Agnes Shanley is senior editor of Pharmaceutical Technology.

Agnes Shanley

When something goes wrong at a facility, the first and easiest explanation is often operator error. But experts say that is rarely the real reason. Today, a growing number of FDA warning letters find that some facilities are not maintaining or following written procedures, whether for process or equipment operation, validation, or quality control testing.  

	Experts trace this problem to a need for more human-centered documentation and training practices, and approaches that empower staff and encourage their active involvement in problem solving and improvement. “Anywhere there is a person-machine interface, there is an opportunity for error” says Jim Morris, executive director of the Health Sciences division of NSF International, a global consulting group that focuses on training, testing, and auditing for pharmaceutical and medical device companies. “The information that operators have about how a process works becomes all the more important,” he says. The more that such information can be provided succinctly and clearly, the greater the chances that procedures will be carried out correctly. 

	Generally, operations that involve bioprocessing equipment come with a high level of complexity, says Morris. However, the highest bar for operators is in sterile operations, he says, due to the nature of the operations and the risk of microbiological contamination. Equipment vendors have responded by developing isolators and enclosed systems that minimize operator contact with the product.

	Use of lean manufacturing and operational excellence techniques has also shown results by reducing waste and errors, and boosting overall productivity. Vetter, a contract development and manufacturing organization, recently implemented such a system for its aseptic filling operations, and realized an overall improvement in production flexibility and efficiency (1).

	Outside of biopharma, changeovers for continuous oral solid dosage (OSD) form processing are extremely complex, says Morris, often involving more than 1000 components to disassemble, clean, and reassemble. Ideally, changeovers should take a day or two, but for continuous OSD facilities, they can require a week or more, depending on the complexity involved (2). Equipment vendors are working on simplifying designs, in projects that involve industry and academia,  but work remains to be done. 

	Operators are the best source of insights on how to improve documentation and processes, and proactive companies are setting up processes that get the operators and technicians who are actually doing the work to provide feedback on procedures and training to see how they might be improved. 

	Seeking input from staff requires creating an open culture in which individuals feel safe bringing up problems and highlighting practices and areas that may need to be improved. “There is a need to move from blame and fear, and to shift the emphasis from a reactive to a proactive culture that provides a nurturing environment [for employees],” says Nuala Calnan, principal of the consulting firm BioPharm Excel, professor at the Technical University of Dublin, and co-leader of the International Society for Pharmaceutical Engineers’ (ISPE’s) and PDA’s quality culture program. 

	But even voicing the idea of employee empowerment can be challenging in a business environment that is constantly changing and focused on reducing costs. In 2019, the pharmaceutical industry saw $278 billion in mergers and acquisitions, 12% of the world’s total, according to Bloomberg analysts (3). Each change in company ownership brings changes in priorities, focus, systems, and procedures. 

	“Where you have a lot of structural and management changes and pressure on costs, change filters its way down to how work is conducted. It’s difficult to work with a lot of continuity, and people will be more prone to error,” says Morris. “The key to improving performance is to set up systems and people for success. Reducing complexity through user-focused documentation systems and risk-based quality systems are key components of success,” he says.

	NSF advances an approach, discussed in a 2019 webcast (4), that is based on triage, or prioritizing efforts based on the severity of potential risks of failure. “Not all events are created equal,” Morris said on the program, “but many sites don’t triage very well, as attested to by poor investigations, a large number of open root cause investigations, and open CAPAs, recurring compliance issues, and high levels of stress.” 

	Successful triage requires establishing clear risk thresholds to distinguish between low-, medium-, and high-level risks and treating them so that staff effort devoted to an event or investigation is a function of the level of risk involved, he said. Training should also be designed so that crucial tasks (particularly the fundamentals of current good manufacturing practices [CGMPs] such as gowning, batch recordkeeping, and data logging) are practiced often and become embedded as habits. 

