US FDA cGMP regulatory compliance by Indian pharma: An impossible dream?

Ram Balani

Current Good Manufacturing Practices (cGMP) compliance that meets US FDA standards is both easy and hard ! Seriously. We’ll explain how below.

Dr Margaret Hamburg, US FDA Commissioner, as we all know by now, recently visited India.

Imagine what most Indian pharma manufacturers must have been thinking about at the eve of this high-profile trip and controversial time for the US FDA Commissioner’s visit to India.

Maybe a mental picture like this one? (See Fig 1)

Fig 1

Mention fda – what comes to mind?

This?

Or perhaps this….

Or even this?

The US FDA Commissioner’s visit to India had a dual purpose, i.e. acknowledge India’s strategic and vital role in the US drugs supply while at the same time bringing in a regulatory ‘whip’. There was a firm acknowledgement from Hamburg that the US is indeed highly dependent on India for its drug supply but vehemently emphasised that there is zero tolerance for drugs manufactured in India destined for American medicine cabinets if they do not comply with US FDA cGMP.

US FDA GMP inspectors now show up without announcement or scheduling at Indian pharma manufacturing gates as they do domestically in the US, what with the increased presence of multiple FDA offices in India. Recently, the Indian pharma industry has been hit with one GMP inspection fiasco after another beyond run-of–the mill Form 483 observations including at once esteemed Indian pharma industry players. We won’t name names, you all know who they are. That said, why is this happening? The answer all points back to our earlier claims of ‘easy’ yet at the same time ‘hard’ above.

Easy, because the US FDA lays out clearly and in great detail the blue-print or compliance road-map via its cGMP statutes or regulations. The US FDA website, www.fda.gov contains extensive links to the cGMP regulations, guidance documents, and various resources to help drug companies comply with the US drug laws.

Specifically, the US FDA publishes the 21 CFR 210 and 211 regulatory statutes (the ‘WHAT’) clearly defining what the US FDA mandates pharma companies should follow plus all sorts of guidance documents to shed more light on the statutes with additional resources to assist drug manufacturers for ‘WHAT’ is expected of them, but NOT the HOW!

Guidance documents published on the US FDA website represents its current thinking on a statute or topic.

They describe FDA’s interpretation of US FDA policy on a regulatory issue (21 CFR 210/211). These documents usually discuss more specific products or issues that relate to the design, production, labelling, promotion, manufacturing, and testing of regulated products.

Therein lies the rub, i.e. the hard part. In India, recently, however, there are increasingly two ways ‘hard’ is manifested, to be specific-there’s what I call (a) ‘hard lite’ and (b) ‘hard core’– we’ll address the first kind below, i.e .the ‘hard lite’ type.

‘Hard lite’ are innocent but remain US FDA-intolerable incidents, occurrences or infractions of cGMP , i.e. caused by lack of cGMP know-how, an honest mistake or lack of understanding, loosely maintained Quality Control (QA), etc. (no malicious intentions). Since the US FDA does not specifically define ‘HOW’ a pharma manufacturer needs to comply with cGMP statutes, it’s left up to every pharma manufacturer to do ‘HOW’ on their own. Enter ‘SOP’ Standard Operating Procedures, defined as ‘written procedures for repetitive use as a practice based on some specifications.’

SOPs are the KEY for bridging the gap between US FDA cGMP statutes (21 CFR 210/211) and a specific pharma drug manufacturing plant site for each drug made. SOPs at the minimum, are written procedures adapted by a specific pharma manufacturer for their own unique products, equipment, people, process and manufacturing location and environment. The SOPs, to be clear, tells the US FDA how each pharma drug manufacturer does its ‘HOW’. The US FDA mandates that if SOPs are not documented or written anywhere, it will assume there are no standards for doing things, and that’s clearly unacceptable. Documenting validated SOPs then putting them to practice thereafter is mandatory at the very least.

Most if not all Indian pharma manufacturers have SOPs in place and are documented more or less so why all these Indian pharma cGMP 483s post cGMP audits or worst, GMP fiascos?

There are several reasons why SOPs created by Indian pharma companies do not do the job as far as the US FDA is concerned and therefore raises concerns or doubts that a specific Indian drug manufacturer is cGMP compliant.

Here’s some of the obvious ones

First and key, the SOPs are not mapped back adequately to the CFR 210/211 statues or in other words the Indian pharma manufacturers ‘HOW’ are inadequately mapped back one-to-one to the US FDA cGMP CFR statues (the ‘WHAT’)?

