A straightforward path to regulatory compliance, data integrity, and computer systems validation
Darryl León, PhD- Senior Product Manager, Thermo Fisher Scientific; Sandi True, PhD- Staff Scientist, Thermo Fisher Scientific.
Throughout the drug development and manufacturing processes, the potential for bacterial and fungal contamination of raw materials, production facilities, and branded products poses a serious threat to drug efficacy and patient safety. Regulators expect manufacturers to have robust environmental monitoring and contamination control strategies in place as part of current good manufacturing practice (cGMP). A validated microbial identification system is a key facet of these programs.
The genotypic method is the gold standard in microbial identification (ID). This method involves using PCR and DNA sequencing for environmental monitoring, detection, and identification of contamination, as well as root cause analysis, and ensures the sterility of raw materials. However, implementation and validation of such a system in the cGMP environment can be overwhelming. Technical expertise with the hardware and software of a proven microbial ID platform, familiarity with regulatory requirements, and the ongoing support of an experienced team of field service engineers, field application specialists, and computer system validation (CSV) experts can be invaluable to any group looking to implement a robust environmental monitoring system.
This white paper covers what you should consider when implementing a microbial identification system, including ensuring data integrity and validating the computer system used for microbial testing in a bioproduction workflow. Read on to learn about:
- Current regulatory guidance concerning validation of microbial ID processes in a GMP environment.
- What to look for when implementing a microbial ID system and various options for validation.
- Real-world examples of companies that used different strategies for implementation and CSV.
Regulatory Expectations for Microbial Control and Identification
Microbial contaminants should be identified at the species level or, where appropriate, at the genus level at frequent intervals to establish a valid, current database of contaminants present in a facility during processing.1 The USP <113> monograph recommends the use of one of the following methods of verification of a microbial identification system:
- Use an existing system to compare with microbial isolates obtained from routine testing. The number of isolates can be as high as 50;
- Test 12–15 referenced stock cultures of different commonly isolated species, for a total of 50 tests; or,
- Confirm 20–50 organism IDs, including 15–20 species that agree with the results from a reference laboratory testing of a split sample.
Accuracy and reproducibility are the most important parameters used to verify the chosen method.
What to Look for in a Microbial Identification System
The ideal microbial identification platform provides accurate results quickly, is easy to use, includes a comprehensive sequence library for bacteria and fungi, and is cost-effective. It would be invaluable to assess a new system on the following parameters: technology, cost, and data quality.
Technology
Choose a system with the required throughput, high accuracy, rapid turnaround time, and simplicity of use. The US Food and Drug Administration (FDA) recognizes DNA sequencing and the genotypic method as the most accurate and precise for the phylogenetic classification of bacteria and fungi.1 An expansive library that includes validated sequence data for a large number and range of species ensures accuracy. It should include polymorphism data and be constantly updated and expanded.
Cost
Assess the relative cost and benefit of in-house microbial testing versus waiting for results from an external testing lab. Choose a system that gives accurate results the first time, eliminating wasted resources to retest unsuccessfully identified samples.
Data quality
Ensure the collection and storage of electronic records is aligned with FDA guidance, which states that data integrity depends on reliable, accurate, usable, complete, and unaltered data.2 A microbial ID system that has been designed with data integrity and compliance in mind is critical for cGMP.
Computer Systems Validation (CSV)
While features of a microbial ID system are important in enabling regulatory compliance, it is essential to base the ultimate procurement decision on an explicit understanding of regulatory requirements to validate the system workflow and have a defined plan to get there from the start. Validation of laboratory systems is defined in various parts of the US FDA Code of Federal Regulations, such as Title 21 (21 CFR): part 211 (Good Manufacturing Practice) and Part 11 (Electronic Records and Electronic Signatures),3 for example. This goes beyond instrument qualification. CSV is a critical and comprehensive path to documenting data integrity to achieve regulatory compliance of a microbial ID system.
Implementation Options
Installation of equipment is usually straightforward and performed by a field service engineer with additional documentation for instrument qualifications (IQ/OQ). Training of operators on the use of the instrument, software, and workflow is often performed by a field application scientist.