	At the same time, standard operating procedures (SOPs) should be made easier for operators and technicians to understand and follow, Morris said. Many pharma and biopharma SOPs still contain unnecessary or redundant information or appear as straight text, which can make them difficult to refer to quickly in a busy work environment where individuals are multi-tasking and frequently interrupted, Morris said on the program.  

	It is also important to address the user-friendliness of SOPs, which are meant, not to satisfy regulators or to function as training aids, but to standardize processes and provide consistency, as Martin Lush, global vice-president for pharma and biotech at NSF International has pointed out (5). At a typical pharmaceutical facility, Morris said on the webcast, there may be 800 SOPs and 200 work instructions in place, where the ideal situation might be to have the reverse (i.e., 200 SOPs and 800 work instructions). 

	In addition, each individual SOP can exceed 50 or 75 pages and can be very difficult to follow, Morris said. He suggested using smart labels, for example, to convert a full page of text into a label that provides built-in instructions, and to use arrows and flowcharts to describe sequential tasks, adding photos and call outs to improve explanations.“We need to make sure that SOPs are well designed so that the information they present is relevant and written so that people can follow it, and this needs to be an area of focus for most, if not all, pharmaceutical companies today,” he says. 

	Morris sees a potential role for virtual and augmented reality, especially in setting up risk-free learning environments, so workers can get close to the environment without posing any contamination or other risk. Embedded video will be especially useful in optimizing SOPs for complex and unique operations, says Morris. 

	He blames inadequate planning for many operations and compliance problems. “In some cases, companies haven’t invested enough in understanding variability, and how a process will perform at scale in their operations. Some don’t spend enough time ensuring that people are prepared for the new way of working before they bring changes online. As a result, they suffer from nonconformances that need to be investigated,”  he says. 

	Empowering those employees closest to problems to solve them is a win-win, freeing managers up for more strategic work, says Calnan. “All too often in a CGMP facility, individuals must operate almost as if they are in a straightjacket within the restrictions of SOPs, regulations, and processes that are in place,” she says. 

	In these situations, the leader may handle all the directing and make all the decisions, says Calnan. “We need to enable qualified workers to make as many of those decisions as close to the call space as possible with all the support that they need,” she says.

	Calnan also advises setting up polices that reward people for preventing or predicting problems. One example, would be rewarding good catches (e.g., discovering whether any crucial documentation is missing before product release) as part of batch documentation. In the end, senior management support is essential for shifting from a reactive to a proactive culture and empowering employees. “Quality culture comes from leaders, and you won’t get that crowdsourcing of problem solving and proactivity from the ground floor up if it isn’t sponsored from the top down,” she says. 

	1. G. Buerkle, “Applying Operational Excellence to Improve Injectable Production,” 

, June 24, 2019.
	2. J. Markarian, “Oral Solid Dosage Continuous Manufacturing Strategies,” 

, April 2, 2019.
	3. G.M. Burnett, “Analysis: Pharmaceutical M&A Accounted for 12% of all Global Deals in the Third Quarter of 2019,” 

, October 15, 2019.
	4. J. Morris, “Implementing a Simplification Strategy,” 

, April 10, 2019.
	5. M. Lush, “SOP Simplification, Part 1,” 


	Vol. 44, No. 1
	January 2020
	Pages: 20-22

	When referring to this article, please cite it as A. Shanley, “Human-Centered Work: How Pharma Can Move  to a Blame-Free Culture” 

Articles

As mergers continue and operations become more complex, simplifying procedures and training can prevent costly morale, quality, and compliance problems.

Human-Centered Work: How Pharma Can Move  to a Blame-Free Culture

	Pharma has come a long way since the late 1980s, when Roy Vagelos, then CEO of Merck, promoted the image of an ethical and compassionate industry by making ivermectin, its treatment for river blindness, available to countries around the world at no cost. At the time, the late Sen. Edward Kennedy called the act “a triumph of the human spirit” (1). 

