Agnes Shanley is senior editor of Pharmaceutical Technology.

Agnes Shanley

Clinical trials pose major manufacturing and distribution challenges, which have been magnified by the trend to outsource more operations. The success of any clinical trial demands strong adherence to GxPs--required good current practices in manufacturing, clinical, distribution, and documentation. The end goal, says Matthew Caponi, senior director of North American depot and production services at PAREXEL, is providing assurance that the rights, safety, and wellbeing of patients are protected, and that the results of the trial will be unbiased and credible. 

	A number of factors, including increasing complexity of drug forms and increased reliance on outsourcing, has made it more difficult to optimize manufacturing, packaging, and distribution for clinical trials. 

	In addition, a growing number of manufacturers are moving from traditional to direct-to-patient clinical trial designs, a shift that will change basic communication, logistics, and the way that manufacturing, patient compliance, and logistics data are exchanged. This article examines some current trends and changes that can be expected in clinical trial logistics in the near future. 

	On the manufacturing side, failure to maintain GMP standards at the clinical stage is resulting in an increased number of new drug approval delays. In 2016, for example, FDA issued a record number of complete response letters (CRLs) for new drugs under development. CRLs detail problems found at pre-approval facility inspections for new drug applications (NDAs) and require that manufacturers or contract partners fix these issues before the NDA approval process can continue. 

	According to John Jenkins, retired director of the Office of New Drugs in FDA’s Center for Drug Evaluation and Research (CDER), the agency issued 14 CRLs for new drugs (1) in 2016, and five involved cGMP issues at contract development and manufacturing organization (CDMO) or contract manufacturing organization (CMO) partner facilities (2).

	Some of these cGMP deficiencies are due to tight timelines and the fact that formulations are becoming more complex, especially as drug development shifts from an emphasis on small molecules to one on biologics, says Sanjay Vyas, corporate vice-president, global head of clinical trial supplies and logistics at PAREXEL.“Clinicians want a simple dose to administer the most robust and efficient drug formulation, but some dosage forms must be administered intravenously instead of orally.”  In addition, he says, a number of new APIs require a difficult synthesis, and the resulting drug products can require special storage and cold-chain handling. 

	Not all that long ago, many oral, solid-dose products were shipped in corrugate, and temperature monitoring was not even needed, says Vyas. “Today, a biologic must be moved in shippers using phase-change material of far more robust and technical design, with temperature monitoring devices to ensure and demonstrate environmental control,” he says. “All of these specific requirements must be supported by a supply logistics chain that can ensure that the material is maintained exactly as required as it moves along the supply chain--the chain of custody must be unbroken and documented as such,” he adds.

	Packaging for clinical trials must not only support the required storage conditions but also enhance patient compliance and ease of use, as well as efficient logistics, says Vyas. “A blister card that clearly shows the morning and evening dose as part of its design will work better than a series of bottles presented to the patient, each with different dosing instructions,” he says, adding that smaller, less complicated packs will help support logistics efforts.  

	Beyond basic manufacturing, the most challenging part of any clinical trial is maintaining the practice of double blinding, which helps to ensure unbiased trial results by preventing patients, healthcare providers, and those who collect and analyze trial data from knowing whether each individual subject in the trial has received the actual drug being studied or a placebo. The challenges posed by blinding requirements run from manufacturing to dosage-form selection, packaging, and distribution. “The range of potential unblinding or at least complicating factors is enormous, and as varied as the products themselves,” says Caponi.

	Even numbering the kits to be used by each individual patient in a clinical trial requires strategy. If the randomization and trial supply management (RTSM) or interactive response technology (IRT) system being used is not configured with blinding in mind, it will be possible for sites to see trends in the dispensation of kit numbers and identify kits that are different from another, explains Tony Street, PAREXEL’s head of global portfolio leadership for clinical trial supplies and logistics. “The use of scrambled rather than sequential numbers eliminates this risk, but this approach can present operational challenges at the warehouse if the selection of kits is completely random,” he says. 

	Street suggests using a hidden sequence number that will not be visible on the kit, which will allow depot and warehouse staff to know the order in which kits will be requested, so that packing can be done most efficiently. “When selecting your RTSM/IRT vendor, it is essential that you work with a team that fully understands the process at study sites and the GMP/GCP implications of system set up. Something as small as the sequential numbers utilized on a patient kit can jeopardize the credibility of an entire clinical trial program,” says Street.

	Avoiding the need for double dummy trial design

	In trials where two compounds are being compared, a double dummy approach may be required, in which each of the drugs and its placebo are given distinctive forms, for example, different colors for oral solid-dosage forms and their placebos. 

	However, careful and early planning can eliminate the need for this approach, says Caponi. “An early decision on dosage form may prevent the need to resort to double dummy designs, in turn, reducing the total number of dosage forms manufactured, as well as the labels produced, packaging components used, and simplifying overall packaging design strategy. “The end result is a dosing regimen that is easier for the patient to maintain and less expensive to produce,” he says.

