Carbasalate_calcium_DataSheet_MedChemExpress

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酒石酸卡巴拉汀的产品说明书

SMILES：O=C(OC1=CC=CC([C@@H](N(C)C)C)=C1)N(CC)C.O=C(O)[C@H](O)[C@@H](O)C(O)=O
参考文献：
[1]. Kurz A, Farlow M, Lefèvre G. Pharmacokinetics of a novel transdermal rivastigmine patch for the treatment of Alzheimer's disease: a review. Int J Clin Pract. 2009 May;63(5):799-805.
中文别名：
酒石酸卡巴拉汀;(S)-N-乙基-N-甲基氨基甲酸-3-[(1-二甲氨基)乙基]苯酯酒石酸盐;卡巴拉汀或利斯的明酒石酸盐;L-酒石酸卡巴拉汀;2,3',4-三溴二苯醚;N-乙基甲基氨基甲酰氯;Rivastigmine L-Tartrate L-酒石酸卡巴拉汀;酒石酸卡巴拉汀 USP标准品;酒石酸卡巴拉汀Rivastigmine tartrate;酒石酸卡巴拉汀标准品;酒石酸卡巴拉汀氢 EP标准品;酒石酸利凡斯的明;卡巴拉丁;卡巴拉汀酒石酸盐;重酒石酸卡巴拉汀;重酒石酸利凡斯的明;(S)-N-乙基-N-甲基氨基甲酸-3-[(S)-1-(二甲氨基)乙基]苯酯酒石酸盐;氘代重酒石酸利斯的明-d6;酒石酸卡巴拉汀中文别名：卡巴拉汀或利斯的明酒石酸盐;酒石酸利伐斯的明;酒石酸利瓦斯汀;利斯的明酒石酸盐;卡巴拉汀重酒石酸盐
熔点
123-1250C
分子式
C18H28N2O8
分子量
400.423
闪点
145ºC
精确量
400.18457
PSA
147.84
LogP
0.6371

Kadcyla（阿道特拉兹瑟唑胺）产品说明书

Clinical Policy: Ado-Trastuzumab Emtansine (Kadcyla) Reference Number: CP.PHAR.229Effective Date: 06.01.16Last Review Date: 05.23Line of Business: Commercial, HIM, Medicaid Coding ImplicationsRevision LogSee Important Reminder at the end of this policy for important regulatory and legal information.DescriptionAdo-trastuzumab emtansine (Kadcyla®) is a human epidermal growth factor receptor 2 protein (HER2)-targeted antibody and microtubule inhibitor conjugate.FDA Approved Indication(s)Kadcyla is indicated as a single agent for the:•Adjuvant treatment of patients with HER2-positive early breast cancer who have residual invasive disease after neoadjuvant taxane and trastuzumab-based treatment.•Treatment of patients with HER2-positive, metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination. Patients should have either:o Received prior therapy for metastatic disease, oro Developed disease recurrence during or within six months of completing adjuvant therapy.Policy/CriteriaProvider must submit documentation (such as office chart notes, lab results or other clinical information) supporting that member has met all approval criteria.It is the policy of health plans affiliated with Centene Corporation® that Kadycla is medically necessary when the following criteria are met:I.Initial Approval CriteriaA.Breast Cancer (must meet all):1.Diagnosis of HER2-positive breast cancer;2.Prescribed by or in consultation with an oncologist;3.Age ≥ 18 years;4.Prescribed as a single agent;5.Documentation of prior use of trastuzumab-based therapy and a taxane;6.Request meets one of the following (a, b, or c):*a.As adjuvant: Dose does not exceed 3.6 mg/kg every 21 days for a maximum of 14doses;b.For metastatic: Dose does not exceed 3.6 mg/kg every 21 days;c.Dose is supported by practice guidelines or peer-reviewed literature for therelevant off-label use (prescriber must submit supporting evidence).*Prescribed regimen must be FDA-approved or recommended by NCCNApproval duration:Medicaid/HIM – 6 monthsCLINICAL P OLICYAdo-Trastuzumab EmtansineCommercial – 6 months or to the member’s renewal date, whichever is longerB.Additional NCCN Recommended Uses (off-label) (must meet all):1.Diagnosis of one of the following (a or b):a.Recurrent, advanced, or metastatic HER2-positive non-small cell lung cancer(NSCLC);b.Recurrent HER2-positive salivary gland tumor;2.Prescribed by or in consultation with an oncologist;3.Age ≥ 18 years;4.Prescribed as a single agent;5.Request meets one of the following (a or b):*a.Dose does not exceed 3.6 mg/kg every 21 days;b.Dose is supported by practice guidelines or peer-reviewed literature for therelevant off-label use (prescriber must submit supporting evidence).*Prescribed regimen must be FDA-approved or recommended by NCCNApproval duration:Medicaid/HIM – 6 monthsCommercial – 6 months or to the member’s renewal date, whichever is longerC.Other diagnoses/indications (must meet 1 or 2):1.If this drug has recently (within the last 6 months) undergone a label change (e.g.,newly approved indication, age expansion, new dosing regimen) that is not yetreflected in this policy, refer to one of the following policies (a or b):a.For drugs on the formulary (commercial, health insurance marketplace) or PDL(Medicaid), the no coverage criteria policy for the relevant line of business:CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, andCP.PMN.255 for Medicaid; orb.For drugs NOT on the formulary (commercial, health insurance marketplace) orPDL (Medicaid), the non-formulary policy for the relevant line of business:CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, andCP.PMN.16 for Medicaid; or2.If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listedunder section III (Diagnoses/Indications for which coverage is NOT authorized) ANDcriterion 1 above does not apply, refer to the off-label use policy for the relevant lineof business: CP.CPA.09 for commercial, HIM.PA.154 for health insurancemarketplace, and CP.PMN.53 for Medicaid.II.Continued TherapyA.All Indications in Section I (must meet all):1.Currently receiving medication via Centene benefit, or documentation supports thatmember is currently receiving Kadcyla for a covered indication and has received thismedication for at least 30 days;2.Member is responding positively to therapy;3.If request is for a dose increase, request meets one of the following (a, b, or c):*a.As adjuvant therapy for breast cancer: New dose does not exceed 3.6 mg/kg every21 days for a maximum of 14 doses;CLINICAL P OLICYAdo-Trastuzumab Emtansineb.For all other indications: New dose does not exceed 3.6 mg/kg every 21 days;c.New dose is supported by practice guidelines or peer-reviewed literature for therelevant off-label use (prescriber must submit supporting evidence).*Prescribed regimen must be FDA-approved or recommended by NCCNApproval duration:Medicaid/HIM – 12 monthsCommercial – 6 months or to the member’s renewal date, whichever is longerB.Other diagnoses/indications (must meet 1 or 2):1.If this drug has recently (within the last 6 months) undergone a label change (e.g.,newly approved indication, age expansion, new dosing regimen) that is not yetreflected in this policy, refer to one of the following policies (a or b):a.For drugs on the formulary (commercial, health insurance marketplace) or PDL(Medicaid), the no coverage criteria policy for the relevant line of business:CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, andCP.PMN.255 for Medicaid; orb.For drugs NOT on the formulary (commercial, health insurance marketplace) orPDL (Medicaid), the non-formulary policy for the relevant line of business:CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, andCP.PMN.16 for Medicaid; or2.If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listedunder section III (Diagnoses/Indications for which coverage is NOT authorized) ANDcriterion 1 above does not apply, refer to the off-label use policy for the relevant lineof business: CP.CPA.09 for commercial, HIM.PA.154 for health insurancemarketplace, and CP.PMN.53 for Medicaid.III.D iagnoses/Indications for which coverage is NOT authorized:A.Non-FDA approved indications, which are not addressed in this policy, unless there issufficient documentation of efficacy and safety according to the off label use policy –CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, andCP.PMN.53 for Medicaid, or evidence of coverage documents.IV.Appendices/General InformationAppendix A: Abbreviation/Acronym KeyFDA: Food and Drug AdministrationHER2: human epidermal growth factor receptor 2 proteinNSCLC: non-small cell lung cancerAppendix