that handling the workload with half the staff isn’t possible; you cannot extract blood from a stone. Sadly, it was much easier to buy our way out of inspections conducted by our local regulator and that became the norm. Because we have had an incompetent and corrupt regulator for decades as the Parliamentary Standing Committee Report says, this behavior has become so ingrained in our industry. Decades of this behavior manifests itself in how we view inspections, a ticket to making money by selling our product, whatever its quality may be.
So the next time you hear someone in the industry talk about moving goal-posts as the reason why they are cited for compliance failure, ask them some pointed questions. Ask them to show you the specific regulation in the CFR which has changed without public comment. Ask them when it was changed and more importantly, what it is that they did before the change that they claim was made.
Ideas and concepts expressed in this blog were the result of a discussion with Barbara Unger, who consults in the area of cGMP and Regulatory compliance. I wish to thank her for her insights.