By Ali Afnan
Over the past few weeks, I’ve had the opportunity to meet both regulated and the regulators from around the world. The story is always the same: Manufacturers may wait expectantly for regulators, but, in the end, all they really want is to get on with business.
At a recent ICH meeting in Bethesda, regulators and industry had very different perspectives on the progress of global pharmaceutical quality initiatives. Regulators from the EU, Japan and the U.S. seemed pleased with ICH’s progress and projected great enthusiasm, both from and away from the podium. To judge from them, one would think that a new era had finally dawned, in which quality was encouraged by good science and complemented by efficient, risk-based regulatory oversight.
Informal, muted discussions in the hallway, out of their earshot, told a very different story.
Many pharmaceutical manufacturing professionals are not convinced that there is a happy new era ahead, or that science has won the day.
Even some of those within industry who have championed recent initiatives now find it hard going: questions from regulators do not seem to have changed from the old days, some say, while others describe increasing requests for “more raw data,” and ask whether such questions aren’t becoming the hallmark of some FDA review offices.
The regulatory process has simply become more complex, some said, without offering incentives.
As the conference went on, the tone of these hallway discussions became increasingly negative, even cynical. “How can we derive maximum benefit from implemented regulatory processes,” some asked.
Others simply took a “worst case” approach, developing action plans based on the assumption that no business benefits could be realized, and that post-approval oversight would prove cumbersome and lacking in the long-promised “regulatory flexibility.”
If this is the reality, in the trenches, then we couldn’t be farther from ICH’s vision of the desired state.
Consider the area of generic drugs, which now make up most of the prescriptions issued in the U.S. The approval process doesn’t seem to have changed much, despite FDA’s Question Based Review (QBR).
When QBR was first launched, manufacturers believed that it would facilitate and encourage good science and streamline. QBR needs to be updated, and allowed to progress without any shackles. Otherwise, the reality of little change, and a backlog of reviews, now estimated at 2,000, will not go away.
The CFR states that an ANDA review should take 180 days; currently it takes about two years.
What is to be gained from risk-based regulations if the business processes underlying drug manufacturing and regulation remain unchanged?
Are regulators simply aligning the hurdles better?
If the solution is only more regulatory guidance, more training of FDA inspectors and reviewers, aren’t we merely adding more space within which quality systems can fail, and counterfeiters can operate?
Instead of adding hurdles, we should be creating a regulatory process that embraces the manufacturing paradigm, taking the risk out of product quality assurance, while adding degrees of freedom for manufacturing, quality and sensible regulatory oversight.
After all, pharmaceutical manufacturing is not rocket science. We all know the scientific, procedural and regulatory issues involved. So why is a universal solution still out of reach?
Late in 2003, FDA’s CDER, following the example of CDRH and the World Trade Organization, identified voluntary, consensual industry standards as the most cost effective, efficient and sensible way to regulate the industry. Such standards have proven themselves in other industries, and, within FDA, CDRH actively works to set standards, instead of issuing new guidances (which is not to say that all pharmaceutical device manufacturers actually follow them).
Such standards, and the organizations that develop them, codified here in the U.S. through ANSI, automatically assure global harmonization. Couldn’t agreed-upon standards, based on experience and knowledge, prove even more effective and efficient than ICH’s lofty, but voluntary, goals?
Several years ago, CDER set up a technical standards-setting committee within ASTM, but then FDA appeared to back away from the standards. Even a Presidential directive, OMB circular A-119, couldn’t motivate the Agency to use standards. Some token work is still going on, but CDER is still far from using standards in place of its own guidances.
Not surprisingly, industry has simply followed FDA’s suit.
There is a risk in failing to use the accumulated knowledge behind voluntary standards, especially where new, complex technologies are involved.
Today, manufacturers in the Far East, and especially China, are gearing up for pharmaceutical development and manufacturing, and preparing to become major players in the field of biosimilars.
China has cracked down on shoddy manufacturers and reduced the number of drug companies operating in the field, and has just updated its GMPs.
Representatives of China’s SFDA, whom I recently spoke with, through translators, are confident that process controls will be sufficient to demonstrate quality control of biological processes.
As an advocate of process control, I should be excited. However, in the U.S. pharmaceutical industry, we’ve already seen what process control brings, in the absence of process and product understanding. This approach does not bode well, particularly in the field of biologics.
Voluntary, consensual standards offer a way to ensure that process and product understanding, and the accumulation of years of practice, are reflected in regulation.
If the world’s regulators are charged with protecting the public, then perhaps it’s time to move beyond ICH, and step up their commitment, and involvement, in voluntary standards-setting. In the end, it is our best hope to achieve science and risk based regulation in an increasingly complex industry.