B: Therapeutic AlternativesNot applicableAppendix C: Contraindications/Boxed Warnings•Contraindication(s): none reported•Boxed warning(s): hepatotoxicity, cardiac toxicity, and embryo-fetal toxicityC LINICAL P OLICYAdo-Trastuzumab EmtansineV. Dosage and AdministrationMaximum Dose Breast cancer Adjuvant therapy for early breast cancer with residual disease3.6 mg/kg IV Q3WK (21-day cycle) for a total of 14 cycles unless there is disease recurrence or unmanageable toxicity.Metastatic breast cancer3.6 mg/kg IV Q3WK (21-day cycle) until disease progression or unmanageable toxicity.3.6 mg/kgVI. Product AvailabilitySingle-use vial: 100 mg, 160 mgVII. References1. Kadcyla Prescribing Information. South San Francisco, CA: Genentech, Inc.; February 2022. Available at: https:///download/pdf/kadcyla_prescribing.pdf. Accessed January 4, 2023.2. Ado-trastuzumab emtansine. In: National Comprehensive Cancer Network Drugs andBiologics Compendium. Available at: /professionals/drug_compendium. Accessed February 7, 2023.3. Minckwitz GV, Huang CS, Mano MS, et al. Trastuzumab emtansine for residual invasive HER2-positive breast c ancer. N Engl J Med 2019;380:617-28.4. National Comprehensive Cancer Network Guidelines. Breast Cancer Version 2.2023. Available at https:///professionals/physician_gls/pdf/breast.pdf. Accessed February 7, 2023.Coding ImplicationsCodes referenced in this clinical policy are for informational purposes only. Inclusion orexclusion of any codes does not guarantee coverage. Providers should reference the most up-to-date sources of professional coding guidance prior to the submission of claims for reimbursement of covered services. J9354 Injection, ado-trastuzumab emtansine, 1 mgDate P&TApproval Date2Q 2019 annual review: expanded COC to all covered indications from just breast cancer; references reviewed and updated.02.05.19 05.19 Criteria added for new FDA indication: adjuvant therapy in early breast cancer with residual disease; references reviewed and updated.06.11.19 08.19C LINICAL P OLICYAdo-Trastuzumab EmtansineDateP&T Approval Date2Q 2020 annual review: no significant changes; revised HIM-medical benefit to HIM line of business; references reviewed and updated. 02.18.20 05.20 2Q 2021 annual review: combined NSCLC and new off-label salivary gland tumor indications supported by NCCN into one off-label section under I.B.; references for HIM line of business off-label use revised from HIM.PHAR.21 to HIM.PA.154; references reviewed and updated.02.05.2105.212Q 2022 annual review: added criterion for single-agent therapy for off-label indications of NSCLC and salivary gland tumor per NCCN; references reviewed and updated.02.15.22 05.22 Template changes applied to other diagnoses/indications.10.07.22 2Q 2023 annual review: no significant changes; clarified for NSCLC that disease is recurrent, advanced, or metastatic per NCCN; references reviewed and updated.01.04.2305.23Important ReminderThis clinical policy has been developed by appropriately experienced and licensed health care professionals based on a review and consideration of currently available generally accepted standards of medical practice; peer-reviewed medical literature; government agency/program approval status; evidence-based guidelines and positions of leading national health professional organizations; views of physicians practicing in relevant clinical areas affected by this clinical policy; and other available clinical information. The Health Plan makes no representations and accepts no liability with respect to the content of any external information used or relied upon in developing this clinical policy. This clinical policy is consistent with standards of medicalpractice current at the time that this clinical policy was approved. “Health Plan” means a health plan that has adopted this clinical policy and that is operated or administered, in whole or in part, by Centene Management Company, LLC, or any of such health plan’s affiliates, as applicable.The purpose of this clinical policy is to provide a guide to medical necessity, which is a component of the guidelines used to assist in making coverage decisions and administering benefits. It does not constitute a contract or guarantee regarding payment or results. Coverage decisions and the administration of benefits are subject to all terms, conditions, exclusions and limitations of the coverage documents (e.g., evidence of coverage, certificate of coverage, policy, contract of insurance, etc.), as well as to state and federal requirements and applicable Health Plan-level administrative policies and procedures.This clinical policy is effective as of the date determined by the Health Plan. The date of posting may not be the effective date of this clinical policy. This clinical policy may be subject to applicable legal and regulatory requirements relating to provider notification. If there is a discrepancy between the effective date of this clinical policy and any applicable legal orregulatory requirement, the requirements of law and regulation shall govern. The Health Plan retains the right to change, amend or withdraw this clinical policy, and additional clinical policies may be developed and adopted as needed, at any time.CLINICAL P OLICYAdo-Trastuzumab EmtansineThis clinical policy does not constitute medical advice, medical treatment or medical care. It is not intended to dictate to providers how to practice medicine. Providers are expected to exercise professional medical judgment in providing the most appropriate care, and are solely responsible for the medical advice and treatment of members. This clinical policy is not intended to recommend treatment for members. Members should consult with their treating physician in connection with diagnosis and treatment decisions.Providers referred to in this clinical policy are independent contractors who exercise independent judgment and over whom the Health Plan has no control or right of control. Providers are not agents or employees of the Health Plan.This clinical policy is the property of the Health Plan. Unauthorized copying, use, and distribution of this clinical policy or any information contained herein are strictly prohibited. Providers, members and their representatives are bound to the terms and conditions expressed herein through the terms of their contracts. Where no such contract exists, providers, members and their representatives agree to be bound by such terms and conditions by providing services to members and/or submitting claims for payment for such services.Note: For Medicaid members, when state Medicaid coverage provisions conflict with the coverage provisions in this clinical policy, state Medicaid coverage provisions take precedence. Please refer to the state Medicaid manual for any coverage provisions pertaining to this clinical policy.©2016 Centene Corporation. All rights reserved. All materials are exclusively owned by Centene Corporation and are protected by United States copyright law and international copyright law. No part of this publication may be reproduced, copied, modified, distributed, displayed, stored in a retrieval system, transmitted in any form or by any means, or otherwise published without the prior written permission of Centene Corporation. You may not alter or remove any trademark, copyright or other notice contained herein. Centene® and Centene Corporation® are registered trademarks exclusively owned by Centene Corporation.。