Any complete implementation program should include:
- Assistance in setting up the laboratory in accordance with good molecular laboratory practices
- Checklist of installation material requirements and procedures
- Introduction to the basics of the workflow and traditional culture methods
- Introduction to the background of the method
- Throughput organization from a few to hundreds of samples per day
- Practical sessions in the workflow
- Software training
- Analysis flow from data collection to identification
- Acceptance criteria for quality analysis
- ID results interpretation
- Qualification services
- Routine system maintenance
- Data archiving
- Recommendations for Performance Qualification Protocols
- CSV
cGMP Compliance Through CSV
Execution of a CSV is beyond the normal installation and training of a microbial ID system provided by field engineers and scientists, yet is fundamental for regulatory compliance in a GMP environment.
To satisfy this requirement, companies have 3 options, each with their own considerations:
1. Hire a third-party consultant for implementation and CSV.
- Do they have experience with regulatory requirements and quality?
- Do they have the technical knowledge of the microbial ID system?
- Will bringing in an additional party increase the complexity of the project?
2. Use internal company resources (e.g., quality and IT departments).
- Do they have experience with the hardware and software features of a microbial ID system?
- Do they have the necessary experience with regulatory requirements?
- Do they have the bandwidth?
3. Choose a microbial ID system manufacturer that can provide:
- Detailed knowledge of regulatory requirements.
- Technical expertise specific to their instrument and software.
- Large and experienced CSV support team.
- Rapid implementation of a validated system.
Not all instrument manufacturers have experience in executing computer systems validation. Before choosing this option, verify the microbial identification system manufacturer has a long history of successful CSV consulting services that consist of:
- Dedicated project management and documentation approvals - A project manager, who guides the customer through the validation process.
- Validation test execution and customer approvals – A validation specialist, who understands industry-specific processes and executes test plans.
- SAE software workflow analysis - This specialist possesses knowledge of the features and functions of the software to be validated.
- Pre-form template documentation – A standard set of documents with flexibility to accommodate customer needs.
A comprehensive CSV consulting service develops and produces documentation to verify that all software features are within scope for data security, auditing, and e-signature and are suitable for their intended use. Industry-standard validation practice uses 12 components to document that a system has achieved or maintained compliance requirements (Table 1).
Real-world experiences implementing and validating microbial identification systems in a cGMP environment
Here are three real-world experiences of customers who implemented a microbial ID system and undertook CSV in their facilities. In all three cases the companies chose to purchase the Applied Biosystems™ MicroSEQ Microbial Identification System™ but undertook the CSV by various means.*
Case study 1 - Use of a third-party contractor for CSV
A company hired an external contractor to create the validation package and documentation for its CSV. For successful validation, the contractor needed to special control and access all the software on the company’s system.
Unfortunately, the contractor had no system training and wasn’t experienced with MicroSEQ ID instruments or the software. As part of the validation process, the contractor created some worst-case scenarios in the software that resulted in software conflicts and errors, that the contractor didn’t know how to resolve. The company had to seek software error resolution from a Thermo Fisher Scientific field service engineer and field application scientist.
Validation, which normally takes weeks to complete, took more than 18 months and included numerous software conflicts that had long resolution times. Users could not use the system until it was validated. The long resolution times meant the company needed to be trained again on the operation of the system once the long validation process had been completed.
The result was considerable additional expense due to the need for outsourced testing during the unexpected timeline for validation from the third party, and an excessively long time to validation.
Case study 2 - Use of internal company resources for CSV
Another company attempted to complete its CSV on its own. Its internal department was responsible for data integration (DI) and data storage (DS) for all computer-based systems based on knowledge of specific technologies and processes, so they thought they had the expertise.
Unfortunately, an FDA audit found DI/DS security risks unique to the way the company set up its MicroSEQ ID System. These included the ability to delete or alter data, which is a considerable problem for a cGMP facility. In addition, data backups were neither compliant nor secure, and there were problems with individual user logins.
The company sought to correct these errors by engaging validation support from Thermo Fisher Scientific. While this temporarily increased turnaround time for their microbial identification—samples had to be sent to an external lab for identification until validation was complete—it minimized the overall downtime, minimized the temporary costs of sending out samples and restored compliance with data integrity requirements.
After validation support, a subsequent FDA audit found that all issues had been resolved.
Case study 3 - Implementation of a regulatory compliant system in only six weeks by Thermo Fisher Scientific
A company needed to implement an additional microbial ID system identical to the one it currently had on site for higher volume samples and redundancy. As a high-throughput laboratory, performing thousands of tests every year, the goal was for this new system to be fully validated and ready to run within six weeks.