	For oral solid-dosage forms, the best solution for blinding may be as simple as over encapsulating the product comparator with the same size capsule, Caponi says. “Injectables present another whole spectrum of issues--questions to ask include: Does your syringe look the same or can it be somehow blinded to the comparator? Is the actual product visually the same color?” he says. 

	It’s especially important to be aware of issues that can result when blinded drugs for clinical trials are manufactured on existing commercial lines, a practice that is becoming more common, and will become to be widespread in the future. 

	Caponi recalls a case in which transdermal pouches were produced at various clinical strengths on a single commercial production line. Each of the pouches was marked so that it could be traced back to the production line, a useful practice for commercial operations. However, when the material was received by the clinical supplies packager, something had to be done to blind these marks, because each mark indicated a difference in strength for each pouch manufactured on that line. 

	The move from traditional to direct-to-patient clinical trials (in which patients take the medication independently in their own homes) is gaining ground, and is likely to result in fundamental changes in the way products are packaged and distributed and how product data are transferred. “Distribution and medical adherence will now be more closely intertwined with the design of the clinical trial itself and the locations of the distribution of the drugs,” says James Streeter, global vice-president of life-sciences product strategy at Oracle.

	In formulation and drug delivery, ease of use and safety will become even more important, because patients themselves, rather than healthcare providers, will be administering dosing, says Vyas.  As a result, products such as infusions or those that need to be reconstituted at the point of use will need to be reformulated, he says, while packaging design will have to become even more streamlined. Biologics manufacturers will also be under greater pressure to develop products that remain stable under a wider range of temperatures and conditions, he adds. 

	Instead of sending large shipments to investigator sites, manufacturers will now be sending multiple, smaller shipments to patients, Vyas says, and logistics planning and patient monitoring data will need to be linked. Planning the last mile of drug delivery to the patient’s home from either the manufacturing plant or the storage depot will become more challenging, he says, because each country has its own different product stability requirements as well as different geographies and climates. 

	“For the clinical supply provider, orchestrating an integrated technology and data sharing capability becomes highly important to ensure that not only the right drugs reach the right patient safely and on time, but also that patient information remains blinded from the sponsor to support regulatory requirements,” says Vyas. Proactive supply chain planning, agility, and integrated technology will be key to success. 

	In the direct-to-patient world, shipping controls and tracking will be handled through new methods that will involve direct contact with patients. Third-party vendors will interact with patients who will get supplies either directly at home or at their local pharmacies, says Oracle’s Streeter.

	Tracking and controlling who gets these drugs will shift from one central operation to individual operations, and regulators will require that patient adherence data be aligned with distribution control, Streeter predicts. In fact, he says, distribution, patient adherence, and overall clinical trial data will no longer be managed separately, but together, because operations teams running the clinical trials will need all three types of data to optimize trial control. In addition, although investigators will still be responsible for patient safety, their operations will also need to be monitored. 

	Blinding and packing the pharmaceuticals used in clinical trials will no longer be controlled at the package level, but at the level of the individual dose, says Streeter, who adds that social media will make blinding more challenging, because patients may inadvertently share information with each other about drugs and their packaging. The need to ensure that dosage form and packaging appear identical will be crucial. Individual dosage forms and their packaging will require unique identifiers, and each will need to be monitored closely, he says.

	Sponsors will have to have the technology required for tracking and monitoring as part of each clinical trial design and as part of their overall data-management toolkit, Streeter says. “We won’t be tracking data at the individual patient’s kit level, but at the level of the individual pill, and data will become part of overall operations data, so a much more coordinated approach to data management will be needed,” he says. 

	Data lineage and even blockchain methodologies will be required so that manufacturers will be able to trace each drug, its packaging, and shipments precisely, Oracle’s Streeter says. As a result, he says, data requirements will explode, requiring large amounts of storage space, analytics and machine learning software to manage and mine.

	“Evidence-based medicine has become the norm in the medical field today, and, as the need grows for real-world evidence in clinical trials, so will the need to break down the silos that still separate manufacturing, patient compliance, and logistics data. Together, these forms of data will provide better overall control, and promise to reduce the overall costs of clinical trials in the future,” he says. 

A Review of CDER’s Novel Drug Approvals for 2016

,” FDAVoice, January 4, 2017.
	2. A. Thayer, “

The Complete Response Letter: The Mail No One Wants to Receive


	Volume 41, Number 11
	November 2017
	Page: 64-67

	When referring to this article, please cite it as A. Shanley, “Moving Toward Direct-to-Patient Models," 

Articles

Despite GxP and data-management challenges, pharma is moving toward new models for clinical trial logistics.

Moving Toward Direct-to-Patient Models

	Blockchain, the digital ledger system that supports the digital currency, bitcoin, is being adapted and evaluated for use in a number of applications and industries, including banking and financial services. Efforts to use blockchain and technologies that it enables, such as smart 

, in pharma are at an earlier stage, but there is a growing recognition that the decentralized platform could offer benefits, allowing supply chain partners to share and verify data in a secure IT environment that is difficult to hack into. Blockchain also allows users to choose the level of data anonymity they want to grant partners, depending on their strategic importance, and how important the data are to their supply-chain roles.