	Since then, as direct-to-consumer advertising took off in the United States, the industry’s image began to change. Bolstered by media coverage of conflicts of interest in promoting products to physicians and first-hand accounts such as Jamie Reidy’s book, Hard Sell: Confessions of a Viagra Salesman (2), the pharma sales representative began to eclipse the devoted researcher in public perception. As regulators and academics pointed out the need for pharma to control manufacturing costs (3), spending on manufacturing and quality were dwarfed by industry spending in other areas. The millennium’s first decade saw criticism over pharma’s expensive political lobbying and its clinical trial and patent extension practices, by physicians including Harvard Medical School professor Marcia Angell. 

	Negative publicity reached a high point in 2015, when former Turing Pharmaceuticals CEO Martin Shkreli increased prices for an anti-infective from $13.50 to $750 per pill (4); and in 2016, when Mylan first came under fire for cornering the market on EpiPen epinephrine (5) auto-injectors and increasing prices by more than 500% over a nine-year period; and Valeant Pharma executives were charged with fraud (6). That same year, the Project on Government Oversight questioned FDA’s ties to the industry through the US Prescription Drug User Fee Act and its scientific independence in approving new rare disease therapies, and also drew attention to pharma’s connection with patient advocacy groups (7).

	Over the past 15 years, US public opinion polls have continued to reflect decreasing public trust in the industry, a trend that has been exacerbated by questions of corporate culpability in the opioid addiction crisis. In 2015, a Kaiser Health Tracking poll found that 72% of US citizens saw drug costs as unreasonable, with 70% believing that drug companies put profits before patients’ lives, and 25% saying they found it difficult to pay for treatments their physicians had prescribed (8). 

	In October of  2019, a year that saw outcry over pricing for insulin, continued shortages of crucial commodity drugs, and Congressional hearings on the topic of drug pricing, a Gallup poll found pharma to be the least-trusted industry in the US (9). In December 2019, an international group of researchers launched the Pathways to Independence project in the 

l to explore how evidence of a drug’s therapeutic value might be gauged more scientifically, divorced from all commercial interests (10). 

	As the public and special interest groups have demanded government action on pricing, a number of proposals would impose limits on pharmaceutical prices, or bring them in line with the prices that patients in other countries pay. Other suggestions have called for establishing an

 focused exclusively on pharmaceutical  pricing (11). 

	While it is not certain that any of these proposals will be voted into law, some observers ask whether both sides of the pricing debate are missing the point. Exploring some of these issues is 

The Great American Drug Deal: A New Prescription for Innovative and Affordable Medicines

, which will hit bookstore shelves on January 20, 2020 (12). Author Peter Kolchinsky is a doctorate-level scientist and founding partner of RA Capital Management, a Boston-based investment fund that focuses on forming and funding biotech companies that are developing new medicines, medical devices, and diagnostics. He shared insights with Pharmaceutical Technology. 

	Distinguishing between  innovation and patent extension

 in response to misunderstandings about drug pricing and innovation costs. “Companies that we are working with and funding to develop new drugs never intended for those drugs to be unaffordable to anyone. They want patients to benefit from their inventions,” he says. But these small innovators would be hurt by sweeping price controls, he says. 

	One problem is that, when the public and Congress look at the drug industry, they see a single, abusive business model when there are really two distinct models, Kolchinsky says. One model drives innovation and needs to be preserved, while the other takes advantage of society and must be reformed. In the first, companies develop new drugs with the hope of marketing them for a period of 10–15 years before they go generic. In the second, they extend the lives of older drugs with new patents, often by making minor upgrades, some of which do not add much value, or simply by exploiting regulatory loopholes so that they can keep harvesting branded revenues. Efforts to reform the industry should largely be focused on the second model, Kolchinsky says, and aim to prevent unjustified patent extensions rather than to impose direct price controls on all drugs. 

	Kolchinsky uses the concept of the  “biotech social contract” to explain what should be expected from innovators, the industry, and society. Public policy should reward innovators for the period during which their drug is patented, after which, Kolchinsky says, a process called “contractual genericization” should be used to prevent companies from engaging in frivolous patent extensions. 

