Ian Uydess

FDA regulatory oversight and enforcement have never been more intense or potentially more costly. According to the business intelligence firm FDAzilla, the agency is on pace in 2011 to break its record for 483s for the third year in a row, issuing well over 10,000 citations a year—that's one every 52 minutes. For biopharmaceutical companies, with their highly complex and expensive operations, the total cost of cGMP compliance continues to constitute a significant percentage of the cost of goods sold. 

Meanwhile, a variety of factors have made compliance and quality more challenging. Complex global supply chains increase the likelihood of lapses. Economic pressures to cut costs can result in compromised processes and increased operational as well as quality risk. Conversely, anxiety about regulatory action and inadequate understanding of risk can lead to expensive gold-plating and redundancy in quality and compliance activities. Company growth, the introduction of new products, and entry into new global markets can also attract an increase in regulatory scrutiny. In mergers and acquisitions, achieving consistency in quality and compliance can be especially daunting, particularly when a traditional small-molecule manufacturer acquires a biologics manufacturer or licenses a biologic product, thereby requiring interaction and compliance with a totally different branch of FDA with which it has little or no prior experience.  

In the face of these pressures, the business case for optimal quality and compliance is compelling: improved operating performance, greater productivity, less compliance risk, less rework, and fewer interruptions of supply to the market resulting in lost revenue. Yet, in many companies, compliance problems persist, often because the company culture consists more of fighting fires than of thinking right-first-time and maintaining a reliable state of quality and compliance throughout the company. For an organization to do this successfully—and sustainably—this mindset and behavior focused on quality compliance must start at the top and be emulated by individuals at all levels and in all functions within the company. Moreover, in a culture of quality, it is important that employees adopt this mindset, not because they have to, but because they understand the importance and benefits of this thinking and behavior and appreciate the risks of not adopting it.   

Consider the wildly divergent views of quality that were uncovered when a major biopharmaceuticals manufacturer undertook a comprehensive assessment of quality across a number of its global operations. The company's manufacturing sites, as well as corporate headquarters, were polled on such questions as how well leadership defined and communicated their vision of the desired quality culture, whether management had identified what was required to create and sustain a quality culture, whether the individual had the tools and resources to get his or her job done correctly, and much more. When asked whether the right behaviors were encouraged for sustaining a quality culture, a strong majority of respondents at one site responded favorably, yet overall, barely one third of the staff polled at several other sites, including their corporate headquarters, responded positively.  

Not every dimension that was assessed turned up such divergence. For example, nearly everyone agreed that they were held accountable for the quality of their work; and by overwhelming majorities throughout the company, respondents agreed that if they observed noncompliant activities they felt comfortable calling it to someone's attention. But in many areas there were wide divergences and in others—like whether the company's people had the skills to do a high quality job—there was low favorability almost across the board. It also emerged that the company was perceived by employees as focusing on short-term fixes in quality issues, and that personal development, teamwork, rewards, and recognition were inadequate for promoting a quality culture. Instead of a single, unified environment, the company had many disparate cultures. 

Transforming organizations to obtain and sustain a quality culture begins with a comprehensive evaluation of the various organizational, procedural, staffing, and other parameters that impact quality within the organization. In other words, all of the activities, attitudes, and interactions that together constitute culture must be considered, including elements such as:									

Quality/compliance governance structures: Are there effective mechanisms for such activities as global change management for new product introductions, processes for regulatory changes, pharmacovigilance, product complaints, quality related councils, and material review boards?

cGMP compliance activities: These include batch/lot issuance, batch review and disposition, deviation management, corrective and preventive action, change control, document control, internal auditing/inspection, risk identification/remediation, annual product review and all of the other relevant processes and procedures. Are they uniform, compliant, and effective at each site, across sites, and across the entire organization? 

Quality metrics: These include such measures as right first time, cycle time, product complaints, regulatory events, action plan attainment, reportable events, and the like. Quality metrics should be appropriate and provide the basis for effective review of quality performance. 

Leadership styles and behaviors: Do leaders take a comprehensive view of quality, communicate that vision effectively throughout the company, and behave in ways that foster and support the efforts of all employees?

Human-resource practices: Are personnel sourced, recruited, hired, and on-boarded in ways that promote a consistent, high-performing quality culture? This can be an even more challenging issue for manufacturers of seasonal vaccines, because they often hire many seasonal workers who may have little long-term allegiance to the company or exposure to the company's values in regard to quality. 

