OR WAIT null SECS
Strong personnel training, detailed SOPs, commitment to data integrity, investigation and implementation of appropriate modern methods, and employing Lean and Six Sigma methodology initiatives are key best practices for the quality control microbiology lab.
The quality control (QC) microbiology laboratory plays an essential role in pharmaceutical manufacturing and product release. It is responsible for multiple tasks, including:
These activities must follow the company’s quality procedures and federal regulations. Because these establish the state of control of the manufacturing environment and are critical for product release, it is imperative that the QC microbiology laboratory perform tests accurately, reliably, and timely.
If product release is delayed, there is additional cost in holding inventory, disruption in the manufacturing schedule, and possible drug shortage and regulatory scrutiny. Even worse, if a contaminated or ineffective product is released, patient health is impacted, and lives are at risk. The manufacturer also suffers regulatory consequences and recalls, a financial loss, and damage to the company reputation.
To meet the necessary high standard of quality in an efficient manner, certain laboratory best practices should be followed regarding training, standard operating procedures (SOPs), data integrity, appropriate rapid methods and technologies, and a commitment to Lean; Sort, Set in order, Shine, Standardize, and Sustain (5S); and Six Sigma concepts. These best practices ensure each technician is operating to the same standard and performing tasks consistently and allow the QC laboratory to increase accuracy and efficiency.
SOPs are a critical component of manufacturing. There have to be written instructions on how to perform each task-not just on the production floor but in the laboratory as well. US 21 Code of Federal Regulations (CFR) 211.100 states (1):
“(a) There shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess. Such procedures shall include all requirements in this subpart. These written procedures, including any changes, shall be drafted, reviewed, and approved by the appropriate organizational units and reviewed and approved by the quality control unit.
“(b) Written production and process control procedures shall be followed in the execution of the various production and process control functions and shall be documented at the time of performance. Any deviation from the written procedures shall be recorded and justified.”
While it can be easy to dismiss the task of writing SOPs as a paperwork exercise, it is important to understand their value. SOPs ensure that every technician is operating the same way, which yields more consistent test results. Procedure training documents should be extremely detailed; it can be dangerous to assume that technicians understand what is implied or what seems like common sense. To that aim, it is important to review procedures regularly to be sure they are up to date; technicians in particular should be sure to review SOPs for accuracy. Pictures, easy schematics, and flowcharts-anything that makes it easier for the lab tech to read, understand, and follow a SOP-should be included in such a document.
Technicians should be trained on each SOP as determined by the laboratory manager and quality assurance department. Typically, each job role has a defined training matrix with all the SOPs listed that relate to those job functions. However, all personnel should also be trained on quality procedures, good manufacturing practices (GMPs), and documentation. Training matrices should be reviewed periodically as job functions evolve over time with additional responsibilities and headcount. Documentation of training is also important as those records are often requested by auditors.
Training should obviously encompass more than just reading the SOP. Particularly for complicated tasks, training should include a period of observation, then practice while under observation, and finally a proficiency test. The laboratory should have defined trainers who are experienced technicians in charge of training. When SOPs are revised, the technicians should be trained on the new version, and skills should also be assessed on a periodic basis.
It is no small investment to teach a new technician how to perform tasks according to the company SOPs. Therefore, to maximize efficiency, training should be strategic so the new technician can contribute to some tasks while still learning others. The laboratory can then manage their workload more effectively.
Data integrity remains a hot topic in the pharmaceutical industry, and regulators are auditing for compliance in this area. While the enforcement may be new, the regulations in 21 CFR 211.180 have been in place for almost 25 years. The focus is not just in the United States, but globally as well. Rx 360, an international pharmaceutical supply chain consortium, provides a comprehensive list (2) of data integrity resources. Data integrity is defined as “the maintenance of, and the assurance of the accuracy and consistency of, data over its entire lifecycle, and is a critical aspect to the design, implementation, and usage of any system which stores, processes, or retrieves data” (3).
It is expected that companies comply with the ALCOA+ (attributable, legible, contemporaneous, original, accurate, complete, consistent, enduring, available) principles of data integrity in Table I. This applies to not only paper-based systems, but computer systems and software as well. For the laboratory, adhering to data integrity principles is critical as their tests are responsible for releasing product to the public. Modification or loss of data could pose a risk to patients.
