Are pharmaceutical quality systems too complex to be effective? According to an industry expert and a regulator, they are, and an injection of simplicity will help manufacturers improve quality performance.
Giving their respective takes on this idea were Bob Rhoades, VP, Quintiles, who represented industry, and Ian Thrussell, Head of Inspections, World Health Organization, representing regulators, both of whom spoke at the “Quality Systems” session of the 2012 PDA FDA Joint Regulatory Conference. Despite representing opposite sides of the industry, both concurred that a quality system can be designed as user-friendly without sacrificing expectations for clear and direct information.
Drawing on his experience providing regulatory consulting for pharmaceutical and biotechnology companies, Rhoades discussed management’s responsibility to quality. He began by drawing from Risky Business: Managing the Quality of America’s Medicines, a book he wrote many years ago that remains pertinent.
“It probably has been awhile since I picked it up and dusted it off,” he said, referring to the book. “The original was written in 2003—almost ten years ago. When I picked it up and started reading it again, probably the most startling feature is that it really all reads like I wrote it yesterday.
He added that this scared him as “an awful lot of it deals with kind of all the things that go bump in the night…because, frankly that’s a lot of the things that my team gets called in to deal with.” He went on to mention that around 80-90% of his team’s work deals with 483 warning letters, consent decrees, etc.
“This has really become a truly global issue,” he said.
He then went on to note that most problems begin gradually and often remain unnoticed until the problems get big enough.
“We didn’t get there in a day,” he said. “Nobody goes to work and says ‘Gee, what non-compliant, non-quality work can I do today?’”
Ultimately, this breeds complexity.
“We’ve allowed complexity to get in our way,” he said. “This is one of the challenges that management has to deal with. Ultimately, we ask employees to sit down and read 80-90 page SOPs and then go follow it to the letter.” Unsurprisingly, he noted that when FDA inspectors encounter lengthy prose SOPs, these inspectors realize compliance remains on shaky ground.
“We really as responsible managers have to find ways to push simplicity,” he implored.
Decision-making is another area that often falls through.
“Trying to get clear decisions articulated and carried out and executed is a really tough thing,” he said. “You really have to have a mechanism for problem-solving.” He followed up by noting that having a clear decision-making path is important due to the dynamic nature of the industry. Often, issues will occur at one site that staff at another site remains unaware of.
“The single biggest missing skillset in our industry today is the ability to conduct a proper investigation—solve a problem, get to root cause, and then turn that into an effective corrective action or preventive action,” he said. “If you can teach your folks to do that [root cause analysis], I will be out of a job.”
He noted that most firms are not proactive enough to conduct this deep level of analysis and instead are merely reactive, focusing on merely completing paperwork.
Rhoades then discussed an epiphany that occurred on vacation in Ireland when he visited Newgrange, an ancient, massive passage tomb built in 3200 B.C. All the stones used to build this 5,000-year-old structure were quarried from a site 70 km away by canoe.
Pointing out that it took three to four generations for the structure to be completed, he mused that today “we have a hard time getting people to follow an SOP twice two days in a row.”
Every year on the winter solstice sunlight comes through a passage built into the tomb for 17 minutes. The rest of the time, the passage is in complete darkness. All of this was accomplished without computers and other modern technology, stressed Rhoades.
“The complexity of this design and the fact that it took multiple generations to put this thing together such that it’s perfect in doing what it’s doing says to me, ‘you know what, we can do this,’” Rhoades said.
“Somehow or another we can carve through all of the things, all of the problems that plague us on a day-to-day basis to get us to a point where we can create our own little Stonehenge, whether it’s in the drug industry, medical devices, or whoever else from biopharma might be represented here today,” he said.
Going back to the industry, he said that management’s role is to make sure compliance happens in a consistent manner. Not surprisingly this is a challenge due to the disparate nature of large companies with disparate groups of people scattered across various sites and even in foreign countries where language barriers can be an issue.