Learning and personal development systems: How broad, deep and effective is the organization's training program? Are personnel given opportunities for further professional development? 

Quality behavior reinforcing mechanisms:  Are performance management policies, rewards, and recognition designed to motivate individual employees as well as teams to consistently strive for quality? 

Quality-related information systems: These include not only IT and enterprise resource planning systems used for document management, deviation management, change control, and the like, but also the way in which information is shared. Are best practices and lessons learned at one site communicated to the other sites within the company to maintain a uniform, high-quality company culture?

Employees' perceptions in relation to quality at the company: As with the example of the biopharmaceuticals company described above, how do employees react to statements that describe the cultural norms and behaviors of a high performance organization with a strong quality culture? 

On the basis of this assessment, it is then possible to characterize the organization's quality culture, or more likely, cultures, as the basis for undertaking transformation. 

Key elements of a successful transformation

From the assessment there should emerge clear recommendations for improvement, including quick wins, and goals for the short-, medium-, and long-terms. Because organizations differ, the particulars of these recommendations for transforming any given culture will vary. But there are some constants in the execution of such recommendations. A centralized project management framework should be put in place to help guide the planning and successful implementation of the recommendations. 

To help drive and sustain changes, a compelling quality culture message must be developed—in effect, internally branding the effort. The message must be clear, relevant, understood by all, and designed to provide a point around which every employee can rally, motivating them to contribute to the effort. Best practices in human resources, organizational development, and leadership should be followed in order to maximize employee engagement, assure effective rewards and recognition, provide timely communication of progress, and institutionalize accomplishments. Finally, appropriate operational-excellence tools should be used to further help assure successful implementation and sustainability of these efforts—as well as to provide the metrics needed to monitor and report progress along the way. 

What should the resulting high performing, sustainable quality culture look like? Again, the particulars may vary from company to company, but such cultures should share the following characteristics (see Figure 1):									

Employees at all levels understand the organization's quality objectives, policies, and procedures and their individual roles in helping to achieve them. 

Leadership at all levels is visibly engaged in supporting the development of a quality culture and effectively engages and motivates others to do the same—leading to self-motivated accountability and sustainability.

Effective communication, enterprise-wide sharing of best practices, engagement of all employees, and rewards and recognition for both teams and individuals maintain the momentum and enthusiasm required for sustainability.

The organization hires people who possess the quality values, norms  and work practices the company desires. 

Staged on-boarding and technical and quality training are deployed at the company, business unit, functional area, and individual levels. 

Consistent and sustainable standards of quality are defined clearly and deployed across the organization in conjunction with quality and compliance systems that enable the organization to achieve those standards. 

The organization distinguishes between people and processes as the root cause of mistakes, and instead of blaming people looks to correct processes. 

Leaders and managers at all levels establish an environment of     trust and collaboration in which challenging issues can be raised without fear of reprisal. 

The organization institutionalizes a process for capturing, analyzing, and incorporating lessons learned from past successes and failures.

As the organization grows and changes, the quality culture is continually monitored and fine-tuned to ensure that it remains effective and sustainable.

The journey from quality culture assessment to transformation to sustainability need not take long or consume massive resources. But it does require the recognition that achieving quality and compliance is not a matter of a discrete, isolated process but of the larger environment in which it takes place.  

 are managing consultants at Tunnell Consulting, 

Articles

Employee training-at all levels-is crucial for moving forward with a successful risk- and quality-based manufacturing strategy.

Developing and Sustaining a Quality Culture

	Pharmaceutical manufacturers conduct more technology transfers now than ever before, yet technology transfer remains far from a core competency in the industry today, according to a recent survey conducted by Tunnell Consulting. Looking at the technology-transfer practices of executives at 10 global pharmaceutical companies, the study found that most companies undertake more than 10 technology transfers per year-whether from development to commercial manufacturing or from one manufacturing site to another-and some execute many more. Yet despite the frequency of transfers, the survey results showed the following problems:

		Corporate decision-makers make technology-transfer plans primarily on the basis of financial and marketing considerations, failing to take into account early enough in the decision-making process the effect that execution will have on the organization.