Any reduction of human error in the laboratory will bolster the company’s data integrity and, consequently, the company’s regulatory position. To this end, many labs are moving to automated equipment and laboratory information management system (LIMS), provided that they are validated and follow ALCOA+, as it minimizes handwritten records and inconsistencies. Streamlined workflows and less handling can significantly speed up testing while providing more reliable data. Examples of this are Charles River’s cartridge technology and robotic system for endotoxin testing. The data output for these are readable, contemporaneous with date and time stamps, attributable with operator logins, original, accurate, and consistent. The data files can be saved electronically to remain enduring, available, and complete.
A particular challenge in the QC laboratory is the difficulty of compliance with maintaining original (or raw) data. For example, the agar plate for bioburden testing cannot be saved so it becomes even more important to have an accurate colony count because that count will become the enduring data. In these cases, many companies are moving to the “four-eye” method where a second technician reviews and signs off on the result. However, this could be considered a subjective test, along with Gram staining. It is possible that two people view color differently or may count one colony as two (or vice versa). How are these different results rectified and justified? Subjective tests should be avoided whenever possible to reduce the workload redundancy and possible discrepancies.
All QC micro labs would benefit from using an efficient LIMS to expedite processes and ensure data integrity compliance. As an example, the Charles River Accugenix microbial identification laboratories have a custom LIMS that manages technician training, equipment, reagents, samples, and testing workflows. Each processing step is documented by scanning a series of barcodes. There is instant feedback to confirm that the technician is trained in that operation, the reagents are within expiry and released by QA, the equipment has been calibrated and appropriate for that step, and that the workflow is being followed. This prevents errors from occurring, documents batch records, and gives the lab the visibility to work efficiently.
Also, in connection to the last section on training, FDA clearly stated in their Data Integrity and Compliance with Drug CGMP Questions and Answers Guidance for Industry that all employees should be trained on data integrity (4). Question 16 of that document says “Training personnel to prevent and detect data integrity issues is consistent with the personnel requirements under CFR 211.25 and 212.10, which state that personnel must have the education, training, and experience, or any combination thereof, to perform their assigned duties.”
Rapid or alternative microbiological methods may provide significant Âbenefits to the pharmaceutical laboratory. It is best practice for the laboratory manager to stay informed of available technologies and to implement them when appropriate. As regulators propose revisions to existing industry guidelines, they specifically call for modern methods to be implemented. Modern methods are defined in the Parenteral Drug Association’s (PDA’s) Technical Report 33 (5) as:
“A novel, modern, and/or fast microbiological testing method that is different from a classical or traditional growth-based method, such as agar-plate counting or recovery in liquid broth media.
“The alternative or rapid method may utilize instrumentation and software to manage the testing and resulting data, and may provide quantitative, qualitative, and/or microbial identification test results.
“Automated technologies that utilize classical growth-based methods may also be designated as being novel, modern, or rapid, based on their scientific principle and approach to microbial detection.”
European Pharmacopoeia (Ph. Eur.) 5.1.6 states: “Alternative methods may be used for in-process samples of pharmaceutical products, for environmental monitoring, and for industrial utilities (e.g., production of water, steam, etc.), thereby contributing to the quality control of those products” (6).
Introducing new technologies may seem daunting, but it needs to be done for long-term advantages as well as progressing the industry’s standards for product quality control. Possible benefits include reduction in costs, faster time to results, less labor, and increased data integrity. To recognize these benefits, however, it is imperative that the rapid methods and technologies are thoroughly vetted and validated. During the evaluation, include the following points of consideration:
Many people are intimidated by the perceived challenges of implementing rapid methods. However, there are many available resources, such as PDA’s TR 33, United States Pharmacopeia (USP) <1232>, Ph. Eur. Informational Chapter 5.1.6, and USP draft <1071>. The vendor should also be able to offer the appropriate regulatory, validation, scientific, and technical support. For example, Charles River’s Celsis instrument for microbial limits and sterility can assist by providing a validation protocol. While there is extra work upfront to validate the method, the payoffs should justify the effort. While some rapid methods and technologies can provide significant value and savings quickly, the wrong system can cause frustration, delay, and waste. Understanding the key criteria in selecting a rapid method will facilitate choosing a system that will best provide rapid, relevant results while minimizing testing risk and optimizing resource allocation.