	Under contractual genericization, all drug companies would have to enter into a contract with a dedicated government agency at the time they file for approval of a new drug. They would not be able to get approval without signing that contract, which would ensure that the drug becomes inexpensive once the initial patent period has expired, Kolchinsky explains. “If a company were to make a legitimate, useful but straightforward upgrade to the drug after it launches, it could then apply for and receive a deferral of the contractual genericization date, permitting six more months of branded revenues, analogous to the way that FDA awards six months’ additional patent exclusivity in exchange for running pediatric trials,” he says. In addition to bringing about contractual genericization, Kolchinsky believes that legislation should focus on insurance reform and ensuring that patients’ out-of-pocket costs are minimized or even eliminated. “Insurance companies have increasingly been shifting costs on to patients, which has intensified public outrage,” he says. 

	One form of price control that is currently being discussed is use of an International Price Index (IPI), requiring that companies set US prices to be comparable to those they charge in European countries. Marc Rodwin, professor of law at Suffolk University in Boston, who has studied the way that European markets measure cost effectiveness and set prices, sees this approach as having potential benefits. Rodwin’s research has focused on practices in France (13), where the government sets a maximum price based on comparing the value of a new drug to that of its closest equivalent treatment. If a company doesn’t like the price, it can walk away, although that rarely occurs, Rodwin says.

	In order for international price benchmarking to work, however, the US would have to consider off-list discounts, Rodwin says. Kolchinsky believes that syncing US drug costs to either list or net prices in other countries would lead to higher prices. “If drug companies have to charge the same for a drug in US and Europe, they will simply export the US price to Europe. In some cases, Europe will refuse to pay, denying patients treatment. With less revenue and profits from Europe, companies would be forced to make up the difference by charging the US more, thus raising the global price and further reducing Europe’s participation,” he says, noting that this view was corroborated by the US Congressional Budget Office’s own analysis (14).

 is the introduction of the concept of contractual genericization to ensure that all drugs go generic without undue delay. 

	But Rodwin counters, “Ending abusive patent extensions will only touch at the margins [of the pricing problem]. The key question is: Must purchasers pay any price that a drug developer says that it wants?”

	Rodwin believes that the idea of a separate government agency focused on pricing could work in the US, but he wants to see it negotiate for launch prices, an approach that Kolchinsky insists would be toxic to innovation. Rodwin says, “The UK developed the National Institute for Health and Care Excellence (NICE) over time, and the US could develop its own approach. It already has a physician payment assessment commission for Medicare.” 

	“If I were advising US legislators, I’d say they need to first establish the principle that they have the ability not to purchase a drug if it’s not worth it, and to use existing resources to establish value. If the federal government established that principle for its own purchasing in the Veterans Administration, Department of Defense, Medicare and Medicaid, the private sector might choose to piggyback on that,”  Rodwin says.

	“If Medicare were to develop a thoughtful way to assess a pharmaceutical’s value like the approach that is used by NICE, or if it developed a system that incorporated the approach used in France (i.e., one that considers the added value of a new drug), large private insurance companies might choose to use this methodology, and we wouldn’t have to change US systems in one fell swoop,” Rodwin says. 

	Even on a limited basis, he says, adopting these approaches could work. “If we could incorporate some of these changes, just for Medicaid and Medicare, which account for nearly half of the market, it would have a substantial impact on government spending and on individual copayments,” he says.

	Kolchinsky argues forcefully against attempts to control launch prices or deny patients access to innovative therapies. “The cuts we can make are in what we spend on old drugs, but we mustn’t cut the incentives for new ones or the response will be a predictable and swift reduction in funding of work to treat any disease that the price-setting government agency appears to undervalue,” he says. As an example of what might go wrong, Kolchinsky points to the dearth of industry investment in antibiotics (15), which has prompted a call for establishing incentives for discovery and development. 