	It comes as no surprise that electrical and electronics engineers, who would be crucial in developing blockchain solutions, are also studying its use in various industries and examining its potential in pharma and healthcare closely. On Oct. 17, 2017, the Institute of Electrical and Electronics Engineers (IEEE) Standards Association disclosed that it had completed and would release its first benchmarking report, 

The State of Blockchain Adoption in the Pharmaceutical Supply Chain

	IEEE’s research into pharma’s experience with blockchain, which began at a 

 that the Institute held at Johns Hopkins University in June 2017, reflects insights from 300 executives, including pharmaceutical manufacturers, distributors, and retail pharmacies and dispensaries, based on their concerns about and opinions of the technology.

	The study aims to explore whether blockchain could help manufacturers, distributors, and dispensaries meet the serialization guidelines established by the US Drug Supply Chain Security Act (DSCSA) of 2013. But, on a broader level, its goal is to identify gaps and barriers to pharma’s adoption of blockchain by asking project leaders at pharmaceutical companies who are actively evaluating the technology a number of fundamental questions that forum attendees had first identified four months ago, including:

			who should pay for blockchain implementation

			who should own the data that result from implementation

			how support for implementation might best be gained from key users and decision-makers

			whether a private or a public blockchain model would work best for pharma’s complex global supply chain.

	Blockchain solutions, IEEE writes in its Executive Summary of the study, would help address pharma’s fragmented and siloed-data access problem, which can hamper effective collaboration and harmonization with multiple trading partners and regulators, since all partners in the pharma supply chain share responsibility for making it work and keeping it safe.

	Two immediate motivators for adopting blockchain, according to IEEE, are the explosive global growth of counterfeit medicines, as well as the pharmaceutical industry’s lack of supply chain transparency, which often leaves it unable to anticipate drug shortages or recalls.

	As IEEE writes, in a digitized world, policy changes alone are not enough to effect improvements in supply chain management, and today’s legacy platforms are ill-equipped to operate in an economy that relies on data sharing.

	Of the 300 respondents to IEEE’s online study, which was independently administered and managed by Ipsos, most executives said that they are actively exploring use of blockchain in their supply operations.  Some have advanced these efforts to the proof-of-concept stage, while roughly 20% are currently involved in a pilot study of the technology.

IEEE saw a direct correlation between an individual’s familiarity with the technology and their company’s participation or level of investment in it. Respondents from all segments of the supply chain said that they viewed blockchain as useful, efficient, valuable and secure, noting that use of blockchains would help them comply with DSCSA requirements.

	As far as top barriers to adoption, wholesalers and dispensary executives saw the main obstacles as lack of user buy-in, the typical challenges that result from implementing any new technology, and the need to connect to all networks.  Manufacturers saw cost, security and network connectivity and integration as top concerns.

	All three groups cited regulatory uncertainty and the need to understand how FDA would define the compliant use of blockchain, as well as visibility of the data and trust, given their supply chain partners’ ability to view company information in an autonomous system.

	In response to questions about who should pay for and own blockchain implementations, most respondents suggest that pharmaceutical manufacturers should be responsible for implementing blockchain and believe that they should also own the data that would be placed in that blockchain.  However, roughly one third of respondents support the idea of shared implementation, in which all trading partners equally benefit, and contribute to implementation.

	Most respondents who are already evaluating blockchain say that they are extremely likely to progress to the next step of study or implementation, confirming IEEE’s observation of a direct correlation between a respondent’s level of familiarity with the technology and his or her enthusiasm for more work in the field.

	Now that barriers are better understood, IEEE is developing a strategic plan that includes standards development, as well as education and awareness programs, to allow the industry to move closer to adopting the technology.  IEEE concluded there is a need for more education about blockchain, and, more generally, a better understanding of what “trust” means on an autonomous platform.

	As a first step to address the need for greater understanding and awareness of the challenges and promise posed by blockchain, IEEE will be holding a workshop in Washington DC on Nov. 8, 2017, at the Eighth Annual Healthcare Distribution Alliance Traceability Seminar, called 

“Cutting to the Trace with Blockchain.” 

IEEE also seeks to develop standards that would be developed and approved through group consensus by a hybrid of technologists, executives, regulators, and academics, to certify that blockchain would be a credible solution for industry applications. 

	Source: IEEE, Executive Summary, October 2017, State of Blockchain Adoption in the Pharmaceutical Supply Chain, Industry Study

Most pharma supply chain partners believe that manufacturers should pay for blockchain implementations, and own the data.

IEEE Releases First Study of Blockchain Adoption in the Pharmaceutical Industry

FDA continues to strengthen its approach to plant inspections (see 

), scoping out roles for inspectors and reviewers, and how they should interact (1). Former FDA investigator Christopher Smith, now a consultant with The FDA Group, shared with 

best practices and things he wishes more pharmaceutical companies would do to prepare for an FDA inspection.
	 

