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Volume 30, Issue 6
This article reviews systems and processes that enable a laboratory to approach troubleshooting in an effective way, while also taking a proactive, preventive approach to managing atypical laboratory scenarios.
In a busy, multifunctional commercial contract laboratory that is focused on the provision of good manufacturing practices (GMP) services for late-stage and/or commercial products, effective and efficient laboratory operations are vital and expected both from regulatory agencies and clients.
The number of therapeutics being tested at one time in a contract laboratory is relatively large; typically, many analytical events run in parallel. This creates an environment where process and control are key. The ability to troubleshoot and investigate within the framework of a well-defined quality system is equally as important.
The key to a successful laboratory operation, therefore, is the coordinated incorporation of the appropriate systems and processes that can ensure full control of project attributes, ranging from the handling and management of out-of-specification measurements, to quick and effective manufacturing support based on the test lab partner’s production challenges. The most efficient and effective laboratory ecosystem is a combination of a well-established environment with a strong team culture, plus well-developed, high-quality systems and testing processes that are united to meet the time-critical needs of laboratory operations.
At the core of an effective and high-performing quality control laboratory are systems and processes designed to provide clear and consistent instructions in line with the most up-to-date regulatory guidance to ensure a quality framework that encompasses a consistent testing approach. Troubleshooting is an expected occurrence and needs to be managed effectively, but there are basic laboratory quality tools that, if used as part of the overall laboratory strategy, can ensure the need to troubleshoot is minimized. It is in the best interest of a contract laboratory to invest in effective and efficient quality systems and management processes that provide clear, real-time insight into activities since contract laboratory business models rely on a strong contribution of direct scientific analytical time, with a first-time-right culture driving operational efficiencies.
Inconsistencies introduced into this environment can bring many challenges and may delay the testing program. These inconsistencies may introduce the creation of quality incidents or a lack of reproducibility within test systems. This is especially likely when biologics test platforms are involved, given the variability associated with them.
Analysts in a biopharmaceutical testing facility are skilled scientists who understand the complexity of working with the drug substance or product involved, and possess practical skills that enable a multitude of testing platforms to be used. One point to remember is that in the world of biopharmaceutical testing, it is uncommon for one test alone to be employed; an orthogonal testing approach to measure the same value using different methodologies is more typical. An orthogonal strategy enables scientists to be guided by the procedures rather than the interpretation of a single test, which reduces the potential for a quality incident. A mature quality system with robust and well-documented test methods and standard operating procedures (SOP), coupled with an extensive training program, provide the strongest backdrop to consistency and proactive reduction of quality gaps.
The laboratory facility should be well designed and appropriate for GMP testing, of a high standard, and ultimately be safe and secure. One of the objectives of any laboratory is to provide the scientist with a user-friendly environment.
A broad definition of troubleshooting is referenced in this article. Troubleshooting includes occurrence management, such as corrective and preventative action planning as part of a formal quality event, and minor laboratory issues not related to a specific test or drug product. Investigations related to product failures (out-of-specification results) or atypical results leading to out-of-trend results need to have appropriate processes clearly set out within the respective quality system, and associated investigations should move forward in a proactive and effective way.
The basics behind effective troubleshooting are well documented, but they shouldn’t be taken for granted. Troubleshooting is an ever-present requirement that needs careful and considerate management, with adequate and thorough issue resolution mechanisms in place. Well-engineered quality systems and processes--in conjunction with well-trained analysts, robust and validated methods, and a suitably designed laboratory facility--are the key ingredients that need to be in place for consistently high-quality laboratory output.
A disciplined approach using basic root cause analysis tools is the most important factor to ensure successful outcomes, regardless of the nature of the atypical occurrence. This is followed closely by the tools used to identify the root cause of the issue, documenting the learning from the occurrence, and capturing the specifics of the troubleshooting exercise so they can be used as part of preventive planning for future projects. Basic tracking and trending tools of key metrics and associated data also can provide a more informed backdrop to any particular event under scrutiny. Quality-related events and other serious issues require a toolkit that incorporates well-known approaches to issue resolution. The toolkit should include the Five Whys, fishbone diagrams (identifying cause and effect), and human error reduction exercises (1,2). For less formal troubleshooting applications, it is still recommended to use some or all of these techniques, as each scenario will require its own level of investigation.