		Senior management significantly underestimates the need for resources and scheduling because its members lack sufficient first-hand knowledge and input from the organization regarding the organizational requirements for supporting technology transfers at the sending and receiving sites, as well as for the numerous support functions that are integral to the process.

		Once high-level decisions have been made, implementation is left in the hands of individual departments, functions, or sites with little, if any, high-level centralized oversight, control, or appropriate metrics.

		The lack of early and effective coordination between the sending and receiving sites, or between development and manufacturing, is further complicated by the absence of clearly defined roles and responsibilities for individuals and teams, lack of open communications, and poor visibility of timelines, progress, and results.

		The transfer runs into problems because a thorough and detailed assessment has not been conducted regarding the comparability between the sending and receiving sites' equipment, environments, and supply chains.

		The participating organizations fail to clearly identify, define, and agree upon which standards and procedures will be followed while conducting transfers, including assurance that all required documentation will be completed in an accurate, timely, and compliant manner.

		The organization fails to take into proper account the impact that technology transfers will have on functions, such as quality, regulatory, laboratory, and supply chain.

		Poor process understanding, coupled with incomplete documentation (i.e., codification) of all the required process parameters, results in attempts to transfer products and processes not under a sufficient and defensible level of control, leading to poor manufacturability at the receiving site.

	The adverse consequences of these common mistakes in the planning and implementation of technology transfer include budget and schedule overruns, disruption of both the sending and receiving organizations, compliance problems, excessive rejects and rework, slower time to market, and supply unreliability. In today's life-sciences business environment, companies can no longer afford such mistakes. They need a technology-transfer process that, like any process, is efficient, cost-effective, sustainable, and repeatable-a core competency that consistently produces maximum strategic impact. Although the components of such a comprehensive technology-transfer capability are many, they can be reduced to two essentials: an overarching technology-transfer framework and rigorous process understanding before transfer. Companies that achieve those two objectives will not only avoid the common mistakes in technology transfer, but also transform the process into a formidable competitive advantage.

Technology transfer encompasses a broad range of activities that must be properly managed for effective, efficient completion. It begins with the end: a definition of when transfer can be considered successful and complete. Technology transfer should be defined as complete when the process is operating in a reliable (i.e., predictable) manner within the established specifications at the receiving site. With this objective in view, an overall framework (see Figure 1) in which that goal can be achieved should include the following ideas.

An overall transfer-program-management process. 

This process includes a governance structure, the establishment of executive sponsorship, and the clear delineation of roles and responsibilities-including the roles of all support functions, such as quality or regulatory-for all transfers. This program-level process enables a company to manage its technology transfers as a portfolio, apply risk-management techniques to the portfolio as a whole, and optimize the return on investment.

A project-level management for the transfer of each product or process. 

This includes a "by design" set of requirements, activities, decision points, milestones, and best practices that ensure timely, well-documented transfer within budget and with minimal impact on product sales. At the project level, the framework encompasses the advances made during the past 25 years in process improvement and risk management and applies those advances to the technology-transfer process.

Gap and risk analysis at program and project levels. 

At the program level, the overall transfer capability should be determined (e.g., plant capabilities and capacities, project management capability, dedicated personnel, level of training, and understanding of regulatory and safety issues) with a view to determining organizational shortfalls and correcting them. At the project level, the project team should closely examine each product or group of products for shortfalls, especially the current state of product-related process understanding and the factors that will determine success at the receiving site, including manufacturing processes, documents, analytical methods, equipment, plant capabilities, and regulatory and safety issues.

Based on the gap analysis, a detailed strategy document must be developed to include all gaps, the means to fill those gaps, and a description of the overall transfer strategy with measures for success. One of those key measures of success will be knowledge transfer. Will the organization be left with experienced personnel who can repeat the process rapidly, consistently, and at lower cost than before?

Technology transfer should be assessed, defined, designed, and managed from a comprehensive value perspective to capture the full benefits of the transfer. Metrics that translate into value could include, but are not limited to, the following: meeting budget, meeting timelines, the validation success rate, the number of FDA observations during preapproval inspection, the regulatory-submission approval rate, labor hours by job title, labor costs (internal and external), capital, expense, and potential effects on sales.

	An overarching framework composed of those features not only creates the conditions necessary for a successful transfer from a technical point of view, but also ensures that the organization reaps the full business benefits of transfers.