“That really is the embodiment of compliance,” Rhoades said. It is the “cornerstone of the quality system.”
Lack of consistency often leads to a perceived disconnect between management and the rest of the staff. Rhoades noted that he often visits facilities where workers on the shop floor feel disconnected from management. In many cases, it is not just a perception but a reality.
“It really is our responsibility to lead the organization,” he said. Leadership, he pointed out, is one of the key foundations of a good quality system.
He wrapped up his presentation by management’s requirements for a good quality system: simple and clear guidelines, paths for direct action and problem-solving, and, in general, being prepared for when things go wrong.
Thrussell then provided a regulator’s perspective on quality systems and compliance culture, which mirrored Rhoades’ talk to some extent. He honed in on what regulators are specifically looking for when they review a company’s quality system.
“Why are quality systems actually necessary,” Thrussell mused rhetorically. “Well, on the one hand quality systems are good for you, they allow you to make whatever you are making, or the process that you are running, they allow it to be more consistent.”
On the other hand, for the regulators, “the reason we’re there and why we want to see the quality systems you have working effectively is because we’re interested, first and foremost, in protecting public health.” He then highlighted that, as shown by the history of medicinal regulations, responses have been two to three steps behind the latest disaster, from a recall of 59 million metered dose inhalers in the late ‘90s that led to the deaths of 17 children to the heparin crisis in 2007.
“Those just seem to keep coming up like a bad penny,” he said. “Every five or six years it seems to happen again. And one really has to ask yourself of why the world isn’t learning about that sort of thing.”
Thrussell pointed out that the major recalls and contamination issues in pharma generally “come down to some underlying cultural issue in the companies.” He told about his involvement in a British facility that manufactured flu vaccines that were later recalled and how that particular facility had a significant history, some good and some bad.
“Underlying what went wrong was matters of corporate quality culture,” he said. “And some of these issues here have to do with culture.”
Often a corporate culture can be influenced by cost-savings. In itself, this is not necessarily a bad thing, Thrussell indicated, citing efforts to reduce the prices of HIV medications in sub-Saharan Africa.
“Cost is very, very important,” he said. “But when in an organization it becomes everything and particularly when it becomes very short term…[when] organizations are not planning for a sustainable future that’s when it starts to be problematic.”
Referring back to Rhoades’ point about simplicity, Thrussell cited the example of an investigation he was involved in at a facility in Pakistan. Here, an excipient was mixed with an active during the formulation of a product that contained a massive overdose of Pyrimethamine. Patients who took the drug received a month’s treatment four times a day. This caused the deaths of over 120 patients.
“It was one of the simplest GMP mix-ups—a mix-up in a dispensary adding the wrong material. We talk a lot about quality systems, rather sophisticated systems, but when things go wrong and they still go wrong today, it’s sometimes the most basic things,” he said. “So one little message away from all this is yes, by all means, we need good quality systems and we need good investigations, but we also need to keep things simple.”
In fact, he noted that continuous improvement has been a hallmark of the industry. Yet, at the same time, while this is a normal human behavior it is often stifled thanks to complexity.
“When people don’t understand their processes, they’re very difficult to improve,” he said. “So, really understanding processes, how they work and keeping them as simple as possible, is absolutely key.”
About the Experts
Bob Rhoades is Vice President, Quality & Compliance Consulting, at Quintiles. Bob has designed and implemented compliance improvement initiatives for major manufacturers in the United States, Europe, India and China. Bob has worked in concert with client counsel on a variety of legal cases and was selected to advise in the contaminated heparin crisis in 2008.
Ian Thrussell is currently one of the UK MHRA GMP Inspectorate Expert Inspectors and a member of the UK’s GMP Inspectorate’s Strategic Group which amongst its roles represents the Agency’s GMP interests at an EU and international level. Ian has a wide experience of international guidance development and implementation. He is rapporteur for the current amendments to Chapter 1 and 2 of the EU Guide.