大肠杆菌高产L丙氨酸

APPLIED GENETICS AND MOLECULAR BIOTECHNOLOGYProduction of L-alanine by metabolically engineered Escherichia coliXueli Zhang&Kaemwich Jantama&J.C.Moore&K.T.Shanmugam&L.O.IngramReceived:23May2007/Revised:13August2007/Accepted:16August2007/Published online:15September2007 #Springer-Verlag2007Abstract Escherichia coli W was genetically engineered to produce L-alanine as the primary fermentation product from sugars by replacing the native D-lactate dehydroge-nase of E.coli SZ194with alanine dehydrogenase from Geobacillus stearothermophilus.As a result,the heterolo-gous alanine dehydrogenase gene was integrated under the regulation of the native D-lactate dehydrogenase(ldhA) promoter.This homologous promoter is growth-regulated and provides high levels of expression during anaerobic fermentation.Strain XZ111accumulated alanine as the primary product during glucose fermentation.The methyl-glyoxal synthase gene(mgsA)was deleted to eliminate low levels of lactate and improve growth,and the catabolic alanine racemase gene(dadX)was deleted to minimize conversion of L-alanine to D-alanine.In these strains,re-duced nicotinamide adenine dinucleotide oxidation during alanine biosynthesis is obligately linked to adenosine triphosphate production and cell growth.This linkage provided a basis for metabolic evolution where selection for improvements in growth coselected for increased glycolytic flux and alanine production.The resulting strain, XZ132,produced1,279mmol alanine from120g l−1 glucose within48h during batch fermentation in the mineral salts medium.The alanine yield was95%on a weight basis(g g−1glucose)with a chiral purity greater than99.5%L-alanine.Keywords Alanine.Fermentation.E.coli.Evolution. GlycolysisIntroductionWorldwide production of L-alanine has been estimated at 500tons per year(Ikeda2003).In pharmaceutical and veterinary applications,L-alanine is used with other L-amino acids as a pre-and postoperative nutrition therapy(Hols et al.1999).Alanine is also used as a food additive because of its sweet taste(Lee et al.2004).The use of L-alanine is limited in part by the current high cost.L-Alanine is pro-duced commercially by the enzymatic decarboxylation of L-aspartic acid using immobilized cells or cell suspensions of Pseudomonas dacunhae as a biocatalyst with a yield greater than90%(Shibatani et al.1979).The substrate for this enzymatic production process,L-aspartate,is usually pro-duced from fumarate by enzymatic catalysis with aspartate ammonia-lyase.Fumaric acid is produced primarily from petroleum,a nonrenewable feedstock.An efficient fermen-tative process with a renewable feedstock such as glucose offers the potential to reduce L-alanine cost and facilitate a broad expansion of the alanine market into other products.Alanine is a central intermediate(Fig.1)and an essential component of cellular proteins.Most microorganisms produce alanine only for biosynthesis using a glutamate–pyruvate transaminase(Hashimoto and Katsumata1998). Some organisms such as Arthrobacter oxydans(Hashimoto and Katsumata1993;Hashimoto and Katsumata1998; Hashimoto and Katsumata1999),Bacillus sphaericus (Ohashima and Soda1979),and Clostridium sp.P2Appl Microbiol Biotechnol(2007)77:355–366DOI10.1007/s00253-007-1170-yElectronic supplementary material The online version of this article (doi:10.1007/s00253-007-1170-y)contains supplementary material, which is available to authorized users.X.Zhang:J.C.Moore:K.T.Shanmugam:L.O.Ingram(*) Department of Microbiology and Cell Science,University of Florida,Box110700,Gainesville,FL32611,USAe-mail:ingram@K.JantamaDepartment of Chemical Engineering,University of Florida, Gainesville,FL32611,USA(Orlygsson et al.1995)produce alanine from pyruvate and ammonia using an reduced nicotinamide adenine dinucleo-tide (NADH)-linked alanine dehydrogenase (ALD).How-ever,fermentations are slow,and yields from the best natural producers are typically 60%or less because of coproduct formation (Hashimoto and Katsumata 1998;Table 1).Plasmid-borne genes encoding NADH-linked ALD have been tested as an approach to develop improved biocatalysts with varying degrees of success (Table 1).Engineered strains of Zymomonas mobilis CP4expressing the B.sphaericus alaD gene produced low levels of racemic alanine during the anaerobic fermentation of 5%glucose (Uhlenbusch et al.1991).A native chromosomal lactate dehydrogenase gene (ldhA )-deleted strain of Lactococcus lactis containing a mutation in alanine racemase was engineered in a similar fashion and produced 12.6g l −1L -alanine from 1.8%glucose (Hols et al.1999).An Escherichia coli aceF ldhA double mutant containing pTrc99A-alaD plasmid produced 32g l −1racemic alanine in 27h during a two-stage (aerobic and anaerobic)fermentation with a yield of 0.63g alanine g −1glucose (Lee et al.2004).With further gene deletions and process optimization,the racemic alanine titer wasincreasedFig.1Alanine pathway in recombinant E.coli .a Native and recom-binant fermentation pathways.The foreign gene,G.stearothermophilus alaD ,is shown in bold .G.stearothermophilus alaD coding region and transcriptional terminator were integrated into the native ldhA gene under transcriptional control of the ldhA promoter.Solid stars represent deletions of native genes in XZ132.Note that the native biosynthetic route for alanine production is omitted for simplicity.ackA Acetate kinase,adhE alcohol/aldehyde dehydrogenase,alaD alanine dehydro-genase (Geobacillus stearothermophilus XL-65-6),aldA aldehyde dehydrogenase A,aldB aldehyde dehydrogenase B,alr alanine race-mase 1,dadX alanine racemase 2,frd fumarate reductase,gloA glyoxalase I,gloB glyoxalase II,gloC glyoxalase III,ldhA D -lactate dehydrogenase,mdh malate dehydrogenase,mgsA methylglyoxal synthase,pflB pyruvate –formate lyase,ppc phosphoenolpyruvate carboxylase,pta phosphate acetyltransferase.b Coupling of ATP production and growth to NADH oxidation and L -alanine production.Glucose is metabolized to pyruvate,ATP,and NADH.Energy conserved in ATP is utilized for growth and homeostasis,regenerating ADP.NADH is oxidized by alanine formation allowing glycolysis and ATP production to continueT a b l e 1C o m p a r i s o n o f a l a n i n e -p r o d u c i n g s t r a i n sO r g a n i s m s M o d i f i e d p r o p e r t yM e d i a ,s u b s t r a t e a n d p r o c e s s c o n d i t i o n sT i m e (h )A l a n i n e (g l −1)Y i e l d (%)L -A l a n i n ep u r i t y (%)R e f e r e n c e E .c o l i X Z 132I n t e g r a t e d G .s t e a r o t h e r m o p h i l u s a l a D ;Δp f l ,Δa c k A ,Δa d h E ,Δl d h A ,Δm g s A ,Δd a d XM i n e r a l m e d i u m ,b a t c h ,g l u c o s e 120g l −148.0114.095>99T h i s s t u d yA r t h r o b a c t e r o x y d a n s H A P -1M i n e r a l m e d i u m ,t w o -s t a g e f e d -b a t c h ,g l u c o s e 150g l −1120825560.0H a s h i m o t o a n d K a t s u m a t a 1998A .o x y d a n s D A N 75A l a n i n e r a c e m a c e d e f i c i e n tM i n e r a l m e d i u m ,t w o -s t a g e f e d -b a t c h ,g l u c o s e 150g l −1,0.2g l −1D -a l a n i n e120775198H a s h i m o t o a n d K a t s u m a t a 1998E c o l i A L 1(p O B P 1)P l a s m i d w i t h A .o x y d a n s H A P -1a l a D M i n e r a l m e d i u m ,g l u c o s e 20g l −1,l i m i t e d o x y g e n40841N o t r e p o r t e dK a t s u m a t a a n d H a s h i m o t o 1996C o r y n e b a c t e r i u m g l u t a m i c u m A L 107(p O B P 107)P l a s m i d w i t h A .o x y d a n s H A P -1a l a DC o r n s t e e p l i q u o r ,g l u c o s e 200g l −1,4g l −1D L -a l a n i n e ,l i m i t e d o x y g e n 707136>99K a t s u m a t a a n d H a s h i m o t o 1996Z y m o m o n a s m o b i l i s C P 4(p Z Y 73)P l a s m i d w i t h B .s p h a e r i c u s I F O 3525a l a D M i n e r a l s a l t s m e d i u m ,s i m p l e b a t c h ,g l u c o s e 50g l −126816N o t r e p o r t e dU h l e n b u s c h e t a l .1991L a c t o c o c c u s l a c t i s N Z 3950(p N Z 2650)P l a s m i d w i t h B .s p h a e r i c u s I F O 3525a l a D Δl d h AR i c h m e d i u m (M 17),g l u c o s e 18g l −117137085–90H o l s e t a l .1999L .l a c t i s P H 3950(p N Z 2650)P l a s m i d w i t h B .s p h a e r i c u s I F O 3525a l a D Δl d h A ,Δa l rR i c h m e d i u m (M 17),g l u c o s e 18g l −1,0.2g l −1D -a l a n i n e 17N o t k n o w nN o t k n o w n >99H o l s e t a l .1999E .c o l i A L S 887(p T r c 99A -a l a D )P l a s m i d w i t h B .s p h a e r i c u s I F O 3525a l a D Δl d h A ,Δa c e FY e a s t e x t r a c t ,t w o -s t a g e b a t c h ,g l u c o s e 50g l −1,a e r o b i c a i r 1l m i n −1273263N o t r e p o r t e d L e e e t a l .2004E .c o l i A L S 929(p T r c 99A -a l a D )P l a s m i d w i t h B .s p h a e r i c u s I F O 3525a l a D Δp f l ,Δp p s ,Δp o x B ,Δl d h A ,Δa c e E FY e a s t e x t r a c t a n d c a s a m i n o a c i d s ,t w o -s t a g e b a t c h (a e r o b i c c e l l g r o w t h a n d a n a e r o b i c f e r m e n t a t i o n )223486N o t r e p o r t e d S m i t h e t a l .2006E .c o l i A L S 929(p T r c 99A -a l a D )P l a s m i d w i t h B .s p h a e r i c u s I F O 3525a l a D Δp f l ,Δp p s ,Δp o x B ,Δl d h A ,Δa c e E FY e a s t e x t r a c t a n d c a s a m i n o a c i d s ,t w o -s t a g e f e d -b a t c h (a e r o b i c c e l l g r o w t h a n d a n a e r o b i c f e r m e n t a t i o n )4888100N o t r e p o r t e d S m i t h e t a l .2006to88g l−1in a more complex process with yields ap-proaching the theoretical maximum(Smith et al.2006). However,this strain produced only racemic alanine,utilized multicopy plasmids requiring antibiotic selection,and required complex media with a complex multistage fermen-tation process(Smith et al.2006).In this study,we developed novel biocatalysts that pro-duce chirally pure L-alanine in batch fermentations without using plasmid-containing biocatalysts,antibiotics,or com-plex nutrients.The resulting strains are based on a deriva-tive of E.coli W(strain SZ194)that produces D-lactate (Zhou et al.2006b).The ldhA gene in SZ194was replaced