	The success of any particular technology transfer depends upon process understanding, or the ability to predict accurately the future performance of a process. It requires complete, methodical, and systematic capture and codification of all process data and information leading to a high level of assurance regarding site-to-site process equivalency. In the case of transfer from development to commercial manufacturing, the goal of process equivalency is complicated by the issues of scale-up-what works in the laboratory may not work in the plant.

To forestall such problems, development and commercial teams should interact early in the process of development. This involvement of manufacturing personnel during development enables development staff to understand scale-up limitations and design appropriate experiments, thus saving time. Conversely, the involvement of development personnel on scale-up teams leads to better management of knowledge transfer. Working together, development and manufacturing personnel can continue to build a broader understanding of what is and is not practical for commercial manufacturing. The result is more intelligent and efficient development activity and a flattening of the learning curve as products move from development to pilot to commercial operations (see Figure 2).

	Unfortunately, in many companies, such interaction does not begin until after successful Phase III trials, in the belief that it is too costly before that stage of development because so many drugs fail. But these same companies then find themselves with little time for achieving sufficient process understanding for successful scale-up. As a result, a process that is less than robust is transferred to manufacturing and encounters time-consuming problems that delay the product's launch. Thus the penny-wise and dollar-foolish refusal to engage manufacturing with development sooner often results in missed revenue, regulatory issues, and nagging production problems that continue to crop up and incur otherwise avoidable costs. In fact, a number of companies that have learned this lesson the hard way are now applying the tools of process understanding much earlier in development to ensure efficient manufacturability later.

	The following three elements help achieve this all-important process understanding:

		Using quality-by-design (QbD) techniques and identifying critical process parameters (CPPs), which are those process parameters that must be maintained within critical limits to achieve the desired quality outcome.

		Identifying drivers of variation and of interactions in critical processes

		Understanding the right process-control strategies.

	QbD establishes a product's design space, which comprises the multivariate relationships that encompass combinations of product design, manufacturing-process design, manufacturing-process parameters, and raw-material quality that ensure suitable quality and performance. By establishing design space in the initial development of a product, the organization gets a head start toward successful transfer to manufacturing. CPPs will have been identified, as well as the drivers of variation and interactions in critical processes. The organization will know how the process will behave under various multivariate conditions, such as are likely to occur at commercial scale.

	The goal for products that weren't developed through QbD and are being transferred from one site to another is, in effect, to achieve a similar level of process understanding retroactively. For example, a product may have been put into production at the initial site without sufficient process characterization before validation, and some of the CPPs might not have been identified. To fill in those blanks, it is advisable to begin by developing qualitative process understanding through focus-group interviews, process maps, and document review. It is also necessary to conduct basic quantitative characterization of the process, using statistical tools such as control charts and CpKs (a statistical measurement of process capability) to provide a quantitative assessment of whether a process parameter is capable of meeting its specification limits. Advanced statistical tools, such as regression analysis and design of experiments (DoE) can help establish the causal relationships and understand interactions between a finished product's release parameters and other in-process parameters and raw-material characteristics.

	The level of process understanding necessary for successful transfer has been achieved when the impact of changes in critical process inputs can be predicted. Process-control problems that might occur in scale-up or site-to-site transfer can thereby be anticipated and preempted. Furthermore, process understanding means that all critical sources of potential variability (and interactions) have been identified and explained, and product specifications are based on understanding of sources of variation and process capability. With this understanding, it is possible to make sure that the transferred process will operate at the center of the multivariate relationships-the operating sweet spot where process predictability and robustness are found.

	Process robustness is a critical success factor for right-first-time transfers that minimize impact on the supply chain. Benefits of these on-time, on-budget transfers include the following items:

		High-quality products with few to no defects, loss, or rework

		Reduced operational and compliance risk

		Higher product development-to-launch success rates

	Together, a carefully constructed technology-transfer framework and greater process understanding will not only help an organization achieve these benefits, but also make sure that it can be done time and time again.

* is a principal and pharmaceutical sector head, and 

is a managing consultant and project manager, both at Tunnell Consulting, 900 East Eighth Avenue, Suite 106, King of Prussia, PA 19406, tel. 610.337.0820, schmidt@tunnellconsulting.com.

	*To whom all correspondence should be addressed.

The authors highlight the need for a technology-transfer process that is efficient, cost-effective, and repeatable, stressing the importance of process understanding. Read this and other preferred organization articles in this special issue.