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Pyrroloquinoline Quinone Disodium Salt (Biopqq™) on Cognitive Functions

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Pyrroloquinoline Quinone Disodium Salt (Biopqq™) on Cognitive Functions GRAS Notice (GRN) No. 641 http://www.fda.gov/Food/IngredientsPackagingLabeling/GRAS/NoticeInventory/default.htm ORIGINAL SUBMISSION ·~~M~ #Jiti~iE~~{)}ff~~0-ijj www.hisunpharm.com February 25, 2016 Dr. Paulette Gaynor . Office-of Food Additive Safety (HFS-200) Center for Food Safety and Applied Nutrition Food and Drug Administration 5100 Paint Branch Parkway College Park, MD 207 40-3835 Dear Dr. Gaynor: Re: GRAS Exemption Claim - Pyrroloquinoline Quinone (PQQ) Disodium Salt In accordance with proposed 21 CFR §170.36 [Notice of a claim for exemption based on a Generally Recognized as Safe (GRAS) determination] published in the Federal Register [62 FR 18938 (17 April 1997)], I am submitting one hard copy and one electronic copy (on CD), as the notifier [Zhejiang Hisun Pharmaceutical Co. Ltd., 46 Waisha Road, Jiaojiang District Taizhou City, Zhejiang Province, P.R. China], a Notice of the determination, on the basis of scientific procedures, that pyrroloquinoline quinone (PQQ) disodium salt, produced by Hisun, as defined in the enclosed documents, is GRAS under specific conditions of use in specified beverage products, and therefore, is exempt from the premarket approval requirements of the Federal, Food, Drug and Cosmetic Act. Information setting forth the basis for the GRAS determination, which includes detailed information on the notified substance and a summary of the basis for the GRAS determination, as well as a consensus opinion of an independent panel of experts in support of the safety of PQQ under the intended conditions of use, also are enclosed for review by the agency. The enclosed electronic files for the Notice entitled, "GRAS Exemption Claim Pyrroloquinoline Quinone (PQQ) Disodium Salt" were scanned for viruses prior to submission and is thus certified as being virus-free using ·McAfee Vi rusS can 8.8. Should you have any questions or concerns regarding this GRAS Notice, please do not hesitate to contact me at any point during the review process so that we may provide a response in a timely manner. Sincerely, (b) (6) Tracy Huang Director, Regulatory Affairs Zhejiang Hisun Pharmaceutical Co. Ltd. Email: [email protected] Tel: +86-576-8882-7802 Fax: +86-576-8852-5877 Zhejiang Hisun Pharmaceutical Co.,Ltd. nilE~ .illtJii15t1! ~li #Jfri *m 46 Waisha Road,Jiaojiang District, wrrr~ 'E:f 1+1nH~rr~K5tr¥:9~46% Taizhou City,Zhejiang Province, IB~~:318000 P.R. China 318000 !til§": 0576-8882 7890, 8882 7988 Tel: +86 576 8882 7890, 8882 7988 Fax: +86 576 8882 7887 1'if•= 0576-8882 7887 HIS UN ~t~liE~~ Wfl[j4l}JE~~f)t1f~~0 j§j www.hisunpharm.com February 25, 2016 Dr. Paulette Gaynor Office of Food Additive Safety (HFS-200) Center for Food Safety and Applied Nutrition Food and Drug Administration 5100 Paint Branch Parkway College Park, MD 207 40-3835 Dear Dr. Gaynor: Re: GRAS Exemption Claim - Pyrroloquinoline Quinone (PQQ) Disodium Salt In accordance with proposed 21 CFR §170.36 [Notice of a claim for exemption based on a Generally Recognized as Safe (GRAS) determination] published in the Federal Register [62 FR 18938 (17 April 1997)], I am submitting one hard copy and one electronic copy (on CD), as the notifier [Zhejiang Hisun Pharmaceutical Co. Ltd., 46 Waisha Road, Jiaojiang District Taizhou City, Zhejiang Province, P.R. China], a Notice of the determination, on the basis of scientific procedures, that pyrroloquinoline quinone (PQQ) disodium salt, produced by Hisun, as defined in the enclosed documents, is GRAS under specific conditions of use in specified beverage products, and therefore, is exempt from the premarket approval requirements of the Federal, Food, Drug and Cosmetic Act. Information setting forth the basis for the GRAS determination, which includes detailed information on the notified substance and a summary of the basis for the GRAS determination, as well as a consensus opinion of an independent panel of experts in support of the safety of PQQ under the intended conditions of use, also are enclosed for review by the agency. The enclosed electronic files for the Notice entitled, "GRAS Exemption Claim Pyrroloquinoline Quinone (PQQ) Disodium Salt" were scanned for viruses prior to submission and is thus certified as being virus-free using McAfee VirusScan 8.8. Should you have any questions or concerns regarding this GRAS Notice, please do not hesitate to contact me at any point during the review process so that we may provide a response in a timely manner. Sincerely, (b) (6) Tracy Huang Director, Regulatory Affairs Zhejiang Hisun Pharmaceutical Co. Ltd. Email: [email protected] Tel: +86-576-8882-7802 Fax: +86-576-8852-5877 Zhejiang Hisun Pharmaceutical Co.,Ltd. mrrr#i.iE~ ~JN:-ffi;ff m-0m 46 Waisha Road,Jiaojiang District, wrrr:tJ'i!Him~rr!R7~¥Y~46% Taizhou City,Zhejiang Province, !1!