Related posts:
- Moving Beyond the Business Case for QbD
- The case has already been made that Quality by Design can make drug manufacturing both faster and cheaper. But success...
- Can QbD Get Its Definitions Straight?
- After all these years, wonders Emil Ciurczak, why is there still so little agreement on basic terminology?...
- Channeling Don McLean
- To paraphrase a great American folk song, pharma's levee is dry. Nostalgia, or the insistence that “pharma is different,” won't...
- What Will the FDA Say? Time to Change the Question
- Ask not what FDA will say about our products and processes, says Contributing Editor Ali Afnan, but rather what we...
- Ali Afnan: Defining Pharmaceutical Quality
- Without true process understanding and control, product quality remains an abstraction that gets reported through specifications, says contributing editor and...
What a pleasure to hear such common sense and direct speaking. If the industry had more people who thought with this clarity and were prepared to say what they thought then it would be in a much better position.
The industry needs to take charge of its own destiny and move forwards along a path already walked and proven in other industries. Consensus standards are the best hope for improving quality and for helping industry to cope with the current plethora of difficulties. Waiting for the regulators to act will simply result in more regulation which does not achieve what industry (or the consumer)needs.
Thanks for commenting! Earlier this year, FDA officials were still voicing support for such standards, so the disconnect between word and deed is surprising.
What do you think would be needed in order to revive development of voluntary pharma industry standards? So far, only a few have really seemed to get anywhere….with excipients, IPEA/IPEC have been working with ANSI to develop standards based on GMPs and that seems to be working out…but others appear to be flashes in the pan…we heard for a while about ISO 15378:2006 for pharma packaging, but not much since, and on the ASTM front, there was E-55, and I recall you were very active on that committee. There was quite a bit of buzz about E-55 for about a year (maybe two) after the PAT guidance came out, then silence.
How would standards be made relevant to pharma and seen by manufacturers as somewhat binding? (Many critics of ISO say that companies may, technically, meet certification requirements,yet have mediocre or worse quality systems in place…and medical device manufacturers, in general, have a terrible quality and compliance record)
Also, how should pharma’s vendors be engaged in any discussion of pharma standards? It would seem that suppliers should be key stakeholders, as they were in automotive QS development, yet they often seem to impede, rather than advance, the discussion.
Not to deluge you with questions…but if you and other readers might share a thought or two that would be great. Especially those who have actually sat on some of these committees and survived (ie. haven’t been run over by a glacier)
FDA has expressed its support for standards vocally at times, and through action at other times, ASTM E55 is a good example. However it remains true that, across the FDA as a whole, an understanding of the real value of consensus standards, and support for their creation, remains an Achilles heal …. the Agency does not walk the talk. This is well demonstrated in the recent report by Kessler and Philips (Philips having 24 years experience at high level in the agency) on another part of the Agency, which states their belief that the Agency could do a much better job of recognising national and international consensus standards and leveraging them in the review process. However the boot is not all on one foot, Kessler and Philips also state that …
“For consensus standards to optimally contribute to public health,
industry needs to support the establishment of more robust standards, including standards with “performance limits,” and to be willing to declare conformity in all premarket submissions. Taking this approach can encourage innovation and afford regulators the confidence that testing against the standard ensures that the device performs as intended and designed.
Furthermore, FDA needs to expand the concept of conforming to standards to include conformance to FDA guidance as a viable and highly desirable approach to securing FDA market authorization.”
If this approach was adopted for PAT and QbD it would transform what is currently a struggling initiative into a vibrant and successful one !
E55 demonstrates neatly both the power of consensus standards and the difficulty of creating them. One E55 standard is E2500, Standard Guide for Specification, Design, and Verification of Pharmaceutical and Biopharmaceutical Manufacturing Systems and Equipment (http://www.astm.org/Standards/E2500.htm). This has been widely used and referenced and is a good example of a consensus standard at its best.
Yet it remains true that E55 is not universally supported, some companies choose specifically not to support the process, and the Agency has blown ‘hot and cold’ over the years.
The standards upon which E55 is currently working , along with its published portfolio, comprise the most comprehensive set of support documents for PAT that are available, yet their use remains patchy … some companies build compliance into their submissions, others ignore them completely.
As Philips and Kessler rightly observe, this is a coin with two sides …. if the industry wants the benefits, then it must be prepared to engage, to contribute, and to use these documents
The benefits of such an approach are clear in other industries (much of the Oil industry is standardised through ASTM consensus standards … the electronics industry widely uses the same approach through a different body)…… the questions are
1) Will the agency walk the talk, and
2) Can the industry see its own self-interest when it is immediately in front of it.