	If an independent pricing agency is established in the US, Kolchinsky thinks it should be structured, not like NICE but like the US Biomedical Advanced Research and Development Authority, which stockpiles biodefense vaccines and guarantees that developers and manufacturers make a specific profit for their highly specialized products. “Such an agency could hold the genericization contract on every drug, guaranteeing that its price would drop to, say, twice the cost of production after initial patents expire. It could modestly extend that date to reward a useful upgrade of the drug after it is launched (e.g., moving from a twice-daily to a daily dose),” says Kolchinsky. 

	There would still be room for drugs to go generic the conventional way, he explains, through competition amongst several generic versions, but if the price didn’t drop low enough due to competition, the contract would serve as a back-stop and the original manufacturer would either have to provide it at the guaranteed low price or else transfer the contract to another company that would honor it. 

	“If multiple companies were interested in the contract, they could bid for it. But at all times someone would be accountable for making the drug and selling it at a modest, yet still profitable price. As a last resort, if a nonprofit company wanted to manufacture the drug, the government could contract with it to make the drugs that nobody wants to make, many of which are in short supply,” Kolchinsky explains.  

	Clearly, the debate over high US drug prices promises to continue. But perhaps, as Kolchinsky suggests, it’s time for all stakeholders -industry, insurers, and the government -to consider obligations, not only to the present generation but to future generations of patients, and to redefine the social contract and the roles they each should play in it.

Editors, “Merck Offers Free Distribution of New River Blindness Drug,” 

Hard Sell: Confessions of a Viagra Salesma

n, (Andrew McNeel Publishing Co., Kansas City, MO, 2005).
	3. S. Neuman, “The Pharmaceutical Industry Wastes $50 Billion a Year Due to Inefficient Manufacturing,” 

, Oct. 9, 2006.
	4. A. Mohdin, “A Drug Firm Defends Raising the Price of a Life-Saving HIV Drug by a Mere 5,000%,” 

, Sept. 22, 2015.
	5. E. Willingham, “Why Did Mylan Raise the Price of the Epi Pen by 400%? Be-cause It Could,” forbes.com, August 21, 2016.
	6.  M.Egan, “Valeant Executives Arrested for Fraud,” 

, Nov. 17, 2016.
	7.  D. Hilzenrath, “FDA Depends on Industry Funding; Money Comes with Strings Attached,” 

, Dec. 1, 2016.
	8.  Di Julio et al., Kaiser Health Tracking Poll,

, Aug. 11, 2015.
	9.  J. McCarthy,  “Big Pharma Sinks to the Bottom of Industry Rankings,” 

, September 2019.
	10.R. Moynihan et al., “Pathways to Independence,” 

, Dec. 3, 2019.
	11.   US Dept. of Health and Human Services, “HHS Advances Payment Model to Lower Drug Costs for Patients,” Press Release, 

, Evelexa Press, Boston, 2020.
	13.   M. Rodwin, “What Can the United States Learn from Pharmaceutical Spending Controls in France?” 

, Nov. 11, 2019.
	14.   P. Swegel, “Effects of Drug Price Negotiations, a Letter to Senator Frank Pallone,” 

, Oct., 11, 2019.
	15.   V. Simplin et al, 


	Vol. 44, No. 1
	January 2020
	Pages: 16-19

	When referring to this article, please cite it as A. Shanley, “Public Opinion: Can Pharma Chart a New Course?” 

As the high cost of drugs continues to erode public opinion, experts ask whether price controls are the best, or only, way to improve
access to medicines and regain the public’s trust.


Public Opinion: Can Pharma Chart a New Course?

The philosopher George Santayana once wrote, “Those who fail to learn from the past are condemned to repeat it.” This is clearly seen in the way that some pharmaceutical manufacturers approach root cause analysis (RCA) and corrective action and preventive action (CAPA).

	Both RCA and CAPA are closely intertwined. For example, tracking and trending complaints allows companies to identify recurring problems that may not be caught during inspections on the manufacturing floor, says Kim Jackson, product manager at MasterControl, a vendor of quality management and CAPA software. It also allows them to determine the true severity of specific problems or failure modes, she says. Furthermore, CAPA effectiveness checks ensure that RCA investigations are sufficiently robust, says pharma quality consultant Ajay Pazhayattil.