~~:318000 P.R. China 318000 ft!.it: 0576-8882 7890, 8882 7988 Te 1: +86 576 8882 7890, 8882 7988 Fax: +86 576 8882 7887 11(~: 0576-8882 7887 GRAS Exemption Claim for Pyrroloquinoline Quinone (PQQ) Disodium Salt Submitted to: Office of Food Additive Safety (HFS-200) Center for Food Safety and Applied Nutrition (CFSAN) Food and Drug Administration 5100 Paint Branch Parkway College Park, MD USA 20740-3835 Submitted by: Zhejiang Hisun Pharmaceutical Co. Ltd. 46 Waisha Road, Jiaojiang District Taizhou City Zhejiang Province 318000 P.R. China February 2016 GRAS Exemption Claim for Pyrroloquinoline Quinone (PQQ) Disodium Salt Table of Contents Page I. GRAS EXEMPTION CLAIM ........................................................................................... 4 I.A Claim of Exemption From the Requirement for Premarket Approval Pursuant to Proposed 21 CFR §170.36(c)(1) [62 FR 18938 (17 April 1997)] (U.S. FDA, 1997) ..................................................................................... 4 I.B Name and Address of Notifier ............................................................................. 4 I.C Common Name(s) of the Notified Substance ...................................................... 4 I.D Conditions of Intended Use ................................................................................. 4 I.E Basis for the GRAS Determination ...................................................................... 5 I.F Availability of Information .................................................................................... 5 II. DETAILED INFORMATION ON THE IDENTITY AND MANUFACTURING OF PYRROLOQUINOLINE QUINONE (PQQ) ...................................................................... 6 II.A Identity ................................................................................................................ 6 II.A.1 Chemical Identity ..................................................................................... 6 II.A.2 Chemical and Physical Characteristics .................................................... 6 II.B Method of Manufacture ....................................................................................... 6 II.B.1 Raw Materials and Processing Aids ........................................................ 6 II.B.2 Manufacturing Process ............................................................................ 9 II.B.3 Process Controls ....................................................................................12 II.C Specifications and Batch Analyses ....................................................................13 II.C.1 Specifications ........................................................................................13 II.C.2 Product Analysis .....................................................................................14 II.C.3 Other Qualitative Analyses .....................................................................14 II.D Stability ..............................................................................................................20 II.D.1 Bulk Stability ........................................................................................20 III. SELF-LIMITING LEVELS OF USE ................................................................................21 IV. DETAILED SUMMARY OF THE BASIS FOR HISUN’S GRAS DETERMINATION ........21 IV.A Estimated Dietary Exposure ...............................................................................24 IV.A.1 Estimated Daily Intake of PQQ from its Intended Food Uses ..................24 IV.A.2 Background Dietary Intake of PQQ from Natural Occurrence in Food Supply ........................................................................................25 IV.B Biological Role of PQQ ......................................................................................27 IV.C Metabolic Fate ...................................................................................................27 IV.D Toxicological Studies .........................................................................................30 IV.D.1 Acute Toxicity Studies ............................................................................30 IV.D.2 Repeated-Dose Studies .........................................................................31 IV.D.3 Other Animal Studies..............................................................................34 IV.D.4 Mutagenicity and Genotoxicity Studies ...................................................36 IV.E Human Studies ..................................................................................................39 IV.F Safety of the Source Organism ..........................................................................40 Zhejiang Hisun Pharmaceutical
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