What impact will recent changes at FDA have on inspections?

: All these changes should benefit industry, FDA, and the consumer. Years ago, when I began my career at FDA, inspectors were frustrated by the disconnect between FDA’s field organization, the Office of Regulatory Affairs (ORA), and the chemists, microbiologists, clinicians, and others in headquarters who were reviewing new drug applications. 

	In some cases, we would inspect a company’s plant and find cGMP issues, and then issue a 483 to the company.  While we worked with the firm on resolving the issues in that 483, we’d sometimes see that the same company had already issued a press release touting approval of its new drug, made at the facility with all the problems. We often wondered why one side of the agency wasn’t communicating more closely with the other.
	That communication has been steadily improving since FDA started the preapproval inspection program in the 1990s, and funding has been reserved to allow reviewers to accompany inspectors on some inspections, or at least to talk to them and, for example, give them a list of top 10 priorities and what to look for, based on their application under review.

	However, these advances have been complicated by the fact that application sponsors today are outsourcing more development, manufacturing, pakaging, and clinical research. Applications have gotten very complex, but any contract partner named in a drug application is subject to inspection and should be ready. 

					Sidebar: Teamwork and specialization to govern facility inspections

					FDA Communications Manager Jeremy Kahn addressed questions about how FDA is changing its approach to facility inspections with 

: How will FDA change the way it inspects pharma plants?  

: FDA’s Program Alignment plan, established in 2013, aims to modernize and strengthen FDA’s ability to keep pace with the acceleration of scientific innovation, global expansion of markets, and new programmatic mandates. On May 15, 2017, the agency announced a new organizational model, in which the entire reporting chain for the Office of Regulatory Affairs’ (ORA) inspection and compliance staff, from employees on the front lines to the assistant commissioners at headquarters, would specialize in a particular commodity, for example focusing on pharmaceutical quality operations. 

					This model represents a significant change from ORA’s previous geography-based model, where employees, regardless of their area of expertise, may have worked in more than one program area. We anticipate that deepening knowledge by specialty area will strengthen ORA’s ability to regulate an increasingly complex and global industry. This approach also ensures that management and compliance can efficiently address issues as they arise.

: How will departments within FDA be connecting and communicating with one another?  

: FDA’s Center for Drug Evaluation and Research (CDER) and ORA are implementing a new, historic concept of operations agreement to more fully integrate the drug review programs with the facility evaluations and inspections for human drugs. The new operating model will be a key element of meeting the commitments under the Generic Drug User Fee Amendments II to communicate final surveillance inspection classifications to facility owners within 90 days of an inspection. FDA will begin to implement this agreement this fall, applying it to all human drugs, in order to more quickly meet this commitment.

Is there still too much emphasis on the clinical side and getting approval, rather than ensuring cGMP compliance?
	
	

There’s still a disconnect in industry between the chemistry, manufacturing, and control (CMC) or the cGMP and facilities side of the application process, and the clinical side.  If I do an audit of a clinical investigator site or a sponsor facility’s clinical program, to help them prepare for an FDA inspection, when I ask questions about the CMC side, representatives from the clinical side are often oblivious to the issues that may have occurred when making or packaging the product.  

	I see this disconnect not so much at virtual companies but at the larger pharma companies. Typically, there will be a vice-president of clinical research, a number of physicians, pharmacologists, statisticians, and other teammates all focused on clinical studies, patient safety, trial protocols, institutional review board oversight, and data capture, but when you ask about manufacturing, you’ll sometimes receive a blank stare, even though GMP issues could affect the results of the clinical study.

 What are some ways in which FDA is eliminating the disconnect between its staffers that industry might emulate?
	
	

: One crucial change has been using appropriate expertise to do the audit, and making audits more of a team effort. The agency has realized that, for example, if an aseptic facility must be inspected, it might be best to have someone with a microbiology background handling it. Similarly, an engineer might be selected to look at water systems and piping, as well as specialized equipment with advanced control features.

Do you take a crossfunctional team with you for mock audits?
	
	

: I try to convey the need to do that, but typically companies are concerned about cost and they’ll just want one person to do the audit for two days. 
	
	

How should companies prepare for a mock audit? 
	
	

: One key suggestion is to be more transparent within their organizations, and with the mock auditors, about what their problems have been. FDA can’t look at everything, and an audit is really only a snapshot of what they have seen that day.  
	
	For a new drug application (NDA), a company has likely spent years developing this product and has lots of data. FDA then comes in and pulls a batch record or the results of a study and audits it. Their inspectors are trying to find out where the problems are.  They have the authority to ask for all deviations and batch failures. People don’t want to show their dirty laundry.
	
	You may have good quality systems in place, but FDA inspectors want to know whether your systems can address problems effectively when things go wrong. The only way you can prepare for that is by knowing where all your skeletons are before a mock audit.  Look for problems and see whether and how they were addressed, and be able to explain that clearly.
	
