GRAS Notice (GRN) No. 758 https://www.fda.gov/Food/IngredientsPackagingLabeling/GRAS/NoticeInventory/default.htm JHeimbach LLC JAN 2 5 2018 January 19, 2018 OFFICE OF FOOD ADDillVE SAFETY Paulette Gaynor, Ph.D. Senior Regulatory Project Manager Division of Biotechnology and GRAS Notice Review (HFS-255) Office ofFood Additive Safety Center for Food Safety and Applied Nutrition Food and Drug Administration 5100 Paint Branch Parkway College Park, MD 20740 Dear Dr. Gaynor: Pursuant to 21 CFR Part 170, Subpart E, Lallemand Health Solutions (Lallemand), through me as its agent, hereby provides notice of a claim that the addition to milk-based term infant formula ofthree strains ofprobiotic bacteria (Lactobacillus helveticus Rosell®-52, Bi.fidobacterium longum ssp. in/antis Rosell®-33, and Bi.fidobacterium bi.fidum Rosell®-71), both individually and in an 80:10:10 blend, is exempt from the premarket approval requirement ofthe Federal Food, Drug, and Cosmetic Act because Lallemand has determined that the intended use is generally recognized as safe (GRAS) based on scientific procedures. As required, one copy ofthe GRAS monograph and one signed copy ofthe statement ofthe Expert Panel are provided. Additionally, I have enclosed a virus-free CD-ROM with the GRAS monograph and the statement ofthe Expert Panel. I apologize for the size ofthe GRAS monograph, but note that it includes information regarding three bacterial strains that have been extensively studied over many years, both alone and in combination. If you have any questions regarding this notification, please feel free to contact me at 804-742-5543 or [email protected]. (b) (6) Truiies T. eimbach, Ph.D., F.A.C.N. President Encl. 923 Water Street, P.O. Box 66, Port Royal Virginia 22535, USA tel. (+1) 804-742-5543 fax (+1) 202-478-0986 [email protected] LALLEMAND HEALTH SOLUTIONS Generally Recognized as Safe (GRAS) Determination for the Use of the Probiotics Lactobacillus helveticus Rosell®- 52 (R0052), Bifidobacterium longum ssp. infantis Rosell®-33 (R0033), and Bifidobacterium bifidum Rosell®-71 (R0071) Prepared by: LALLEMAND HEALTH SOLUTIONS Regulatory Affairs 17975 rue des Gouverneurs Mirabel, Québec, Canada J7J 2K7 Tel (450) 433-9139 And JHeimbach LLC 923 Water Street P.O. Box 66 Port Royal VA 22535 USA Tel (804) 742-5543 1 LALLEMAND HEALTH SOLUTIONS TABLE OF CONTENTS LIST OF TABLES ....................................................................................................................... 5 LIST OF FIGURES..................................................................................................................... 7 PART 1. SIGNED STATEMENTS AND CERTIFICATION.......................................................... 8 1.1. GRAS NOTICE SUBMISSION................................................................................................8 1.2. NAME AND ADDRESS OF NOTIFIER .......................................................................................8 1.3. NAME OF NOTIFIED ORGANISMS ..........................................................................................9 1.4. INTENDED CONDITIONS OF USE ...........................................................................................9 1.5. STATUTORY BASIS FOR GRAS STATUS ...............................................................................9 1.6. PREMARKET EXEMPT STATUS ...........................................................................................10 1.7. AVAILABILITY OF INFORMATION ..........................................................................................10 1.8. FREEDOM OF INFORMATION ACT STATEMENT.....................................................................10 1.9. CERTIFICATION.................................................................................................................10 1.10. FSIS STATEMENT...........................................................................................................10 1.11. NAME AND TITLE OF SIGNER ...........................................................................................10 PART 2. IDENTITY, METHOD OF MANUFACTURE, SPECIFICATIONS, AND TECHNICAL EFFECT ................................................................................................................................... 11 2.1. NAMES OF THE GRAS ORGANISMS ...................................................................................11 2.2. SOURCES OF THE GRAS ORGANISMS ...............................................................................11 2.3. DESCRIPTIONS OF THE GRAS ORGANISMS ........................................................................11 2.3.1. Lactobacillus helveticus Rosell®-52 (R0052) ...........................................................12 2.3.1.1. Phenotypic Identification of Lactobacillus helveticus Rosell®-52 (R0052) .........13 2.3.1.2. Genotypic identification of Lactobacillus helveticus Rosell®-52 (R0052) ...........16 2.3.2. Bifidobacterium longum ssp. infantis Rosell®-33 (R0033)........................................22 2.3.2.1. Phenotypic identification of Bifidobacterium longum ssp. infantis Rosell®-33 (R0033)..........................................................................................................................24 2.3.2.2. Genotypic identification of B. longum ssp. infantis Rosell®-33 (R0033).............26 2.3.3. Bifidobacterium bifidum Rosell®-71 (R0071) ..........................................................29 2.3.3.1. Phenotypic identification of Bifidobacterium bifidum Rosell®-71 (R0071)..........30 2.3.3.2. Genotypic identification of Bifidobacterium bifidum Rosell®-71 (R0071) ...........32 2.4. GENOMIC ANALYSIS..........................................................................................................35 2.4.1. Lactobacillus helveticus Rosell®-52 (R0052) ...........................................................35 2.4.1.1. Sequencing.......................................................................................................35 2.4.1.2. Annotation of the Genome ................................................................................36 2.4.1.3. Annotation of the Plasmid .................................................................................36 2.4.1.4. Results of the Genomic Analysis.......................................................................36 2.4.2. Bifidobacterium longum ssp. infantis Rosell®-33 (R0033).......................................38 2.4.2.1. Sequencing.......................................................................................................38 2.4.2.2. Annotation of the Genome ................................................................................38 2.4.2.3. Annotation of Plasmids .....................................................................................39 2.4.2.4. Results of the Genomic Analysis.......................................................................39 2.4.3. Bifidobacterium bifidum Rosell®-71 (R0071) ..........................................................40 2 LALLEMAND HEALTH SOLUTIONS 2.4.3.1. Sequencing.......................................................................................................40 2.4.3.2. Annotation of the Genome ................................................................................41 2.4.3.3. Annotation of Plasmids .....................................................................................42 2.4.3.4. Results of the Genomic Analysis.......................................................................42 2.5. PRODUCTION PROCESS ....................................................................................................44 2.5.1 Manufacturing Process of the Bacterial Strains.........................................................45 2.5.2. Blending of the Three Bacterial Strains....................................................................48 2.6. SPECIFICATIONS...............................................................................................................50 2.6.1 Specifications of the Bacterial Powder ......................................................................50 2.6.2. Specifications of the Blend of the Three Bacterial Strains ........................................56 2.7. HEAVY METALS ................................................................................................................58 2.8 STABILITY .........................................................................................................................59 PART 3. DIETARY EXPOSURE (EDI) ..................................................................................... 61 PART 4: SELF-LIMITING LEVELS OF USE............................................................................ 62 PART 5: EXPERIENCE BASED ON COMMON USE IN FOOD .............................................. 63 PART 6: NARRATIVE .............................................................................................................. 64 6.1. RECOGNIZED SAFETY OF LACTIC ACID BACTERIA ...............................................................64 6.2. HISTORY OF CONSUMPTION OF NOTIFIED BACTERIAL STRAINS............................................66 6.2.1. History of Consumption of Lactobacillus helveticus Rosell®-52 (R0052)..................66 6.2.2. History of Consumption of Bifidobacterium longum ssp. infantis Rosell®-33 (R0033) ..........................................................................................................................................68 6.2.3. History