with a single,chromosomally integrated copy of the ALD gene from the thermophile,Geobacillus stearothermophilus XL-65-6(formerly B.stearothermophilus;Lai and Ingram 1993).After additional deletions of alanine racemase (dadX)and methylglyoxal synthase(mgsA)and metabolic evolution,the resulting strain produced L-alanine at high titers(over1M)and yields in batch fermentations using the mineral salts medium.Materials and methodsStrains,plasmids,media,and growth conditionsThe strains and plasmids used in this study are listed in Table2.Strain SZ194was previously engineered from a derivative of E.coli W(ATCC9637)and served as a starting point for constructions(Zhou et al.2006b).G. stearothermophilus XL-65-6(Lai and Ingram1993)was used for cloning the ALD gene.During sequencing of chro-mosomal genes,we discovered a20-year-old error in culture labeling.Strain SZ194,the parent used to construct the alanine strains,is a derivative of E.coli W(ATCC9637). Other constructs for ethanol production and lactate produc-tion that have been reported previously as derivatives of E. coli B are now known to be derivates of E.coli W(ATCC 9637).Primers used in this study are listed in Table3.During strain construction,cultures were grown aerobi-cally at30,37,or39°C in Luria broth(10g l−1Difco tryptone,5g l−1Difco yeast extract,and5g l−1NaCl) containing2%(w/v)glucose or5%(w/v)arabinose. Ampicillin(50mg l−1),tetracycline(12.5mg l−1), kanamycin(50mg l−1),or chloramphenicol(40mg l−1) were added as needed.For initial tests of fermentative alanine production,strains were grown without antibiotics at37°C in NBS mineral salts medium(Causey et al.2004) supplemented with100mM ammonia sulfate,1mM betaine,and2%(w/v)glucose.Fermentation experiments (2–12%sugar)were carried out in NBS medium and AM1 medium(Martinez et al.2007).Broth was maintained at pH 7by the automatic addition of5M NH4OH.Genetic methodsStandard methods were used for genomic deoxyribonucleic acid(DNA)extraction(Qiagen,Valencia,CA),polymerase chain reaction(PCR)amplification(Stratagene,La Jolla CA,and Invitrogen,Carlsbad,CA),transformation,plas-mid extration(Qiagen),and restriction endonuclease diges-tion(New England Biolabs,Ipswich,MA).Methods for foreign gene(alaD)integration and for chromosomal gene (mgsA and dadX)deletion are described below.DNA sequencing was provided by the University of Florida Interdisciplinary Center for Biotechnology Research.The Biocyc and Metacyc databases(Karp et al.2005)were instrumental in the design and completion of these studies. Cloning the alanine dehydrogenase gene alaD from G. stearothermophilus XL-65-6and detection of the enzyme activityThe primers for amplifying alaD from G.stearothermophilus XL-65-6were designed based on the alaD sequence of G. stearothermophilus strain10.The forward primers(5′–3′GGAAAAA GGAGGAAAAAGTG ATGAAGATCGG CATT)included the ribosomal-binding region(bold)and the amino terminus(italicized).The reverse primer(5′–3′GAA GGAGTTGATCATTGTTTAACGAGAGAGG)was down-stream from the putative transcriptional terminator region (Table3).ALD was verified in clones using an activity stain (Kuroda et al.1990).E.coli TOP10F′harboring plasmids containing alaD was grown on Luria–Bertani(LB)plates at 37°C,then transferred to a Whatman7.0-cm filter paper. The filter was immersed in10mM potassium phosphate buffer(pH7.2)and incubated for20min at80°C for lysis of the cells and denaturation of the E.coli proteins.The dried filter paper was assayed in a reaction mixture containing50mM L-alanine,50mM Tris–HCl buffer (pH9.0),0.625mM NAD+,0.064mM phenazine metho-sulfate,and0.24mM nitro blue tetrazolium.The cells with ALD appeared as blue spots on the filter.Integration of alaD into E.coli SZ194The alaD gene was integrated into the chromosomal ldhA gene of SZ194.The fragment(Sma I–Kpn I,1.7kb)con-taining a tet gene flanked by two FRT sites was isolated from pLOI2065and cloned into pLOI4211between a unique Bam HI site(Klenow-treated)and Kpn I site to produce plasmid pLOI4213(6.0kb).In this plasmid,transcription of alaD and tet are oriented in the same direction.The Apa I(treated with T4DNA polymerase to produce a blunt end)–Kpn I fragment(2.2kb)containing alaD and tet was isolated from pLOI4213and cloned into pLOI2395Table2 E.coli strains and plasmids used in this studyRelevant characteristics Source or referenceStrainsSZ194plfB frd adhE ackA deletions Zhou et al.2006bXZ103-110SZ194,ldhA::FRT-tet-FRT::This studyG.stearothermophilus alaDXZ111XZ105,ldhA::G.stearothermophilus alaD This studyXZ112XZ111,metabolic evolution in NBS medium with2%glucose This studyXZ113XZ112,metabolic evolution in NBS medium with5%glucose This studyXZ115XZ113,metabolic evolution in NBS medium with8%glucose This studyXZ121XZ115,mgsA deletion This studyXZ123XZ121,metabolic evolution in NBS medium with8%glucose This studyXZ126XZ123,dadX deletion This studyXZ129XZ126,metabolic evolution in NBS medium with8%glucose This studyXZ130XZ129,metabolic evolution in AM1medium with8%glucose This studyXZ131XZ130,metabolic evolution in AM1medium with10%glucose This studyXZ132XZ131,metabolic evolution in AM1medium with12%glucose This studyPlasmidspCR2.1-TOPO bla kan;TOPO TA cloning vector InvitrogenDatsenko and Wanner2000pKD46Blaγβexo(Red recombinase),temperature conditionalpSC101repliconpFT-A Bla flp,temperature conditional pSC101replicon Posfai et al.1997pEL04cat-sacB targeting cassette Lee et al.2001;Thomason et al.2005 pLOI2224kan;R6K conditional integration vector Martinez-Morales et al.1999pLOI2065bla;FRT-tet-FRT cassette Zhou et al.2003bpLOI2395bla;ldhA franked by two Asc I site Zhou et al.2003apLOI3421 1.8kbp SmaI fragment containing aac Wood et al.2005pLOI4151bla cat;cat-sacB cassette This studyalaD integrationThis studypLOI4211bla kan alaD;alaD(PCR)from G.stearothermophilus XL-65-6cloned into pCR2.1-TOPO vectorpLOI4213bla kan;alaD-FRT-tet-FRT Kpn I-Sma I fragment(FRT-tet-FRT)This studyfrom pLOI2065cloned into Kpn I-BamH I(blunted)site of pLOI4211This studypLOI4214bla kan;ldhA’-alaD-FRT-tet-FRT-ldhA”Apa I(blunted)-Kpn I fragment(alaD-FRT-tet-FRT)from pLOI4213cloned into ldhA at Hinc II-Kpn Isites of pLOI2395This studypLOI4215kan;ldhA’-alaD-FRT-tet-FRT-ldhA”Asc I fragment(ldhA’-alaD-FRT-tet-FRT-‘ldhA)from pLOI4214cloned into Asc I sites of pLOI2224mgsA deletionThis studypLOI4228bla kan;yccT’-mgsA-helD’(PCR)from E.coli W clonedinto PCR2.1-TOPO vectorThis studypLOI4229cat-sacB cassette PCR amplified from pLOI4151(Eco RV digested)cloned into mgsA in pLOI4228This studypLOI4230PCR fragment amplified from pLOI4228(using mgsA-1/mgsA-2primers),kinase treated,and self-ligateddadX deletionThis studypLOI4216bla kan;dadA’-dadX-cvrA’(PCR)from E.coli W clonedinto PCR2.1-TOPO vectorpLOI4218cat-sacB cassette PCR amplified from pLOI4151(Eco RV digested)This studycloned into dadX in pLOI4216This studypLOI4220PCR fragment amplified from pLOI4216(using dadX-4/dadX-5primers),kinase treated,and self-ligated(Hinc II to Kpn I sites)to produce pLOI4214(6.5kb).In this plasmid,ldhA ,alaD ,and tet genes are transcribed in the same direction.The Asc I fragment (4.3kb)containing these three genes was isolated from pLOI4214and cloned into the R6K integration vector pLOI2224to produce pLOI4215(6.2kb).Plasmid pLOI4215contains resistance genes for both tetracycline and kanamycin (Fig.2).The Asc I fragment (4.3kb)containing ldhA ,alaD ,and tet genes was isolated from pLOI4215,further cut by Xmn I to eliminate any remaining uncut plasmid DNA,and electroporated into SZ194containing the Red recombinase plasmid pKD46(Datsenko and Wanner 2000).Integrants were selected for tetracycline resistance,confirmed by sensitivity to kanamycin and ampicillin and by PCR analysis using the primers of ldhA and its neighboring genes ydbH and hslJ (Table 3).Deletion of mgsA and dadX genesA modified method for deleting E.coli chromosomal genes was developed using two steps of homologous recom-bination (Thomason et al.2005).With this method,no antibiotic genes or scar sequences remain on the chromo-some after gene deletion.In the first recombination,part of the target gene was replaced by a DNA cassette containing a chloramphenicol resistance gene (cat )and levansucrase gene (sacB ).In the second recombination,the cat –sacBcassette was removed by selection for resistance to sucrose.Cells containing the sacB gene accumulate levan during incubation with sucrose and are killed.Surviving recombi-nants are highly enriched for loss of the cat –sacB cassette.A new cassette was constructed as a template to facilitate gene deletions.The cat –sacB region was amplified from pEL04(Lee et al.2001;Thomason et al.2005)by PCR using the JM catsacB up Nhe I and JM catsacB down Nhe I primers (Table 3),digested with Nhe I,and ligated into the corresponding site in pLOI3421to produced pLOI4151.The cat –sacB cassette was amplified by PCR using pLOI4151as a template with the cat -up2and sacB -down2primers (Eco RV site included in each primer),digested with Eco RV ,and used in subsequent ligations.The mgsA gene and neighboring 500-bp regions (yccT ′–mgsA –helD ′,1,435bp)were amplified using the mgsA -up and mgsA -down primers and cloned into the pCR 2.1-TOPO vector (Invitrogen)to produce plasmid pLOI4228.A 1,000-fold diluted plasmid preparation of this plasmid served as a template for inside-out amplification using the mgsA -1and mgsA -2primers (both within the mgsA gene and facing outward).The resulting 4,958-bp fragment containing the replicon was ligated to the Eco RV-digested cat –sacB cassette from pLOI4151to produce pLOI4229(Fig.3a).This 4,958-bp fragment was also used to construct a second plasmid,pLOI4230(Fig.3b),by phosphorylation and self-ligation.In pLOI4230,the central region of mgsA is deleted (yccT ′–mgsA ′–mgsA ″–helD ′).After digestion of pLOI4229and pLOI4230with Xmn I (within the vector),each served as a template for amplifica-tion using the mgsA -up and mgsA -down primers to produce linear DNA for integration step 1(yccT ′–mgsA ′–cat –sacB –mgsA ″–helD ′)and step II (yccT ′–mgsA ′–mgsA ″–helD ′),respectively.After electroporation of the step 1fragment into XZ115containing pKD46(Red recombinase)and 2h ofTable 3Primers used in this study Primers SequencealaD -forward GGAAAAAGGAGGAAAAAGTGATGAA GATCGGCATTalaD -reverse GAAGGAGTTGATCATTGTTTAACGA GAGAGGldhA -forward AGTACCTGCAACAGGTGAAC ldhA -reverse CAGGCGACGGAATACGTCAT ldhA -up (ydbH )CTGATAACGCAGTTGCTGGA ldhA -down (hslJ )TTCATTAAATCCGCCAGCTTJM catsacB up NheI TTAGCTAGCATGTGACGGAAGATC ACTTCGJM catsacB down NheI CCGCTAGCATCAAAGGGAAAACTGT CCATATcat -up2AGAGAGGATATCTGTGACGGAAGAT CACTTCGsacB -down2AGAGAGGATATCGAATTGATCCGGT GGATGACmgsA -up CAGCTCATCAACCAGGTCAA mgsA -down AAAAGCCGTCACGTTATTGG mgsA -1AGCGTTATCTCGCGGACCGT mgsA -2AAGTGCGAGTCGTCAGTTCC dadX -up AGGCTACTCGCTGACCATTC dadX -down GGTTGTCGGTGACCAGGTAG dadX -4TGGGCTATGAGTTGATGTGC dadX -5CTGTATCGGACGGGTCATCTFig.2Integration vector used for chromosomal insertion of G.stearothermophilus alaD into E.coli ldhA .Sequence encoding the N-terminal and C-terminal regions are designated ldhA ′and ldhA ″,respectivelyincubation at 30°C to allow expression and segregation,recombinants were selected for chloramphenicol (40mg l −1)and ampicillin (50mg l −1)resistance in Luria broth at 30°C (18h).Three clones were selected,grown in Luria broth containing ampicillin and 5%(w/v)arabinose (to induce expression of red recombinase),and prepared for electro-poration.After electroporation with the step 2fragment,cells were incubated at 30°C for 4h and then transferred into a 250-ml flask containing 100ml of modified LB (100mM 3-(N -morpholino)propanesulfonic acid [MOPS]buffer added and NaCl omitted)containing 10%sucrose.After overnight incubation (30°C),clones were selected on modified LB plates (no NaCl;100mM MOPS added)containing 6%sucrose (39°C,16h).Resulting clones were tested for loss of ampicillin and chloramphenicol resistance.Construction was confirmed by PCR using the mgsA-up/down primer set.A clone containing a deletion in the central region of mgsA was selected and designated XZ121.The dadX gene was deleted in a manner analogous to that used to delete the mgsA gene.Primers for dadX deletion are shown in Table 3,and the corresponding plasmids are shown in Table 2.FermentationNBS mineral salts medium (Causey et al.2004)with 1mM betaine (Zhou et al.2006a )was used in the initial fermentation (pH 7.0).Preinoculum was grown by inocu-lating three colonies into a 250ml flask (100ml NBS medium,2%glucose,and 100mM ammonium sulfate).After 16h (37°C,120rpm),this preinoculum was diluted into 500-ml fermentation fleakers containing 300ml NBS medium (2–8%glucose,100mM ammonium sulfate,and 1mM betaine)with 33mg cell dry weight (CDW)l −1.In early experiments,pH was maintained at 7.0by automat-ically adding 2M potassium hydroxide.In later experi-ments,5M ammonium hydroxide was used to maintain pH,and a low salt medium,AM1(Martinez et al.2007),was used to replace the NBS medium for fermentation (8–12%glucose).AM1medium contains much less salt and has been optimized for E.coli .Metabolic evolutionCells from pH-controlled fermentations were serially transferred at 24-h intervals to facilitate metabolic evolution through competitive,growth-based selection (Fig.1b).At the beginning,sequentially transferred cultures were inoc-ulated with an initial density of 33mg CDW l −1.As growth increased,the inoculum was changed to a 1:100dilution and subsequently to a 1:300dilution.Periodically,clones were isolated from these experiments,assigned new strain designations,and frozen for storage.AnalysesCell mass was estimated by measuring the optical density at anic acids and glucose concentrations were mea-sured by high-performance liquid chromatography (HPLC,Underwood et al.2002).Analysis of fermentation products by mass spectroscopy and amino acid analyzer were provided by the University of Florida Interdisciplinary Center for Bio-technology Research.Alanine was found to be the predominant product.The alanine concentration and isomeric purity were further measured by HPLC using the Chiralpak MA(+)chiral column (Chiral Technologies,West Chester,PA).ResultCloning of the alanine dehydrogenase geneALD is found in Bacillus (and Geobacillus )species where it plays a pivotal role in energy generation during sporulation (Ohashima and Soda 1979;Kuroda et al.1990).ALD from B.sphaericus IFO3525has beenwidelyFig.3Plasmids used to delete mgsA .Plasmid pLOI4229(a )was used to delete the mgsA gene and insert the cat-sacB cassette in the first recombina-tion step.Plasmid pLOI4230(b )was used to remove the cat-sacB cassette to create a deletion devoid of foreign sequence.Se-quence encoding the N-terminal and C-terminal regions are des-ignated mgsA ′and mgsA ″,respectivelyused with varying degrees of success to engineer alanine production in recombinant bacteria(Uhlenbusch et al. 1991;Hols et al.1999;Lee et al.2004;Smith et al.2006). Selection of the B.sphaericus IFO3525is presumed to be due in part to the high specific activity(Ohashima and Soda 1979).In contrast,we have selected a thermostable ALD from the thermophile,G.stearothermophilus XL-65-6, based on our prior experience in expressing genes from this organism in recombinant E.coli(Burchhardt and Ingram 1992;Lai and Ingram1993;Lai and Ingram1995).The ribosomal-binding region,coding region,and tran-scriptional terminator of alaD were amplified from G. stearothermophilus XL-65-6and sequenced(EF154460in GenBank).The deduced amino acid sequence was identical to that reported for Geobacillus kaustophilus HTA426and very similar to G.stearothermophilus strain10(99%iden-tity)and G.stearothermophilus strain IFO12550(94% identity).The nucleotide sequence(65%identity)and the deduced ALD amino acid sequence(74%identity)were quite different from the B.sphaericus IFO3525gene,the gene pre-viously used for alanine production in recombinant bacteria.Modification of E.coli W for homoalanine productionE.coli W strain SZ194(pflB frdBC adhE ackA)was previously constructed to produce only D-lactic acid.All major fermentation pathways except lactate have been blocked in this strain by gene deletions(Fig.1a).To convert this strain to the production of alanine,part of the native ldhA-coding region was replaced by a DNA fragment containing the ribosomal-binding region,coding region,and transcriptional terminator of alaD from G. stearothermophilus XL-65-6.The promoterless alaD was oriented in the same direction as ldhA to allow expression from the native ldhA promoter(Fig.2).After electroporation,approximately500colonies were recovered with tetracycline resistance and sensitivity to kana-mycin,consistent with a double-crossover event.These colo-nies were further examined by PCR using ldhA forward and reverse primer set(Table3).Only eight colonies of the500 tested were correct based on an analysis of PCR fragments. These eight colonies were further verified using primer sets for alaD,ldhA forward and alaD reverse,alaD forward and ldhA reverse,and ldhA outside primers(Table3)and de-signated XZ103,XZ104,XZ105,XZ106,XZ107,XZ108, XZ109,and XZ110,respectively.These eight strains were initially tested in15-ml screw-cap tubes containing NBS medium with2%glucose and100mM ammonium sulfate, which were filled to the brim.Strain XZ105appeared to grow faster than the other strains(37°C for48h)and was selected for further development.XZ105was transformed with pFT-A,which contains an inducible flippase(FLP)recombinase(Martinez-Morales et al.1999;Posfai et al.1997).The chromosomal FRT-flanked tet gene in XZ105was removed by inducing the FLP recombinase.After growing in39°C to eliminate the temperature-sensitive plasmid pFT-A,resulting strain was designated XZ111.Expression of G.stearothermophilus alaD in XZ111is transcriptionally regulated by the ldhA promoter,the same promoter that regulates the production of lactate dehydrogenase(dominant fermentation pathway) in native E.coli.pH-controlled batch fermentation for alanine production Alanine production by strain XZ111was tested in500-ml fermentation vessels containing300ml NBS medium, 20g l−1glucose,100mM ammonium sulfate,and1mM betaine.Broth pH was automatically controlled by adding 2N potassium hydroxide.After96h,181mM alanine was produced.The alanine yield from total glucose was 81%(g/g),and84%based on glucose that had been metabo-lized.The chiral purity of L-alanine was96.1%(Table4). Very low levels of other products(lactate,succinate,ace-tate,ethanol)were present,typically below1mM.This result demonstrated that the integrated G.stearothermophilus alaD gene as a single chromosomal copy under the control of the native ldhA promoter can provide sufficient levels of ALD to support E.coli growth from the production of alanine as the sole fermentation product.Metabolic evolution of strain XZ111Although XZ111could accumulate alanine as the primary product,incubation times were long,and volumetric productivity was limited.When using a high-glucose concentration(80g l−1),growth and alanine productivity were further reduced(Table4).In this strain,adenosine triphosphate(ATP)production and growth are tightly coupled to NADH oxidation and alanine production by ALD(Fig.1b).This coupling provided a basis for strain improvement by selecting for increased growth during serial cultivation,i.e.,metabolic evolution.Cells with increased growth because of spontaneous mutations will successively displace their parents while coselecting for increased alanine productivity.Serial transfers of XZ111were carried out at24-h intervals in NBS mineral salts medium with1mM betaine.Cultures were first transferred in the medium containing20g l−1 glucose,and the pH was controlled by automatically adding 2N potassium hydroxide.However,after ten transfers to strain XZ112,little improvement was observed(data not shown).Because ammonia is essential for alanine pro-duction,it was thought that ammonia may be limiting for fermentation.Two normals potassium hydroxide containing 1N ammonia carbonate and5N ammonia hydroxide alone。