The final best practice to note for the QC laboratory is a commitment to Lean manufacturing, 5S, and Six Sigma concepts. Lean and 5S principles are designed for maximizing efficiency by minimizing waste and Six Sigma is focused on continuous improvement. They are harmonized philosophies in the sense that Lean and 5S can identify areas of improvement and Six Sigma can facilitate the process. Since the lab is busy with many activities, implementing some of these concepts can save time and money.
First, the laboratory can identify areas of improvement based on Six Sigma’s eight areas of waste, sometimes referred to by the acronym “DOWNTIME.” These eight areas include: defects, overproduction, waiting, non-utilized talent, transportation, inventory, motion, and extra processing. For example, defects in the lab could be downed instruments or raw materials that do not pass incoming inspection. Any failed or invalid test would also be considered a defect. Then the Six Sigma principles of DMAIC (define, measure, analyze, improve, control) could be applied. Lean principles defined the problem, and in the example of an out of service instrument, the “measure” (or metric for tracking) may be the number of times the instrument goes down in six months or how long it takes to make it functional again. “Analyze” is the period of collecting data and reviewing the metric for trends or conclusions. “Improve” consists of designing and implementing a solution, which could be additional preventative maintenance of the instrument. Finally, “control” the problem by ensuring the implemented solution truly solved the problem and no other problems appear. The idea is that this is not a static, one-time event, but a dynamic and ongoing process.
5S can also help reduce waste in the laboratory. The concept encourages simplification by keeping only what you need and organizing materials. This can save time by making it easier to find the necessary supplies and prevent mistakes by Âeliminating Âunnecessary options. For instance, keeping multiple sets of each reagent makes it more difficult to find the particular one you need and increases the probability that a wrong or expired reagent could be used. By sorting through and discarding expired reagents, and organizing what’s left, human error is minimized.
The best practices discussed in this article for the pharmaceutical and biotechnology laboratory integrate well with each other. A robust training program includes GMP documentation and thus data integrity principles. Implementing a rapid method may reduce time (and waste) and labor (simplified training) while supporting data integrity. Continuous improvement of lab operations facilitates training and reduces inefficiencies so the value it brings can be recognized in both the long and short term.
Given all the laboratory’s responsibilities and its role in releasing product, implementing these best practices will enable the microbiology laboratory to operate accurately, reliably, and timely. Strong personnel training, detailed SOPs, commitment to data integrity, investigation and implementation of appropriate modern methods, and employing Lean and Six Sigma methodology initiatives support the entire company’s pledge to manufacture safe and effective products.
1. Current Good Manufacturing Practice for Finished Pharmaceuticals, 21 CFR § 211.100 2018.
2. “Data Integrity Library,” Rx360, https://rx-360.org/resources/data-integrity-library/data-integrity-library/, accessed 09 July 2019.
3. J. Boritz, International Journal of Accounting Information Systems (Elsevier, Archived from the original on 5 Oct. 5, 2011), accessed July 9, 2019.
4. FDA, Data Integrity and Compliance with Drug CGMP Questions and Answers, Guidance for Industry, (FDA, December 2018), www.fda.gov/media/119267/download.
5. PDA, Evaluation, Validation and Implementation of Alternative and Rapid Microbiological Methods (Parenteral Drug Association. Revised 2013).
6. Jouette, Sébastien, PhD “European Pharmacopoeia (Ph. Eur.) 5.1.6 Alternative Methods for Control of Microbiological Quality,” Presentation at EDQM Symposium on Microbiology 10-11 October, www.edqm.eu/sites/default/files/rapid_microbiological_methods_regulatory_perspectives_1-october2017.pdf, accessed July 9, 2019.
Vol. 32, No. 8
When referring to this article, please cite it as J. Rayser, "Best Practices in the QC Micro Laboratory," BioPharm International 32 (8) August 2019.