	Both concepts are crucial for establishing continuous improvement and a true culture of quality, and achieving the goals established by International Council for Harmonization (ICH) Q 12. “Efforts always pay off because they prevent supply disruptions and resulting revenue loss,” says Pazhayattil. Addressing them incorrectly, however, can lead to product quality failures as well as noncompliance with current good manufacturing practices (CGMPs). In some cases, particularly for over-the-counter (OTC) drugs, the problems highlighted in warning letters had already been pointed out previously in FDA Form 483s (1), suggesting a need for more senior management involvement and greater investment in CGMP compliance. Inspectors pointed to inadequate validation and conformance to written procedures, as well as deficient RCA and CAPA. In some cases, root causes for batch or product testing failures were either insufficiently investigated or not probed at all (2,3).

	Experts see a number of reasons for this situation, including the need for a more rigorous approach to risk assessment and a better understanding of the cost of poor quality. “If we as an industry could step up and own the cost of poor quality, if we could measure it, we’d be horrified at how much we pay, not just for failing to solve issues but for repeatedly solving the same ones,” says Nuala Calnan, principal of the consulting firm BioPharm Excel and professor at the Technical University of Dublin. “The number of personhours and CAPAs that arise from these investigations is eyewatering. We don’t add them all up and have a trackable number (i.e., ‘that’s how much it cost us not to get to root cause and to keep on failing’),” she says.

	But there has also been a lack of good RCA training at many pharmaceutical manufacturers. In October 2019, the International Society for Pharmaceutical Engineers (ISPE) and the Parenteral Drug Association (PDA) launched their joint Quality Culture guidance series with a module devoted to best practices for RCA (4), in an attempt to address this problem. Its goal is to help shift the industry’s focus from compliance to prevention. “Pharma companies typically cover fundamentals (e.g., how to use tools such as Five Whys and Ishikawa fishbone diagrams), but teaching people how to use tools and templates isn’t training them to look at the underlying science behind RCA decision making and why it is so important,” says Calnan, who is also coleader of ISPE’s quality culture initiative and one of the authors of the new RCA module.

	Advanced training in the techniques and critical thinking required for investigators, and application of proven RCA tools such as mapping, brainstorming, cause-and-effect, and Five Whys are crucial to improving the state of RCA in the industry, says Pazhayattil. “It’s important not to get stuck on using the same methodology each time, since different problems will call for different solutions,” suggests Marzena Ingram, a senior pharma quality manager who comments as an industry professional rather than on behalf of her company.

	Impeding a better approach to RCA at many companies is an ingrained focus on regulatory compliance and being inspection-ready. “Many quality departments must focus on feeding the compliance system rather than considering quality as a broader responsibility. Often, we’re being driven to close out investigations within 30 days because compliance metrics tell us we need to do that, so we’re not addressing root cause,” says Calnan. In some cases, companies may over-respond to smaller quality problems by launching too many full-scale RCA investigations, says Jackson. “When a company goes into full alert, all-hands-on-deck mode for every issue that arises, not only does time get wasted, but employees become jaded and less likely to do due diligence when a real issue presents itself,” she says. “Taking a risk-based approach to escalations and root cause investigations saves efforts for issues that truly pose a risk to patient health and safety,” she says. Jackson suggests that each quality event be investigated first at a lower level to determine the most likely cause, and then evaluated for risk, says Jackson.

	Another fatal flaw in many RCA programs is that the approaches typically address only part of the problem, the symptoms of the problem, or its direct cause, rather than the fundamental reason why it happened. For example, operator error, which is often cited as the reason for quality problems, usually shows that the system of controls in place for the process and product has failed, rather than any single individual, Calnan says.  In other cases, the reason behind the direct cause for one batch’s failure (e.g., a product or labeling mix-up) may be solved without considering the series of events that caused the mix-up to occur in the first place.  In all these cases, companies wind up cutting and pasting the same solutions to each new problem, whether or not they have worked in the past. “Because the root cause hasn’t been addressed, the problems will recur,” Calnan says.