分子生物学词汇(中英文对照表 )

API阿巴卡韦杂质列表

项目报批纯度高于 98%
阿巴卡韦 Abacavir
N/A杂质 E源自impurity E10mg 25mg 50mg 100mg 更大规格请咨询
项目报批纯度高于 98%
扬信医药代理各品种杂质对照品:舒更葡糖钠杂质，达托霉素杂质，依维莫司杂质，他克莫司杂质，阿奇霉素杂质，克拉维酸钾杂质，红霉素杂质，克拉霉素杂质，林可霉素杂质，罗红霉素杂质，克林霉素杂质，恩曲他滨杂质，艾地那非杂质，瑞卢戈利杂质，艾氟康唑杂质等；并提供 COA、NMR、HPLC、MS 等结构确证图谱。
中文名称英文名称
CAS
阿巴卡韦杂质 A
Abacavir impurity A
136470-77-4
阿巴卡韦杂质 B
Abacavir impurity B
136470-79-6
阿巴卡韦杂质 C
Abacavir impurity C
120503-69-7
阿巴卡韦杂质列表集
规格
用途
10mg 25mg 50mg 100mg 更大规格请咨询
项目报批纯度高于 98%
10mg 25mg 50mg 100mg 更大规格请咨询
项目报批纯度高于 98%
10mg 25mg 50mg 100mg 更大规格请咨询
项目报批纯度高于 98%
结构式
阿巴卡韦杂质 D
Abacavir impurity D
1904-98-9
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α-甲基-β-二甲氨基苯丙酮盐酸盐的沸点

α-甲基-β-二甲氨基苯丙酮盐酸盐的沸点
α-甲基-β-二甲氨基苯丙酮盐酸盐，也称为苯巴比妥。

它是一种药物，常用于镇痛和镇静作用，同时也有抗惊厥和抗癫痫的作用。

它属于苯丙酮类药物。

苯巴比妥是一种乙酰胆碱酰化酶抑制剂，能够增加γ-氨基丁酸的释放，从而产生镇静和抗癫痫作用。

苯巴比妥最常使用的剂型是口服片剂和注射液。

它可以治疗各种类型的癫痫，包括强直性癫痫、肌阵挛性癫痫和复杂部分性癫痫。

此外，它还可以用于治疗白日梦、焦虑症、失眠、偏头痛等疾病，但是由于副作用严重，常用的剂量已经有所降低。

苯巴比妥在水中很难溶解，但在酸性环境下会转化为水溶性盐酸盐。

它的沸点为
350-360℃，熔点为175-177℃。

由于它在体内的代谢速度较慢，因此需要小心使用，以免出现过量或中毒的情况。

常见的副作用包括嗜睡、头晕、恶心、呕吐、视力模糊、共济失调、心功能减弱、呼吸循环抑制、肝、肾功能损害等。

总之，苯巴比妥是一种常见的用于治疗癫痫的药物，但需要根据医生的指示和药品说明来使用，并且需要格外小心，以避免可能的副作用和不良反应。

一部分具体重要添加剂中英文

丙酸钙Calcium propionate硅酸钙Calcium silicate硬脂酰乳酸钙Calcium stearoyl lactylate硫酸钙Calcium sulphate小蜡烛树蜡Candelilla wax焦糖色(不加氨生产) Caramel colour, class I焦糖色(亚硫酸铵法) Caramel colour, class II--caustic sulfite process焦糖色(加氨生产) Caramel colour, class Ⅲ--ammonia process焦糖色(亚硫酸铵法) Caramel colour, class Ⅳ--ammonia sulphite process植物炭黑Carbon black二氧化碳Carbon dioxide巴西棕榈蜡Carnauba wax角豆胶(槐豆胶) Carob bean gum卡拉胶Carrageenan红花黄Carthamus yellow辣椒橙Chilli orange甲壳素(几丁质) Chitosan氯气Chlorine二氧化氯Chlorine dioxide叶绿素铜钠盐Chlorophyllins copper complex, sodium and potassium salts叶绿素Chlorophylls胆碱盐Choline salts桂醛Cinnamaldehyde柠檬酸Citric acid柠檬酸和脂肪酸甘油酯Citric and fatty acid esters of glycerol可可壳色Cocao pigment菊花黄浸膏Coreopsis yellow extract越桔红Cowberry red姜黄素Curcumin凝结多糖Curdlanβ-环糊精β-Cyclodextrin脱氢乙酸Dehydroacetic acidβ-葡聚糖酶Dextranase糊精(黄糊精、白糊精、焙炒淀粉) Dextrins, white and yellow roasted starch双乙酰酒石酸单(双)甘油酯Diacetyl tartaric acid esters of mono- and diglycerides硫代二丙酸二月桂酯Dilauryl thiodipropionate焦碳酸二甲酯Dimethyl dicarbonate聚二甲基硅氧烷Dimethyl polysiloxane联苯醚Diphenol oxide5’-鸟苷酸二钾Dipotassium 5’-guanylate磷酸氢二钾Dipotassium hydrogen phosphate5’-鸟苷酸二钠Disodium 5’-guanylate 5’-肌苷酸二钠Disodium 5’-inosinate5’-呈味核苷酸二钠Disodium 5’-ribonucleotides乙二胺四乙酸二钠Disodium ethylene-diamine- tetra-acetate磷酸二氢钠Disodium hydrogen phosphate柠檬酸亚锡二钠Disodium stannous citrate琥珀酸二钠Disodium succinate二淀粉磷酸酯Distarch phosphate十二烷基二甲基溴化胺Dodecyl dimethyl benzyl ammonium bromide高碳醇脂肪酸酯复合物DSA-5酶处理淀粉Enzyme treated starch异抗坏血酸Erythorbic acid (isoascorbic acid)赤藓糖醇Erythritol赤藓红(赤藓红铝色淀) Erythrosine乙氧基喹Ethoxy quin乙基纤维素Ethyl cellulose羟乙基纤维素乙基醚Ethyl hydroxyethyl cellulose对羟基苯甲酸乙酯Ethyl p-hydroxybenzoate坚牢绿Fast green FCF柠檬酸铁铵Ferric ammonium citrate葡糖酸亚铁Ferrous gluconate乳酸亚铁Ferrous lactate甲酸Formic acid富马酸Fumaric acidγ-环糊精栀子蓝Gardenia blue栀子黄Gardenia yellow明胶Gelatin洁冷胶Gellan gum糖化酶制剂Glucoamylase葡萄酸δ内酯Glucono-δ-lactone葡萄糖氧化酶Glucose oxidase (Aspergillus niger, var.)L-谷氨酸L - Glutamic acid五碳双缩醛(戊二醛) Glutaraldehyde甘油Glycerol氢化松香甘油酯Glycerol esters of partially hydrogenated wood rosin松香甘油酯Glycerol ester of wood rosin辛、癸酸甘油酸酯Glyceryl caprylate-caprate葡萄皮红Grape skin extract紫草红Gromwell pigment愈创树脂Guaiac resin鸟苷酸Guanylic acid瓜尔豆胶Guar gum阿拉伯胶Gum arabic六亚甲基四胺Hexamethylene tetramine玫瑰茄红Hibiscetin沙棘黄Hippophae rhamnoides yellow海萝胶Hunori gel盐酸Hydrochloric acid过氧化氢(或过碳酸钠) Hydrogen peroxide羟丙基纤维素Hydroxypropyl cellulose羟丙基二淀粉磷酸酯Hydroxypropyl distarch phosphate 羟丙基甲基纤维素Hydroxypropyl methyl cellulose羟丙基淀粉Hydroxypropyl starch固定化葡萄糖异构酶Immobilized glucose isomerase preparation靛蓝(靛蓝铝色淀) Indigotine5’-肌苷酸5’-Inosinic acid聚乙烯聚呲咯烷酮Insouluble polyvinylpyrrolidone异麦芽糖醇Isomalt柠檬酸异丙酯Isopropyl citrates酸枣色Jujube pigment高粱红Kaoliang colour刺梧桐胶Karaya gum魔芋甘露聚糖Konjac flour紫胶红(虫胶红) Lac dye乳酸Lactic acid乳酸和脂肪酸甘油酯Lactic and fatty acid esters of glycerol乳糖醇LactitolL-半胱氨酸盐酸盐L-Cysteine monohydrochloride卵磷脂Lecithins甘草Licorice root甘草抗氧物Licorice root antioxidant亚麻籽胶(富兰克胶) Linseed gum脂酶LipasesL-α-天冬氨酰-N-(2,2,4,4-四甲基-3-硫化三亚甲基)-D丙氨酰胺(阿力甜) L-α-Aspartyl-N-(2,2,4,4-tetramethyl-3-thietanyl)-D-alanihamide (Alitame)溶菌酶Lysozyme碳酸镁Magnesium carbonate氯化镁Magnesium chloride葡糖酸镁Magnesium gluconate二谷氨酸镁Magnesium glutamate碱式碳酸镁Magnesium hydrogen carbonate氢氧化镁Magnesium hydroxide乳酸镁Magnesium lactate, D, L-氧化镁Magnesium oxide硅酸镁Magnesium silicate (synthetic)玉米黄Maize yellow苹果酸Malic acid, D, L-麦芽糖醇Maltitol (including maltitol syrup)甘露糖醇Mannitol偏酒石酸Metatartaric acid甲基纤维素Methyl cellulose 纤维素甲乙醚Methyl ethyl cellulose微晶纤维素Microcrystalline cellulose微晶腊Microcrystalline wax密蒙黄Mi-mong yellow白色油(液体石蜡) Mineral oil酒石酸、乙酸和脂肪酸混合甘油酯Mixed tartaric, acetic and fatty acid esters of glycerol (mixed)改性大豆磷脂Modified soybean phospholipid红曲红Monascus colors单硬脂酸甘油酯(单、双、三甘油酯)Mono- and diglyceridesL-谷氨酸铵Monoammonium glutamate, L-甘草酸胺Monoammonium glycyrrhizinateL-谷氨酸钾Monopotassium glutamate, L-甘草酸一钾及三钾Monopotassium glycyrrhinate磷酸二氢钠Monosodium dihydrogen phosphateL-谷氨酸钠Monosodium glutamate, L-单淀粉磷酸酯Monostarch phosphate吗啉脂肪酸盐(果蜡) Morpholine fatty acid salt fruit wax 桑椹红Mulberry red天然苋菜红Natural amaranthus redacidulant(additive) 酸化剂；生酸素(添加剂)addition agent 添加剂additive 添加剂；加成的adjunct 添加剂，增补物，辅助原料affix 添加；添加剂，添加物ashless additive 无灰添加剂chemical addition agent 添加剂，化学添加剂chemical additive 添加剂，化学添加剂CAP (食用)色素添加剂申请书(美)CCFA 食品添加剂法规委员会CCFAC食品添加剂和污染物法规委员会CFAA 中国食品添加剂生产应用工业协会CTCSFA 中国食品添加剂标准化技术委员会codex of food chemicals 食品用化学品法规color adjunct 色素添加剂；颜色增补剂intentional additive 有意添加剂，故意(加入的)添加剂intentional food additive 有意食品添加剂，故意(加入的)食品添加剂IFAC 国际食品添加剂委员会JFAA 日本食品添加剂协会JSFA 日本食品添加剂标准JFAA(Japan Food Additives Associtatioin) 日本食品添加剂协会JECFA(Jonint FAO/WHO Expert Committee on Food Additives)食品添加剂联合专家委员会mineral additive 矿物添加剂multifunctional additive 多功能(多效)添加剂negative list (食品添加剂)禁止使用的一览表；否决单neutraceutical [具有预防疾病性质的一类食品添加剂，如β-胡萝卜素]nonnutritive additive 无营养添加剂nutritional additive 营养性添加剂PL(positive list) (食品添加剂的)准许使用名单positive list(PL) (食品添加剂的)准话使用名单Red book 红皮书[指美国FDA1982年出版的食品添加剂安全评价的毒物学原则一书]tableting adjunct 压片添加剂unintentional additives 无意添加剂，非故意(加入的)添加剂unintentional food additive 无意食品添加剂，非故意(加入的)食品添加剂，意外的食品添加剂。