Second reason why SOPs might fail is because they’re not enforced diligently in practice, i.e though company specifically have SOPs in writing and done correctly once in a while, new personnel or hires are not trained for example, hence they deviate from the practice of the official documented SOPs, i.e. creates exceptions and inconsistency leading up to adulterated drugs sooner or later.

Third reason could be that SOPs after documenting are left alone to gather cobwebs while in the meantime new drug products or delivery are put in place (e.g. liquids instead of gelatin capsules), new manufacturing steps are introduced or old controls replaced (e.g. new equipment commissioned on-line). FDA expects you to document what you say you’ll do and do what you write, easier said than done. SOPs, if enforced help maintain safe and effective drug manufacturing consistency apart from validating to the US FDA that a manufacturer is cGMP regulations compliant during audits. They are mandatory to the ultimate goal of any Indian pharmaceutical drug manufacturer to manufacture safe and effective medicines with assured quality each and every time.

What ‘hard lite’ is can best be understood with examples. Below is an actual US FDA 483 observation from the US FDA website contained in a warning letter issued to an Indian pharma company:

US FDA 483: “Written records of major equipment cleaning and use are inaccurate and do not provide assurance that persons double-checked the performance of equipment cleaning, because there is no assurance that those persons responsible for determining that work was performed were present at the time of equipment cleaning [21 CFR 211.182].”

And here below straight out of the US FDA website is an extract defining 21 CFR 211.182, the relevant matching cGMP statute to the warning infraction above:

PART 211: Current good manufacturing practice for finished pharmaceuticals Subpart J–Records and Reports Sec. 211.182 Equipment cleaning and use log.”

Sec. 211.182 Equipment cleaning and use log.”

“A written record of major equipment cleaning, maintenance (except routine maintenance such as lubrication and adjustments), and use shall be included in individual equipment logs that show the date, time, product, and lot number of each batch processed. The persons performing and double-checking the cleaning and maintenance (or, if the cleaning and maintenance is performed using automated equipment under 211.68, just the person verifying the cleaning and maintenance done by the automated equipment) shall date and sign or initial the log indicating that the work was performed. Entries in the log shall be in chronological order.”

A good SOP as you can deduce, would include references to accuracy of the log, some mechanism that assures the US FDA that persons cleaning the equipment and additionally one assigned to double-check the cleaning process and its maintenance must sign and date cleaning entries into the logs thus confirming the cleaning process. Not rocket science but more often than not, most pharma companies fail to accomplish such procedures for one reason or another.

The second type (b) ‘hard core’ is all together an entirely different matter i.e. not only is cGMP not observed but there is deception or malicious intent to cover up lack of compliance, a mistake or worst, falsify data. All are big ‘no-no’s with the US FDA. Sorry, but there’s no SOPs for cheating with the US FDA, I’m afraid.

The US FDA has zero tolerance not only for adulterated drugs but not surprisingly also for omissions, deception and creative, false reporting. Doing that could very well help turn Hamburg’s and her US FDA brigades’ whip into a hangman’s noose. And from what we’ve observed lately in India, it has!

Below is another actual US FDA 483 observation from another warning letter off the US FDA website:

From US FDA 483

“a. On March 18, 2013, an FDA investigator identified the presence of torn raw data records in the waste area and asked one of your firm’s QA Officers to remove these torn raw data records for the investigator’s review. This QA Officer presented the FDA investigator with approximately 20 paper records, none of which included raw data entries identified in the waste area earlier during the inspection. The FDA investigator asked three times if there were any more records found in the waste area, and the QA Officer responded to each question, “no, this is all of the records”. The FDA investigator then revisited the waste area and found that the raw data records had been removed and placed in a different holding bag.”

Withholding or falsifying drug manufacturing quality control data has been a recurring theme at facility inspections that the US FDA has discovered recently in India. It emerged as recurring problems at a facility owned by India’s poster company referenced above for which the company eventually pleaded guilty.

‘Hard-core’ deviations

‘Hardcore’ incidents are clearly a corporate management and moral imperative challenge, i.e it requires a re-calibration of ethics, adequate oversight and maybe investments on personnel training and pre-emptive and timely governance to prevent cGMP malfunctions . Trust and verify seems like the cure for these times with pharma India.

It’s been reported that cGMP quality management translates to 25 per cent or more of product manufacturing costs. Indian pharma manufacturers surely need to wake up and understand that even with such steep costs, these days, it’s a small price to pay to do-or-die so to speak. And that’s why cGMP for Indian pharma companies is both easy and hard.