	Success with RCA requires rooting out any potential sources of bias, says Pazhayattil. “It is human nature to pre-empt causes of failures, but theoretical assumptions should never bias an investigator,” he says. For example, an investigator may unconsciously or consciously, focus on the area that he or she is more familiar with (e.g., process engineering or analytical methods). “Generating sound supporting proof is critical to confirming root causes and developing a science- and data-driven investigation method,” he says.

	“Coming into an investigation with a biased opinion, even if you are fairly sure you’re right, is a surefire way to miss the opportunity to investigate with an open mind,” says Ingram. “No ideas are bad ideas, so it’s best for teams to brainstorm, throw all possibilities up on the board and then rule out, systematically and with proper justification,” she says.

	Calnan also sees an overemphasis on consensus-building as impeding the effectiveness of pharma risk management and RCA. With group efforts such as failure modes and effects analysis (FMEA), which require teams to agree on a numerical value to assign to each specific risk, there may be a failure to invite diversity of opinion or different perspectives.

	“Consensus [can become] the enemy of good critical thinking and risk management,” she says. When teams are analyzing a quality problem, Calnan suggests that one or more members play devil’s advocate and ask for data or other evidence to support any hypotheses. “In some cases, companies may be pushing for agreement way too soon, before they’ve spent enough time or applied any real rigor to identifying the real issues that are causing the problem,” she says.

	“There is very little in pharma’s processes that gets us back out there, onto the lab or manufacturing floor, to shake down the cursory one liner that was given as the reason for the problem. As a result, companies often solve for the wrong problem. When they haven’t even identified the right problem, how can they get to its root cause?” Calnan asks.

	Another obstacle to improvement is the fact that the industry doesn’t typically view failures as an opportunity for learning, says Calnan. “All too often, we have to classify failures, include them in an investigation report, and apply a CAPA to them to move them off our desks so that we can get to the next round of firefighting,” she says.

	Trending to pinpoint sources of variability

	Trending should be done regularly, as suggested by FDA’s revised process validation guidance, to find where sources of variation and potential risk and failure are developing, she says. Market complaints, stability data trends, and multivariate analysis of critical process parameters and critical quality attributes are all sources of data for continuous quality improvement, says Pazhayattil.

	In addition to evaluating risk for individual events, monitoring should be put in place to help identify recurring trends that should be investigated, says Richards. If an issue is recurring, or multiple events point to the same recurring cause, the recurrence can be investigated, and a risk assessment performed on the trend. Based on that, a company could continue to monitor, setting a threshold of acceptance, or initiate a full root cause investigation and CAPA, she says.

	When a full root cause investigation is warranted, having a standard methodology can help streamline the analysis, she says. For example, the use of Five Whys provides structure to the investigation and can help contain its scope while ensuring thoroughness.

	Staffing cross-functional teams offers an opportunity to ensure that the right skill sets are available for RCA. “I am seeing more such teams in action today, but many of them still take an ‘us vs. them’ approach,” says Calnan. This often comes out most clearly in the interpretation of such phrases as ‘the quality department is responsible for closing out the investigation.’  While not meant as an excuse to pass the buck, this phrase often results in quality executives having to develop solutions without enough input and insight from the team, including insights from those much closer to the problem,” says Calnan.

	“The belief that the responsibility to assess and address root cause is ‘someone else’s problem’ is a typical pitfall in pharma RCA programs,” says Ingram. “All departments, even those that may not have direct involvement, should play a role in identifying, analyzing, and effectively solving the problem,” she says.

	Training and knowledge management can also be an obstacle in some companies, where subject matter experts (SMEs) are almost empowered not to share knowledge. “SMEs need to see themselves as knowledge stewards and trainers for the next generation, and essential to creating a learning organization,” says Calnan.