	For FDA, the key question is not whether you had the problem but what you did about it. Unfortunately, people usually want to focus on their successes.  FDA may want to believe them, but they are, after all, cops on the beat. They won’t pull you over to say ‘You’re a great driver,’ but because they want to issue a speeding ticket. Companies need to prepare for that. 
	
	

How do you typically set up the audits?
	
	

: When I perform mock audits with fellow consultants, clients often ask us to pretend to be FDA inspectors. However, very early in the audit, it often becomes clear that their employees aren’t addressing things as they should. In such cases, we need to stop, take our FDA hats off, and coach them. In some cases, they may not be explaining the reason for an issue clearly, or may have the wrong person explain it. So the audit becomes a continuous ‘hats on, hats off’ exercise. In most cases, their employees have never been through an inspection and have no idea what to expect.
	
	

Where have you seen the greatest improvement in getting companies to understand FDA’s expectations during an audit?
	
	

: One of the biggest things I’ve been able to help companies do is to review how they’ve managed and documented the handling of problems that have come up in the past. We’ll often look at an investigation report, either a lab failure, manufacturing deviation, or a clinical site problem, that happened a while ago.  
	
	They’ll show what happened and dig out some kind of report, but what becomes very clear is that the decisionmaking around resolving the problem was poorly documented. Three years ago, everyone understood why the decision was made, but key staffers have left and businesses have changed, so now people are looking for complete documentation and can’t find answers. The documentation must be clear and complete during the problem resolution stage, if it is to be clear years later.

: How can managers be sure they’re answering the right questions?

: As product development progresses, it is crucial to stay on top of things. You don’t want to discover problems after you’ve filed the NDA. You need to have difficult conversations with staff and contract partners before filing, and relevant documentation must be in order.

: Are companies taking a team approach, internally, to audits?

: We are starting to see more firms doing internal audits with teams, where, for example, the quality assurance department does a mock audit of a key operation, but brings in a manufacturing operations expert, an engineer from metrology, and an IT staffer to help. After all, quality assurance staffers can’t be experts in everything.

: It depends on the complexity of the product and the size of the operation. For instance, an oral solid-dosage form manufacturer who has filed many NDAs will have fewer challenges when filing an NDA for a traditional process than a manufacturer who is using a new process and new equipment. The new process will likely require more frequent audits.

: What should companies do when they are working with vendors overseas that may be used to less stringent regulatory oversight?

: The most important thing to clarify with FDA is how you handle vendor selection, auditing, and monitoring. It’s amazing how often sponsors don’t check on day-to-day performance of some of their contract partners. Recently, I just worked with a mid-sized company that had filed an NDA, and half way through clinical studies they found that the offshore contract research organization (CRO) they were working with was doing a poor job. They could have caught problems earlier if they had been paying attention. Strong selection and oversight are crucial.

	And this goes for subsidiary contractors too. One company had hired a contractor to handle its water treatment issues. When I asked about this contractor, the plant manager handed me four lab notebooks. There were no signatures or any other signs that anyone from his company’s quality department had been observing and signing off on this contractor’s performance. These are the kinds of things that prevent you from being in control, and they’re red flags for FDA inspectors.

Integration of FDA Facility Evaluation and Inspection Program for Human Drugs: A Concept of Operations

	When referring to this article, please cite it as A. Shanley, “Teaming Up for FDA Inspections," 

Just as FDA strengthens ties between reviewers and plant inspectors, proactive manufacturers are involving different disciplines in preparation for FDA audits. 

Teaming Up for FDA  Inspections

Six Sigma, both a statistical term and a method developed by Bill Smith, an engineer at Motorola in the 1980s, has allowed companies in a number of industries to improve their business processes, product quality, and overall financial performance. The concept was championed by Jack Welsh when he was CEO of GE, and a number of pharmaceutical companies, including Merck and Johnson & Johnson (J&J) adopted the practice enthusiastically in the past.  
	
	The principles of Lean Manufacturing, including its focus on the customer and employees and its emphasis on minimizing waste, enriched Six Sigma’s overall framework of “Design, Measure, Analyze, Improve, and Control” (DMAIC). The resulting “Lean Six Sigma” (LSS) programs allowed companies in a number of industries to achieve significant improvements in efficiency and product quality.  
	However, LSS programs need senior management support if they are to work, says consultant and statistician Ron Snee, coauthor of 

Leading Six Sigma - A Step-by-Step Guide Based on  Experiences with GE and Other Six Sigma Companies

. 
	
	In cases where this has happened, improvements have been dramatic, he says. Snee recalls one company outside of pharma whose Six Sigma programs were driven first by three managers, saving a few million dollars a year, snowballing into $30 million in savings over five years, after the CEO assigned a vice-president-level champion to the project.
	
