Appendix I – Guidelines for Work with Toxins of Biological Origin (pages 470-481)

The table of contents (TOC) for Appendix I has listed nine sections (to include references) under the “Guidelines for Work with…” heading with corresponding page numbers to make it simple to go directly to a specific section by listed page number whereas the BMBL-5 only listed “Guidelines for Work with Toxins…” in the TOC. No longer used is the description of “toxins comprise a broad range of poisons”. The BMBL-6 describes properties of toxins using molecular level characteristics in the opening description.

Appendix J – NIH Oversight of Research Involving Recombinant Biosafety Issues (page 484)

The spirit of this appendix is essentially the same. All changes reflect updated verbiage such as the NIH structural change from the Office of Biotechnology Activities (OBA) to the Office of Science Policy (OSP) or to match the current requirements in the NIH Guidelines which have been updated multiple times since the last BMBL. The removal of the RAC has also been addressed.

Appendix K – Inactivation and Verification (pages 486-501)

The purpose of Appendix K is to describe inactivation methods or strategies that allow for the preservation of characteristic(s) relevant to further analysis or study of pathogens, viral nucleic acid sequences, or toxins and verification of inactivation.

The guidance outlines selection of an appropriate inactivation method considering the pathogen, viral nucleic acid sequences, or toxins, the targets and/or actions of the inactivation method, as well as consideration of numerous factors that have a bearing on the development of the inactivation protocol or method of removing the pathogen from the material.

Tables summarize the advantages and disadvantages of physical, chemical, chemical activated by physical treatment, natural and emerging antimicrobial strategies, and combination methods for inactivation methods.

To ensure the inactivation procedure is adequate for the conditions, process controls for validation and verification or viability testing parameters are described.

Institutional oversight, review, and approval is recommended to ensure adequate confirmation of inactivation and separation/removal procedures are developed. Documentation and recordkeeping of inactivation/verification procedures are to be developed by the entity to track materials that are moved from a higher to lower containment. Administrative controls should address appropriate risk assessment and mitigation if a failure or variance of inactivation procedure occurs and have a plan for communication, root cause analysis, and incident response.

Regular review of inactivation and verification procedures to ensure continued efficacy as well as when a failure in the procedure occurs.

For consistent inactivation, consider the reagent sources and equipment maintenance used in inactivation procedures.

Personnel executing the inactivation procedures should also be trained and demonstrate proficiency.

Appendix L – Sustainability (pages 504-512)

The BMBL-6 includes suggestions for existing laboratories and new facilities to conserve resources.

Appendix M – Large-Scale Biosafety (pages 515-526)

This entirely new appendix, specific for activities involving greater than 10 liters of biohazardous agents, is analogous to, but substantially different from, Appendix K the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (NIH Guidelines). The focus of this appendix is the risk assessment process rather than a prescriptive set of requirements for four physical containment levels. The bulk of the appendix addresses risk mitigation strategies using engineering controls, work practice and administrative controls, and PPE. This section also addresses the change in manufacturing processes from fixed equipment, such as large steel fermentation tanks, to single-use equipment including the “ballroom” concept of manufacturing. Several pages are devoted to the containment requirements and example risk points associated with single-use equipment.

N – Clinical laboratories (pages 529-541)

This is a new appendix in BMBL-6. Appendix N highlights the fact that a CLIA lab director is already subject to strict expectations and statutory regulations that place responsibility for positive and negative outcomes squarely on the lab director. Appendix N suggests that a biorisk management system in a clinical lab can use a system of SOPs, training, and QC that will be familiar to staff and managers for CLIA compliance. This new section in the BMBL-6 provides some practical approaches for effective BRM programs in a clinical laboratory setting while taking into consideration the unique nuances/challenges facing them such as unknown samples, point-of-care (POC) and bedside testing and unavailability of facility/resources for risk mitigation.

Notable topics in this appendix include:

• Biorisk Management
• Mitigation measures emphasizing Engineering controls, Administrative (and work practice) controls, and PPE.
• Prior experience with the 2014-2015 Ebola outbreak.
• Proactive specification of “trigger points”, such as positive cultures appearing in certain specimen types, that prompt workers to increase biocontainment.
• Leveraging an existing culture of quality control to promote a culture of safety based on SOPs, training, and emergency response plans and drills. Consideration of risk ethics, risk tolerance, and risk aversion to hazardous work at the institutional and personal level.