	Beyond training and procedures, pharma’s quality metrics themselves must change if RCA and quality programs are to improve, Calnan says.  She points to a need for leading (rather than lagging) metrics that are aligned with overall patient and business priorities. One example, she says, would be measuring the ratio of preventive actions to corrective actions within CAPA systems, and setting a target to move performance to the next level.

	In addition, Calnan says, recurring deviations need to be correctly coded and accounted for. Currently, most companies don’t code errors in a transparent way that would make it easy to see when they recur. “They’re looking for the exact same error to happen on the exact same line or process, rather than asking whether there are common root causes and coding those causes appropriately,” she says. For example, an organization can have one problem in a lab and another on the manufacturing floor that may seem very different yet share the same root causes.

	A number of technologies are available that promise to improve the way pharma handles RCA and to make the process easier. More powerful data analytics approaches are already being used to allow data to be drawn from disparate databases to be used for risk analysis and RCA, says Calnan. “Technology can also be leveraged to gather failure modes and occurrence data to better inform risk assessments, preventing unnecessary RCA activities when a simple mitigation would suffice,” says Jackson.

	Machine learning and artificial intelligence (AI) tools (e.g., predictive modeling for equipment maintenance, manufacturing process control, and real-time release) are also emerging, says Pazhayattil, who is currently working on research into AI in pharmaceutical manufacturing with CalSouthern. However, it will be a long time before these technologies are found routinely on every pharmaceutical manufacturing plant floor, says Calnan. 

	Although modern equipment (e.g., filling equipment that incorporates automation and isolators) can help improve overall operations, Calnan believes that it is not essential to preventing failures. In addition, she says, doing RCA correctly needn’t be expensive. “As an industry, we need to get on with real training. People need to understand the science behind failure, and to understand the differences as well as the connections between risk and failure,” she says.

	1. ECA GMP, “A Look at FDA’s Warning Letters Over the Last Months,” 

FDA Warning Letter to Torrent Pharmaceuticals

, Sept. 10, 2019.
	4. ISPE, “ISPE and PDA Guide to Improving Quality Culture, Module 1: Root Cause Analysis,” 


	Vol. 44, No. 1
	January 2020
	Pages: 60–62

	When referring to this article, please cite it as A. Shanley, “Getting to the Root of Quality Problems” 

Focusing on symptoms instead of root causes locks teams into a corrective, rather than preventive, mindset. 

Getting to the Root of Quality Problems

Concentrating on symptoms instead of root causes locks teams into a corrective, rather than precautionary, approach.

Finding the Source of Quality Problems

Long a staple for quality by design and solid dosage form manufacturing, design of experiments is becoming an integral part of biopharma upstream process development, as equipment evolves and use of process analytical technology increases.

	Design of experiments (DoE) is used by drug developers to gain deeper insights into their products and processes.

	By using statistical methods to perform multivariate analysis, the approach allows users to assess the impact of various factors on each other and on an outcome or may make these techniques easier to apply.

eBook: Regulatory Sourcebook, December 2019
	December 2019
	Pages: 14–16

	When referring to this article, please cite it as A. Shanley, “Moving from Compliance to Quality," 

Pharmaceutical Technology Regulatory Sourcebook eBook

Long a staple for quality by design and solid dosage form manufacturing, design of experiments is becoming an integral part of biopharma upstream process development.

Design of Experiments Gains Ground in Biopharma Development

Regulators and pharmaceutical manufacturers are debating the best way to measure quality. Discussions center on management and corporate cultures and how they impact operational excellence and customer-focused quality. Observers see the need for more proactive pharmaceutical company managers who actively support and invest in quality efforts and employee training.

Pharmaceutical Technology’s December 2019 Regulatory Sourcebook

eBook: Regulatory Sourcebook, December 2019
	December 2019
	Pages: 6–10

Too narrow a focus on regulatory compliance may prevent organizations from embracing-and profiting from-quality and operational excellence.