	A decade ago, LSS programs were trumpeted by many pharma companies. Today, efforts are more subdued, and not only in the pharmaceutical industry. “It has been a challenge in other industries as well, to maintain excitement and initiatives around Lean Six Sigma,” says consultant Tara Scherder, a chemical engineer and statistician. Now a partner with Synolostats, Scherder trained employees throughout the enterprise as part of Merck Sigma, Merck’s formal enterprise-level Lean Six Sigma program. Today, LSS programs that once spanned the enterprise live on in a muted fashion, limited mostly to smaller initiatives in manufacturing. 

	Why has LSS failed to become standard practice at more pharmaceutical companies? For one thing, Snee says, people misunderstand the concept.  “Some think it’s only about quality improvement, while others just see it as training.  It’s actually about improving the overall performance of an organization.” In addition, he notes, some may be fixated on the definition of Six Sigma, in terms of number of defects. 
	
	In the process, Snee says, managers may fail to integrate programs and efforts with the bigger picture, and overall management goals.  “Programs must be relevant to the needs of the business,” notes Scherder. “You must be agile and focus on business context and solutions, not statistical tools,” she says, especially because these tools are a relatively small piece of a larger business solution, and they are often not required at all. 

	That overemphasis on statistics was a weakness in many corporate training programs in the past, says Scherder, at the expense of other beneficial, relevant principles and activities that should be part of LSS. For example, she says, it takes time, and mentoring, for individuals to absorb statistical concepts, and to apply them properly to specific business issues, considering the context of the data involved. “Typically, non-trivial statistical concepts (e.g., design of experiments) come fast and furious at the student without time for practice, or adequate interpretation,” she says. This can lead to a statistical toolbox mentality, in lieu of statistical thinking. Often, she notes, problems won’t even require a statistical solution. “Learning how to assess business and data context and the need and choice of statistical method requires time and contextual practice. This won’t be found in JMP or Minitab or any other statistical software out there,” she says, noting that the “toolbox mentality” naturally leads to non-value-added analysis instead of the simplest solution. 

	Scherder is also concerned about pharma being compared to other manufacturing industries and criticized for failing to achieve Six Sigma levels. For one thing, notes Snee, Six Sigma has not been achieved for all processes, even within electronics or automotive industries, and it may not always be desirable to achieve it, given business goals. Consider the myriad processes involved in producing a pharmaceutical tablet, Snee says. Which steps would make sense to bring to Six Sigma levels? “Implementing the six sigma improvement process does not mean that a company has attained, or planned to attain six sigma quality in its processes.”

	“Admittedly, the industry has room for improvement in the adoption of LSS principles,” says Scherder, “but simple comparisons to other industries are unfair.” Consider, for instance, the relative ease of incremental change. The regulatory burden associated with process changes in pharmaceutical manufacturing is extremely high compared to that in other industries, which impedes motivation for continual improvement, she says. 
	
	Industry and regulators recognize the benefit associated with reducing this burden over the lifecycle of a product. Signs of progress include the 2016 draft FDA guidance for comparability protocols, and the drafting of a guidance (ICH Q12) for lifecycle management of post approval changes by the International Council for Harmonization (ICH).

	In addition, in pharma, manufacturers  do not always have customer-based specifications, such as tolerance for a car component, or the dimensions of a semiconductor wafer, says Scherder.  Instead, specs are often derived from process performance. This is particularly true for some biopharma attributes, where the mechanism of action to the patient cannot be simply described, she says. In these cases, the sigma quality level is essentially bounded to three, she explains, because the specifications are based on the expected distribution (the mean +/- 3 standard deviations, or similar statistical interval).  
	
	Historically, Scherder notes, when variability has improved over time, regulators have required update of the specifications to reflect the tighter performance even though the tighter specifications were not required for patient safety or efficacy. This practice caps the sigma quality level at three or less, she says, because the specifications bracket only the new performance.  This type of specification adjustment is not prevalent in other industries.  
	
	The use of specification ranges that simply bracket the expected process variability in lieu of true customer derived specifications must be considered in any valuation or comparison of pharma industry sigma quality performance. Clinically relevant specifications (customer derived in terms of LSS), are receiving more attention within the industry. The topic is discussed in a paper by Yu and Kopcha (1) (see 

), and the International Society of Pharmaceutical Engineers has established a working group to focus on this issue, she says.  
	 

	Although Merck’s CEO, and a few other CEOs in pharma, supported Six Sigma and Lean Sigma, “pharma has not yet had a Jack Welch figure,” notes Snee, while companies may abandon an approach that focuses on individual projects.

	But problems with some past programs may also be to blame, says Scherder. At some companies, she says, there may have been too much emphasis on training large numbers of Black Belts who went forth with an arsenal of complex statistical tools to solve problems. Over time, at some companies, the title Black Belt may have become synonymous with ‘someone who complicates things.’ “Today, business priorities have become highly focused,” says Scherder. “You have to prove yourself to be relevant and effective in moving product along the lifecycle,” she says, or improvement programs will be considered a cost that can be eliminated. 