Dr Afnan is far from a lone voice calling for this change.
It is sensible. It is warranted. It has real benefits
….. but when will it happen????
Very interesting conversation, I agree the development and adoption of consensus standards (E55) is going to be key to the wide acceptance and success of QbD and PAT. Furthermore, I think it is one important vehicle for the industry to change the question,
What Will the FDA Say? Time to Change the Question (http://www.pharmaqbd.com/what_will_fda_say/).
With the ‘three tenors’ (http://www.pharmaqbd.com/watts_leaving_fda/) gone from the FDA, it is time for the industry to step up and play its own tune.
One of the questions on standards is why did we get to these “emotion based” regulations. Good science and good manufacturing practices would not have gotten us there. Was it greed or short cuts or public/political emotions that forced governments to set these standards? There are standards for “consultants” “good lighting” and even bath rooms.
Regulations are necessary but has anyone ever done a calculation of the financial burden of things that may seem necessary but are and should be done by the companies if they want to be WORLD CLASS. I believe Pharmaceuticals are WORLD CLASS. Regulations have to be science based on emotion based. If someone is thinking of change, that would be difficult when world class companies are being fined and selling products that have higher than specified amounts of API in their products.
We need to demonstrate that “Science based practices” will produce quality products rather than “regulation based” practices. I am still saying that we need to have regulations but not such that they stifle innovation.
It might be worth benchmarking other industries to see how they manage their chemical operations.
I think you have misunderstood the role and benefits of consensus standards. They are created for mutual benefit. The process of drafting them should engage all the relevant parties and allow them to have their say and have an active role. The standards provide a commonly accepted baseline which reduces workload, standardises submissions, and provides a common basis for evaluation across industry and regulator alike.
They work ! Look at most other industries.
On the subject of pharmaceuticals being ‘WORLD CLASS’ …. can you be clear on what basis you are making this statement. On virtually every measure used to evaluate world class status, pharmaceutical manufacturing fails to score better than average (for external evaluations of this see for instance the tables on manufacturing performance published in the gold Sheet every 4 years or so …. Pharma is consistently behind the field … or the data published by Benson and McCabe in Pharmaceutical Engineering a few years ago).
Again, we only have to look to other industries to see that ‘science/risk-based’ practices outperform regulation-based practices time and again both in the delivery of product quality improvement and the the support for innovation. The presence of such practices is one reason which the electronics industry is able to innovate its way to a new manufacturing technology base every 5 years or so …. Moore’s Law is based on this ability, and it has run true since the 1970s. Pharmaceutical innovation in manufacturing over the same period is a distinct third-best in this race.
Benchmarking is a great idea … have you tried to persuade pharmaceutical managers to benchmark outside their own industry ?? A very limited number do (and benefit hugely from it) … most stick to the conventional dictat that ‘pharmaceuticals are different …’
J&J drug overage would not have happened if they were WORLD CLASS for their financial and manufacturing controls. Variances should have been noticed at the end of each month. They missed it. That is not world class. One BIG Pharma distributed injectables with metal shavings. Contaminated Ciprofloxacin was distributed. Thay all should have been caught if every “T” was being crossed and “I” dotted.
Your last comment says it all. Unless we have a sword dangling (loss of one’s job) on our head, change is going to a challenge.
World Class? In a November article in Automation World, penned by a Research Analyst at Aberdeen Group, Best-In-Class companies are performing at 32 percent higher OEE with 25 percent less unscheduled asset downtime. One new trend, Best-in-Class companies are four times more likely to be focusing on minimizing safety incidents as the “Laggard” companies (under performers).
http://www.automationworld.com/columns-7811
I have attended many pharma packaging and automation events, and I can guarantee you rarely does a pharma operation stack up against soft drinks or beer companies when it comes to OEE and unscheduled downtime. I remember hearing one pharma packager talk about shutting down the line for lunch! A line that took 45 minutes or more to start up again! Sophisticated yes, World Class, afraid not,
World Class? In a November article in Automation World, penned by a Research Analyst at Aberdeen Group, Best-In-Class companies are performing at 32 percent higher OEE with 25 percent less unscheduled asset downtime. One new trend, Best-in-Class companies are four times more likely to be focusing on minimizing safety incidents as the “Laggard” companies (under performers).
http://www.automationworld.com/columns-7811
I have attended many pharma packaging and automation events, and I can guarantee you rarely does a pharma operation stack up against soft drinks or beer companies when it comes to OEE and unscheduled downtime. I remember hearing one pharma packager talk about shutting down the line for lunch! A line that took 45 minutes or more to start up again! Sophisticated yes, World Class, afraid not.