Since a significant proportion of atypical occurrences are directly related to human error, it is important not to underestimate the importance of having team members trained in the use of human error reduction processes. These processes include identifying the specific human error that led to the issue, the process change that resolved the issue, and the steps necessary to minimize the possibility of a repeat. A strong quality system should then have the capability to incorporate the preventive steps into methods/SOPs as part of continual improvement efforts.
In the short term, it may appear that getting a good proportion of the team members trained in tools such as human error reduction, the Five Whys, fishbone analysis, etc., is a time-consuming and lengthy process. However, the organization will resolve issues faster, create more robust preventive actions, and improve quality over the longer term. The benefits of having troubleshooting prowess should be viewed as having the same level of importance as proficiency in the procedures themselves.
Continuous laboratory improvements lead to a reduced need for troubleshooting. Combining the right mix of all the key components mentioned previously provides the foundation necessary for an effective laboratory operation. A key source of potential variability--the analysts--always should be a fundamental part of the lab strategy. They need to have the requisite basic skills and a strong understanding of quality processes and procedures, as well as an appreciation of and synergy with the products they are testing.
Working in a contract analytical laboratory has many advantages for a developing scientist, and provides a fast-paced environment enabling continuous improvement opportunities. Among them are the diversity of the products, the wide range of technical platforms, and the increased exposure to technical and process challenges. Laboratory objectives and strategy in this setting should have an even balance of quality measures, process improvements, client deliverables, and personal development opportunities.
Another area to target for continuous improvement is process and procedures. SOPs need to be constructed from the end user’s viewpoint, and they need to reflect the structure required from a quality and regulatory perspective. Flow charts and other methods of visualizing the processes that accompany the written procedure can be an effective way to ensure a common understanding of the process and reducing inconsistencies, which may not immediately be apparent in long, written instructions.
In addition, 5S, Six Sigma, and general process excellence skill sets are useful tools as long as they are complemented by and supported in the workplace environment (3). The overall workplace balance is important to ensure the science, quality, and first-time-right attributes are supported in an appropriate way. This environment should view troubleshooting as an opportunity to learn and improve processes, not as an exercise to point out the negatives.
When troubleshooting points to a quick fix, document the issue via a quality system, implement changes, and close out the incident with necessary laboratory management approvals. When the issue is more complex, assemble the appropriate people to process the available information and ensure the ensuing actions are well defined and approved before implementation, always maintaining a view in future prevention.
Determining where an issue falls on the severity and risk scales is one of the key skills of effective troubleshooting. Get the right balance and approach from the beginning, and an appropriate resolution will be more efficiently and effectively constructed. Get the wrong balance and the result may be a process change, and an over-engineered, lengthy solution.
Ensuring that laboratory systems and collected data provide management and process control oversight, and using this information in the course of the decision-making process, is important to ensure a fact-based resolution rather than one based on circumstantial evidence. Keeping a log of all laboratory activities leading to errors that can be easily cross-referenced at a point in time also helps lead to a potential solution because it provides a greater ability to determine if engineers have previously encountered the same issue, and, if so, how it was resolved.
The key to a successful laboratory operation includes the coordinated incorporation of the appropriate systems and processes that enable the lab to effectively approach troubleshooting, while also taking a proactive approach to managing potential atypical scenarios. While following those steps won’t guarantee success, it improves the possibility of preventing an issue before it happens and reinforces a culture of continuous improvement.
1. Centers for Medicare & Medicaid Services, “Five Whys Tool for Root Cause Analysis,” accessed April 18, 2017.
2. Centers for Medicare & Medicaid Services, “How to Use the Fishbone Tool for Root Cause Analysis,” accessed April 18, 2017.
3. Kaizen Institute “About 5S,” accessed April 18, 2017.
Volume 30, Number 6
When referring to this article, please cite it as C. Forsdyke, "Troubleshooting Lab Operations: Be Proactive, Not Reactive," BioPharm International 30 (6) 2017.