	Scherder sees a need for pharma’s LSS programs to focus on the fundamental concept of understanding and controlling variability and driving that throughout the organization. She also sees a need to incorporate the best aspects of Lean thinking in training. “The concentration on many statistical tools taught too quickly comes at the price of holistic problem solving. Instead, we need to develop problem solvers who will drive statistical thinking throughout an organization, to understand variability, reduce waste, and improve processes,” she says.  
	
	“Everyone needs to have a line of sight from product/process development to commercial supply and back. Application of statistical thinking across an organization would enable the connections needed to optimally develop and continually improve processes,” she says. What would happen, she asks, if process and analytical development professionals were made aware of long term variability that could affect process capability and continual improvement?
	
	Resource prioritization should be given to activities that will provide value or protection to the patient.“If a process exhibits high process capability, there’s no patient benefit to chasing variability that has negligible safety or efficacy implications. In such cases, patient needs are better served by resources spent on new product development, and less capable processes,” she notes. 
	
	Finally, she says, there needs to be a focus on activities that will add value to the patient. Some companies have developed LSS approaches incorporating the best elements of both DMAIC and Lean. Amgen, for example, took an approach that focused on process monitoring, incorporating elements of Lean, and setting targets for process capability to improve individual process performance and reduce cycle time as well as overall waste (2). 

, 528 (2017), pp. 354-359 (June 2017).
	2. M. Van Trieste, “The Journey from Good to Great: Process Monitoring Leads to Improving Product Quality,” paper presented at the Second Annual FDA/PQRI Conference, October 5, 2015. 

	When referring to this article, please cite it as A. Shanley, “Reinventing Lean Six Sigma for the Pharmaceutical Industry," 

Instead of rigidly applying statistical tools, experts suggest that pharma embrace statistical thinking, but focus on reducing variability and adding value for patients.

Reinventing Lean Six Sigma for the Pharmaceutical Industry

	In June 2017, Lawrence Yu, deputy director of the Office of Pharmaceutical Quality (OPQ), Center for Drug Evaluation and Research (CDER), and his FDA colleague, Michael Kopcha, published a paper on how Six Sigma might help the pharmaceutical industry modernize and improve its quality management systems and overall performance (1).  

	Yu and Kopcha highlighted the importance of Six Sigma approaches to continuous improvement, as the pharmaceutical industry moves from management- to performance-based regulation, and toward specifications that are based on clinically relevant goals.  Yu discussed where he sees Six Sigma going with Pharmaceutical Technology.

: Why hasn’t Six Sigma become standard operating procedure for most pharma companies today? 

: The pharmaceutical industry has traditionally focused more on the discovery and development of new drugs than continual improvement of manufacturing processes. Further, there are relatively few economic incentives for manufacturers to leverage quality. Consumers are not always able to recognize quality, and it’s been a relatively recent effort for regulators to place greater emphasis on the measurement of quality. This has created an environment in which there can be a reluctance to adopt Six Sigma and introduce innovations in manufacturing. Still, while Six Sigma is not necessarily standard operating procedure in the industry, there are several examples of pharma companies that have overcome any misunderstandings or problems and embraced it to see clear economic benefits including greatly reduced error rates and cost savings.

: What would be needed to make Six Sigma more widely used in pharma?

: The path to get there includes economic drivers, performance-based regulation, quality by design, advanced manufacturing technologies, and continuous improvement and operational excellence. To fully realize the benefits of Six Sigma, there need to be economic factors that recognize and incentivize quality. From the regulatory perspective, shifts from predominantly management-based regulation to performance-based regulation can give industry the flexibility to more readily address and improve quality. Clearly, emerging manufacturing technologies can help with the drive toward Six Sigma, including continuous manufacturing and advanced [process analytical technology (PAT)]. The pharmaceutical sector must embrace quality by design while adopting these new technologies. Finally, continuous improvement and operational excellence must be part of the overall effort to improve the quality of new and legacy drug products. 
	

: Are there certain areas where, as articulated for discrete manufacturing, Six Sigma will not yield results for pharma? 

: In other industries, product and process understanding is the norm. Optimization is always a critical step in improving quality and reducing cost. In the pharmaceutical industry, ‘compliance’ with regulatory expectations is often the critical goal. To better serve the patient and move beyond compliance, the industry should emphasize quality, and regulators should create an environment amenable to innovation. One example of such innovation is continuous manufacturing; another is PAT. However, given that Six Sigma is a set of techniques for process improvement, manufacturers can apply it whether their process is discrete or continuous, provided they focus on specifications based on clinical relevance.

: What is the most pragmatic way to ease a company into using the approach?  What steps are needed?

: Perhaps most importantly, a company needs to commit to quality and recognize that quality-focused efforts can be cost effective. As a step, a company can start to use process capability to measure quality, something the pharmaceutical industry has widely adopted over the past several years. Another powerful step is embracing and committing to a culture of quality and continuous improvement. To foster a company taking this approach, regulators need to create an environment that appropriately balances risks with regulatory expectations (for example, regarding testing and inspections) based on a company’s level of process capability and other quality matrices.