The company shared this need with Thermo Fisher Scientific. At the same time as purchasing the instrumentation, they also contracted Thermo Fisher Scientific’s CSV consulting services, which integrated seamlessly with all of its other specialists: technical sales specialists, field service engineers, field application scientists, and CSV compliance team members. All of the preloaded CSV documents from the current system—i.e., all the documents listed in Table 1—were applied to the new one.
A library validation plan was also created for the company. This allowed it to have less downtime on its new system, a benefit for this high-throughput lab.
A tight implementation schedule was possible due to the preloaded documents, a prepared library validation plan, and coordination between the field teams. This allowed the new system to be operational and begin microbial identification within the specified six-week timeline.
The result was no downtime at the customer site. The company was able to use its existing system and keep it running while the new one was put in place. Then, when the new system was in place, updates to the libraries on its existing platform were made, and they had an immediate expansion of capabilities.
MicroSEQ Microbial ID System: Single source for implementation toward regulatory compliance
The MicroSEQ Microbial ID System is a high-throughput, comparative DNA sequencing technology for the accurate identification of bacteria, fungi, and yeast. MicroSEQ ID uses a genotypic method based on sequence-based analysis of ribosomal genes in bacteria and fungi. It supports recommended qualification guidelines from the International Conference on Harmonization (ICH), the US Pharmacopeia (USP), the European Pharmacopoeia (EUP), and the Japanese Pharmacopoeia (JP). As such, it has been adopted by 23 of the top 25 pharmaceutical companies globally, with 20 having multisite adoptions.
The MicroSEQ Rapid Microbial ID System includes PCR and sequencing kits, a PCR thermal cycler, the genetic analyzer with various throughput options (such as the Applied Biosystems™ SeqStudio™ family of genetic analyzers) the MicroSEQ ID software, and validated bacterial and fungal libraries. For more information, visit the MicroSEQ page.
Customers have the option to receive support from the time they purchase the instrument through installation and training, and then through CSV. Thermo Fisher Scientific has a long history of successful project management, test execution, documentation, validation, and customer approvals.
Accurate identification to species level
MicroSEQ ID compares sequenced DNA to proprietary validated libraries of more than 12,000 known microbial species. A field application specialist can help customers create their own custom library to compare an unknown sequence to the database. It creates reports and phylogenetic trees and provides security, audit, and e-signature (SAE) compliant reports. This workflow allows an electronic chain of custody to support data integrity and enables compliance with 21 CFR Part 11.
Rapid 5-step implementation
The timeline between purchase and implementation varies depending on customer availability, with a typical engagement lasting 10–12 weeks.
Purchase - Customer buys instrument and consulting service
Installation and training - Instrument installed and qualified by local field service engineer and training provided by a field application specialist
Project management and documentation approvals - The project manager engages with customers to guide them through the validation process
Validation test execution and customer approvals - CSV specialist executes test plans
Customer implementation - Customer begins microbial identification
Why choose Thermo Fisher Scientific?
Thermo Fisher Scientific offers a complete microbial identification solution, including instrumentation, assays, software, service, and support to facilitate regulatory compliance. We offer complete visibility into the CSV process, project planning, documentation reviews, test execution, and summary of results to facilitate regulatory compliance and allow a successful transition into production.
Our integrated team—project managers, and CSV specialists—have completed hundreds of consulting engagements for clients, in the process saving them time, money, and compliance headaches.
Be sure to visit the MicroSEQ page to learn more about the platform, and how the extensive network can help you implement and validate your microbial identification system.
References
1. FDA. 2004. Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice: Guidance for Industry. Available from: https://www.fda.gov/ regulatory-information/search-fda-guidance-documents/sterile-drug-products-produced-aseptic-processing-current-good-manufacturing-practice
2. FDA. 2003. Electronic Records; Electronic Signatures - Scope and Application: Guidance for Industry. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/part-11-electronic-records-electronic-signatures-scope-and-application
3. FDA. 2019. Data Integrity and Compliance With Drug CGMP – Questions and Answers: Guidance for Industry. Available from: https://www.fda.gov/regulatory-information/ search-fda-guidance-documents/data-integrity-and-compliance-drug-cgmp-questions-and-answers
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