Assuring compliance to the regulatory guidelines for microbial monitoring during the production of dietary supplements and probiotics requires a thorough understanding of the regulatory environment and understanding the different methodologies available for microbial identification and differential strain typing. Many nutraceutical products have health-related claims and are produced with natural ingredients of botanical or animal origin, which are known to have microorganisms present. As a result, regulatory agencies are scrutinizing the application of cGMP (current good manufacturing practice) quality control (QC) measures by manufacturers to ensure product safety for consumers. Therefore, many companies strategically make the decision to outsource this work because it is not part of their core competency.
1. Microbial Identification and Characterization
A contract laboratory must understand a supplement company’s business model and work with it as a strategic partner, not just a service provider. The laboratory must provide in-depth technical expertise and test methods designed to effectively and consistently give accurate species-level identifications. This information is required for tracking and trending events, managing risk and implementing appropriate corrective actions into processes, which ultimately result in product safety. The library database used for microbial identifications will have the greatest impact on the accuracy, reproducibility and cost. Database libraries that are deficient will lead to errors in species-level identification, or inconclusive results that will directly lead to higher costs due to additional testing for identification. For superior service, the contract laboratory should perform frequent library updates encompassing taxonomic changes and adding novel organisms that have been encountered. Library species coverage should be reflective of not only the most frequently occurring organisms in a manufacturing environment, but also the less frequently encountered environmental species. Libraries must go well beyond the IVD (ion vapor deposited aluminum) or clinical pathogens for the greatest ability to achieve a correct species-level identification for the program.
2. Available Technologies
Many technology platforms are available for microbial identifications: phenotypic systems that rely on biochemical reactions, mass spectrum (MALDI-TOF) systems that analyze ribosomal protein spectra and DNA sequence-based systems. The goal is finding the right platform for microbiological identification that is accurate, robust and reliable for the purpose of monitoring the state of environmental control and reasonable cost. Objectivity is required to analyze and interpret product claims against historical performance indices to determine the right outsourcing solution. Some criteria to consider in a technology evaluation are: the library coverage, expected number of identifications, acceptable error rate, the number of samples requiring retest, growth requirements, sample preparation methods, test limitations, the time to first results, and cost to acquire, validate and operate.
3. Testing and Documentation
Our industry is heavily regulated, and compliance to regulatory statutes is a strict requirement. On-site vendor qualification by an audit team to ensure the service provider has implemented and enforces a comprehensive quality management system is necessary. Regulators hold different industry segments accountable to specific guidelines and standards. Depending on the industry segment, auditors must ensure the service provider complies and conforms to the regulations and the expectations of the internal operating standards. An audit of the laboratory should include the validation process used to determine new entries or taxonomy corrections to the library database.
4. Capacity and Flexibility
Business needs are dynamic. When a supplement brand is contracting a service, it needs to know the impact the demands have on its supplier. A company should interview its prospective provider to determine the impact that its volume will have on its operation and ability to deliver results in the expected timeframe. Volume capacity, testing and sample preparation methods can drive turnaround times. Business is not only about making the sale;it is about delivery of a promise.
A provider should be flexible in order to meet business and operational objectives. For routine identifications, long turnaround times (TAT) may be acceptable (one to two weeks). However, when an adverse event, an excursion or a sterility failure occurs, timing for a result is critical and working with a flexible partner that can deliver results quickly (same day from an isolated colony) for an investigation is essential for operation. The intangible benefits of flexible TATs can minimize the economic impact to the manufacturing operation by accelerating recovery time from contamination events while not overspending on routine environment isolates. The platform used for identifications can dictate the best case and TAT before a result is available. Classical phenotypic methods that depend on biochemical reactions catalyzed by the organism can be variable, and dependent on growth parameters. Most of these systems require offline testing such as gram stain, oxidase, coagulase, etc., before determining the appropriate test card. These factors can contribute to a longer TAT. Contrary to the typical phenotypic methods, MALDI-TOF and DNA sequencing do not require upfront tests and can yield results within a fraction of day.
When enlisting the services of a contract laboratory, ease of use is an important consideration. Sample preparation and requisition forms should not hinder one’s ability to send microbial samples for identification. Sample preparation methods are driven by the methodology. For example, phenotypic methods require a live culture plate or slant, shipped overnight. Alternatively, a viable colony is not required for genotypic methods. For this reason, alternative shipping methods can be utilized such as FTA elute micro cards, DNA extraction preparations or ethanol extracts for your isolates. These alternative shipping methods save shipping costs, but allow for original sample plate retention. MALDI-TOF technology, which normally require fresh culture for identification, does have alternative sample prep methods. Ethanol extracts can be used provided the culture was extracted less than 48 hours after growth appeared; the culture was not previously stored at refrigerator temperatures; and the sample did not begin to sporulate. These alternative shipping methods allow customers with multiple sites to ship samples from anywhere in the world and have a uniform quality identification results. These alternative shipping methods must include qualified validation studies. The use of electronic or web secure, communication for request forms for sample identification testing and test results can also result in time and savings.
6. Price Comparison
Internal management support to outsource requires a financial analysis to demonstrate that a company can achieve comparable or improved performance at a cost savings over in-house testing. This demonstration must include more than comparing the annual reagent and consumable costs divided by the annual number of identifications. To determine true cost per sample identity requires an analysis that includes investigating of both fixed and variable costs attributed to obtaining identifications as well as the inclusion of expected key performance indicators.
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Mark Calmann is the associate director of marketing at Charles River, supporting the endotoxin and microbial detection business. For the last four years, his efforts have been focused on contract laboratory service for microbial identification. He has more than 30 years of marketing and product management experience, working at Charles River, Accugenix, BioMedical Consultants LLC., Cerionx and Johnson & Johnson. His experience includes commercial development strategies, product management, advertising, sales support and customer education programs.