: What will be needed to move the overall sigma level of the industry?

: The ultimate focus for regulators and industry should always be on benefit to the patient. As improvements in pharmaceutical quality directly benefit patients by helping avoid potential shortages and product recalls, it is in everyone’s interest to raise the level of quality above its current state. 

	A key step is collectively embracing and committing to a culture of quality. In a culture of quality, employees not only follow quality guidelines, but consistently observe quality-focused actions and receive quality-focused communications. This culture requires consistent senior management support and clearly communicated vision, values, and quality goals. For example, performance expectations for individuals throughout a company can clearly link to quality goals and initiatives.

	When referring to this article, please cite it as A. Shanley, “Six Sigma and the Path to Quality," 

Lawrence Yu, deputy director of the Office of Pharmaceutical Quality (OPQ), Center for Drug Evaluation and Research (CDER), and his FDA
colleague, Michael Kopcha highlight the importance of Six Sigma approaches to continuous improvement in the pharmaceutical industry. 

Six Sigma and the Path to Quality

	As they develop new cold-chain services for their pharma customers, more carriers and third-party logistics companies are using Internet of things (IoT) technology to improve product monitoring and address data gaps that can result in wasted product and recalls. “With IoT, customers can be aware of potential problems as products approach their temperature storage boundaries, allowing them to ship replacement product and communicate with customers sooner,” says Vidya Subramanian, cofounder and vice-president of products for Roambee. 

	In 2016, DHL broadened the IoT offerings within its Temperature Management Solutions, says David Bang, CEO of global forwarding and freight for DHL’s Life Conex. The company is currently running a global IoT meshed network, and working with more than 30 airlines, ocean carriers, and technology providers, says Bang. FedEx is also using IoT for pharma and healthcare customers via its Sensaware programme, says Patrick Maier, marketing manager of Healthcare Solutions at FedEx. SenseAware, he explains, monitors current location, temperature, light exposure, relative humidity, shock thresholds, and barometric pressure, allowing shipments to be tracked in real time. 

	Technology providers are offering solutions to both logistics companies and manufacturers. An example is Roambee, whose IoT solution for cold chain and product traceability, the Bee, is a wireless, battery-powered IoT sensor that reports on product or asset location and condition, providing real-time data on temperature, humidity, position within the carrier vehicle, location, and other conditions. The solution is offered on a “pay-as-you-go” basis. Once sensors have been used, they can either be redeployed or returned.

	GlaxoSmithKline (GSK) has used the sensors to prevent product theft and diversion, placing Bees in third-party logistics suppliers’ vehicles moving product out of its factories. The company had banned night driving to help prevent product diversion, but without real-time data, found the ban hard to enforce. Using Bees made it possible to enforce the ban and prevented product diversion, the company reports (1). 

	Working with sensor suppliers, but focusing on the data management issues involved with IoT is Bristlecone Labs, set up in April 2016 by Mahindra Industries. The company works with a number of sensor providers and has several pharma customers, says Sweeni Poroth, cofounder and vice-president of products. Bristlecone and Roambee are working on approaches that would work with blockchain to offer chain-of-custody and condition monitoring, with electronic proof of delivery and a record of condition-monitoring data, says Subramanian. “Currently, these data don’t get saved. They may be printed out, but can be altered,” he says.

	Working with T-Systems, a vendor of private cloud hosting, the companies are developing a proof of concept that would use blockchain-based smart contracts, with Roambee offering real-time product tracking, Bristlecone offering Hyperledger expertise and encrypting data that would be shared by manufacturer and supply chain partners, and T-Systems providing the cloud data hosting. This approach would provide real-time feedback on global shipments, analytics on the whereabouts of shipments, and alerts on noncompliant conditions, says Jim Sabogal, healthcare and life-sciences leader with T-Systems. Smart contracts would trigger penalties whenever a distributor allowed product to be shipped at suboptimal conditions.

	In August 2017, Ambrosus Technologies and Trek Pharmaceuticals launched a programme to evaluate blockchain and smart contracts for manufacturing and supply chain (2). But such approaches will have to prove themselves in the field. “The biggest issue with a system like blockchain is the accuracy of data input into the system,” says Mark Sawicki, chief commercial officer at Cryoport. “We regularly see inconsistencies from third parties relating to scan codes and purported location of packages. Without accountability, these inconsistencies would be problematic,” he says.

			Case Study: GSK Pharmaceuticals, roambee.com, 

www.roambee.com/our-customers/case-studies/case-study-glaxosmithkline

			The editors of Pharmaceutical Technology, “Trek Pharmaceuticals to Test Blockchain-Based Smart Contracts for Clinical Supply Safety,” 

www.pharmtech.com/trek-therapeutics-test-blockchain-based-smart-contracts-clinical-supply-chain-safety

Internet of things, advanced analytics, and blockchain solutions such as smart contracts promise to give manufacturers more control over products and supply chains.