美国细胞治疗产品统一标识共同标准

United States Consensus Standard for the Uniform Labeling of Cellular Therapy Products using ISBT 128Version 1.1.0June 2009United StatesConsensus Standard for theUniform Labeling ofCellular Therapy ProductsUsing ISBT 128Version 1.0.0May 2009Published byICCBBA in collaboration with:AABB, American Society for Blood and Marrow Transplantation (ASBMT), American Society for Apheresis (ASFA), Foundation for the Accreditation of Cellular Therapy (FACT), International Society for Cellular Therapy (ISCT), and the National Marrow DonorProgram (NMDP)ICCBBA, PO Box 11309, San Bernardino, California, USATelephone: 1.909.793.6516Fax: 1.909.793.6214 E-mail: iccbba@Website: WarrantyICCBBA, Inc provides no warranty that the use of ISBT 128 is suitable for any particular purpose and the selection, use, efficiency, and suitability of ISBT 128 is the sole responsibility of the Licensed User.There are no guarantees or warranties attached to this Standard other than that ICCBBA, Inc agrees to furnish registered and licensed end-users with the most up-to-date information available. Successful implementation of this Standard, and use of any accompanying database table(s), depend(s) upon the correct incorporation of the rules and table contents into the software used by or provided to the registered and licensed facility. I CCBBA, Inc makes no other warranties of any kind, whether expressed or implied, including any implied warranty of merchantability or fitness for any particular purpose. Further information can be found at .LiabilityICCBBA, Inc's liability is limited to that specified in the ICCBBA, Inc. License Agreement which is available on the ICCBBA Website. Under no circumstances shall ICCBBA, Inc's liability exceed the current annual license fee, and ICCBBA, Inc will in no circumstances be liable for any damages whatsoever, including without limitation damages for loss of data, business or goodwill, or any other consequential losses of any nature arising from the use of ISBT 128.COPYRIGHT NOTICE AND LICENSING INFORMATIONISBT 128 is not in the public domain and is protected by law. Implementation of ISBT 128 requires the end-user to register with ICCBBA, Inc and to pay an annual license fee. License fees are established by the ICCBBA, Inc Board of Directors to cover the expenses of maintaining and extending ISBT 128, and making available current versions of the documents and database tables that are needed to implement this Standard.This Standard is intended for the use of those implementing ISBT 128, regulatory agencies, and software developers and other manufacturers that support end-users.Although it is made available to anyone wishing to obtain a copy, national “Guidelines” describing its use in a particular country may be an additional source of information for the end-user. If such “Guidelines” exist, they must be consulted because there are options in ISBT 128, and country-specific information pertaining to the particular use of such options will only be found in such “Guidelines.”Any use of this Standard, or the accompanying database tables, by other than registered and licensed facilities, or facilities that have obtained their computer software from a registered and licensed developer, is strictly forbidden. Copying any portion of the Standard, or of any accompanying database table, either in electronic or other format, without express written permission from ICCBBA, Inc is strictly forbidden. Posting of any portion of the Standard, or of any accompanying database table, to any online service by anyone other than ICCBBA, Inc is strictly forbidden.AcknowledgementWe wish to thank the members of the US Consensus Standard – Cellular Therapy Advisory Group for their contributions in the development of this standard. The members were:Sallie Allman (NMDP)Harjunkder Chana (ISCT)Pat Distler (ICCBBA)Mary Beth Fisk (AABB)Adrian Gee (FACT)Asiya Imam (ISCT)William Janssen (ASBMT)Diane Kadidlo (AABB)Mary Grable McLeod (AABB)Fran Rabe (NMDP)Joseph Schwartz (ASFA)Leigh Sims-Poston (ISCT)Phyllis Warkentin (FACT)AABB Staff LiaisonKathy LoperFDA LiaisonEllen LazarusEditorial BoardPaul Ashford, CEng, MBCS, SRCSExecutive Director, ICCBBA Suzanne Butch, MA, MT(ASCP)SBBAnn Arbor, Michigan, USASuzy Grabowski, BA, BB(ASCP)SBBHouston, Texas, USAJørgen Georgsen, MDOdense, DenmarkMario Muon, MDCoimbra, PortugalEditorPat Distler, MS, MT(ASCP)SBBTechnical Director, ICCBBATable of Contents1 INTRODUCTION (10)1.1U NRESOLVED I SSUE (10)1.2R EQUESTING AN E XEMPTION OR A LTERNATIVE TO AN FDA R EQUIREMENT (10)2 BACKGROUND (12)3 ISBT 128 DATA STRUCTURES (13)3.1ISBT128D ATA I DENTIFIERS (13)3.2D ATA C ONTENT (13)4 CONCATENATION (15)5 DELIVERY SYSTEMS (17)5.1L INEAR BAR CODES (C ODE 128 REQUIRED) (17)5.2T WO-DIMENSIONAL BAR CODES (D ATA M ATRIX R ECOMMENDED) (17)5.3RFID (18)5.4EDI M ESSAGES (18)6 ISBT 128 DATA STRUCTURES (19)6.1D ONATION I DENTIFICATION N UMBER (D ATA S TRUCTURE 001) (19)6.1.1 US Specification (20)6.2ABO/R H (D ATA S TRUCTURE 002) (23)6.2.1 US Specification (23)6.3P RODUCT CODE (D ATA S TRUCTURE 003) (27)6.3.1 A-D National or Local Codes (28)6.3.2 US Specification (28)6.4E XPIRATION D ATE AND T IME(D ATA S TRUCTURE 005) (29)6.4.1 US Specification (29)6.5C OLLECTION D ATE (AND T IME)(D ATA S TRUCTURES 006 AND 007) (31)6.5.1 US Specification (32)6.6D ONOR I DENTIFICATION N UMBER (D ATA S TRUCTURE 019) (33)6.6.1 US Specification (33)6.7M ANUFACTURER’S I NFORMATION D ATA S TRUCTURES (34)6.7.1 Container Manufacturer and Catalog Number (Data Structure 017) (34)6.7.2 Container Lot Number (Data Structure 018) (35)6.8C OMPOUND M ESSAGE D ATA S TRUCTURE (023) (36)6.8.1 US Specification (37)6.9P ATIENT D ATE OF B IRTH D ATA S TRUCTURE (024) (38)6.9.1 US Specification (38)6.10P ATIENT I DENTIFICATION N UMBER (025) (39)6.10.1 US Specification (39)6.11I NFECTIOUS M ARKERS (D ATA S TRUCTURE 027) (40)6.11.1 US Specification (41)6.12D ATA S TRUCTURES D EFINED FOR N ATIONAL OR R EGIONAL U SE (42)7 EXAMPLES OF DATA STRUCTURE INFORMATION USE (43)7.1U SE O F F LAG C HARACTERS (D ATA S TRUCTURE 001) (43)7.2U SE OF D IVISION C ODES (D ATA S TRUCTURE 003) (44)7.3U SE OF C OMPOUND M ESSAGE D ATA S TRUCTURE (D ATA S TRUCTURE 023) (45)8 UNIFORM LABELING USING ISBT 128 (46)8.1C ONCEPTS (46)8.2B ASE L ABEL (47)8.2.1 100 mm x 106 mm Base Label (47)8.2.2 Small Base Label (48)8.3F INAL P RODUCT -F ULL L ABEL (49)8.3.1 Upper Left Quadrant (49)8.3.2 Lower Left Quadrant (52)8.3.3 Upper Right Quadrant (55)8.3.4 Lower Right Quadrant (60)8.4F INAL P RODUCT –P ARTIAL L ABELS (63)8.4.1 Minimum information (63)8.4.2 Optional information (63)8.4.3 Use of 2-D labels (64)8.5A TTACHED AND A CCOMPANYING L ABELING (64)9 US TEXT REQUIREMENTS (65)9.1C LASS T EXT (65)9.2M ODIFIER T EXT (65)9.3A TTRIBUTE T EXT (65)9.3.1 Intended Use Group (65)9.3.2 Manipulation Group (66)9.3.3 Cryoprotectant Group (67)9.3.4 Blood Component from Third Party Donor Group (67)9.3.5 Preparation: Other Additives Group (68)9.3.6 Genetically Modified Group (68)9.4D ONATION TYPES (69)10 LABEL EXAMPLES (70)10.1S TANDARD (100 MM BY 100 MM LABELS) (70)10.1.1 Base label (70)10.1.2 Final labels (70)10.2P OOLED P RODUCTS (75)10.3P RODUCTS C OLLECTED U NDER I NVESTIGATIONAL P ROTOCOLS (76)10.3.1 Blinded Studies (76)10.3.2 Non-Blinded Studies (77)10.4P RODUCTS N OT FOR A DMINISTRATION (78)10.5P ARTIAL L ABELS (79)11 DATABASES AND REFERENCE TABLES (83)11.1F ACILITY C ODE D ATABASE (83)11.2P RODUCT C ODE D ATABASE (83)11.3S PECIAL T ESTING (84)11.4M ANUFACTURERS ID (84)11.5S TRUCTURED C OMPOUND M ESSAGES (84)12 GLOSSARY (85)13 ABBREVIATIONS (89)INDEX (91)TABLESTable 1Data Structure 002: Blood Groups [ABO and RhD], Including Optional Type of Donation or Collection Information (25)Table 2 Data Structure 002: Special Messages (26)Table 3 Data Structures 024 and 025: Patient Date of Birth and Patient Identification Number location codes (39)Table 4 Minimum Information on Partial Labels (63)Table 5 Intended Use Group Text (65)Table 6 Manipulation Group Text (66)Table 7 Cryoprotectant Group Text (67)Table 8 Blood Component from Third Party Donor Group Text (67)Table 9 Preparation: Other Additives Group Text (68)Table 10 Genetically Modified Group Text (68)Table 11 Donation Types for Use with Product Code Data Structure (69)Table 12 Abbreviations Used in This Document (89)Table 13 Acceptable Abbreviations for Labeling Products (90)FIGURESFigure 1 Data Structure (13)Figure 2 Example of Data Content on a Label (14)Figure 3 Label Showing Placement of Bar Codes for Concatenation (15)Figure 4 Comparison of 2-D and Linear Bar Codes (17)Figure 5 Text When Expiration is Default Time of 23:59 (30)Figure 6 Product Division Coding (44)Figure 7 Compound Message Example within a Data Matrix (2-D) Symbol (45)Figure 8 Using ISBT 128 to Overcome Language Barriers (46)Figure 9 100 mm x 106 mm Base Label (47)Figure 10 Small Container Base Label (48)Figure 11 Upper Left Quadrant – Confidential Facility (50)Figure 12 Upper Left Quadrant – 351 Products (licensed product, with “Rx Only”) (50)Figure 13 Upper Left Quadrant – 361 Products (51)Figure 14 Upper Left Quadrant - Collection Time Not Needed (51)Figure 15 Upper Left Quadrant with Bar Coded Collection Date/Time (51)Figure 16 Text Size Relationships on Product Label (52)Figure 17 Multiple "Non-Specific" Attributes (53)Figure 18 Divided Product Label (53)Figure 19 Lower Left Quadrant (54)Figure 20 Upper Right Quadrant, No Intended Recipient, Rh Positive (55)Figure 21 ABO/Rh, No Intended Recipient, Rh Negative (55)Figure 22 ABO/Rh Label with Intended Recipient (56)Figure 23 Special Message in Place of ABO/Rh (56)Figure 24 Upper Right Quadrant – Biohazard (57)Figure 25 Upper Right Quadrant - Unrelated Donor (58)Figure 26 Upper Right Quadrant - Related Donor, First or Second Degree (58)Figure 27 Upper Right Quadrant - Related Donor, Other than First or Second Degree (59)Figure 28 Upper Right Quadrant - Autologous Donor, Biohazard (59)Figure 29 Lower Right Quadrant - Unknown Recipient (60)Figure 30 Lower Right Quadrant - Expiration Date Not Bar Coded (61)Figure 31 Lower Right Quadrant - Expiration Date/Time Bar Code and Text (61)Figure 32 Lower Right Quadrant – Default Expiration Time of Midnight (61)Figure 33 Lower Right Quadrant – Autologous Donation (62)Figure 34 Full Collection Label – Unrelated Donor (351 Product) (71)Figure 35 Full Collection Label – Related Donor 1st or 2nd Degree (361 Product) (71)Figure 36 Full Collection Label – Related Donor Other (351 Product) (72)Figure 37 Full Distribution Label (351 Label) (72)Figure 38 Full Distribution Label (361 Product) (73)Figure 39 Sample Product Code Labels (74)Figure 40 Pooled Product Label (75)Figure 41 Investigational Product - Blinded Study (76)Figure 42 Investigational Product – Non-Blinded Study (77)Figure 43 Product Not for Administration (78)Figure 44 48 mm x 76 mm Folded Label (Linear Bar Codes) (79)Figure 45 48 mm x 76 mm Folded Label (2-D bar code) (79)Figure 46 96 mm x 38 mm Folded Label (Linear Bar Codes) (80)Figure 47 96 mm x 38 mm Folded Label (2-D Bar Code) (80)Figure 48 Cryo Vial Label (Linear Bar Codes) (80)Figure 49 Cryo Vial Labels (2-D Bar Codes) (80)Figure 50 Cryopreservation Labels (81)Figure 51 Investigation Products - Partial Labels (82)Figure 52 Illustration of the Terms Eye-Readable Text, Bar Code Text, and Additional Label Text (88)1 IntroductionISBT 128 is an international information standard for blood, tissue, and cellular therapy products. A balance exists between what information on a product label must be strictly standardized in order to achieve the goals of an international standard and what may be left to the discretion of national authorities. These elements are defined in the ISBT 128 Standard Technical Specification.Essentially, the definition of data structures and the placement of bar codes, and their corresponding eye readable text (the text version of the data content of the bar code) that appears immediately beneath a bar code, are strictly standardized. These label elements must appear exactly as specified in the ISBT 128 Standard Technical Specification. Bar code text (the interpretation of the information in the bar code) and other text are generally left to national authorities to define in order to accommodate different languages and regulatory requirements. Additionally, the use of some data structures (e.g., collection date) are nationally defined.The United States Consensus Standard for the Uniform Labeling of Cellular Therapy Products Using ISBT 128 defines for the United States the areas that are the prerogative of national authorities. It must be used in conjunction with the ISBT 128 Standard Technical Specification to design labels for cellular therapy products. Every effort has been made to ensure label designs suggested in this document are in compliance with AABB, FACT, NMDP, and FDA requirements. However, cellular therapy is very much an evolving field and requirements are still being developed. This document will be updated regularly to ensure compliance with new requirements. It is important to note that applicable FDA regulations take precedence over any requirements in this document. For newer products, it would be advisable to confirm labeling requirements with the FDA during the product development process.1.1 Unresolved IssueAt the time of releasing this document, the mechanism(s) for maintaining the confidentiality of the collection facility for products shipped through a Registry has not been determined. At a minimum, the name of the collection facility will not appear in text on the label. Various options to further increase confidentiality are still being explored by the Cellular Therapy Coding and Labeling Advisory Group. When a decision is reached about the labeling of these products, the information will be shared immediately.1.2 Requesting an Exemption or Alternative to an FDARequirementIn some instances, a facility may request an exemption from, or alternative to, an FDA requirement discussed in subpart C or D of 21 CFR 1271 and as illustrated in this document. This might be relevant, for example, in the case where the inclusion of the donor name, when the donor is not a first- or second-degree blood relative, is felt to add a measure of safety for the recipient to prevent mix-ups or improper release. Such a request to the FDA would have to be accompanied by supporting information including a description of the proposed alternativemethod of meeting the regulatory requirements. The regulations for requesting such an exemption are found in Sec. 1271.155.US Consensus Standard for Uniform Labeling of Cellular Therapy Products using ISBT 128 Version ControlChapter,Section orTable inVersion 1.0.0 Chapter,Section orTable inVersion 1.1.0Change Rationale1 8.4.1, Table 4 8.4.1, Table 4 Added intended recipientinformation to requirements forpartial label FACT requirement2 BackgroundISBT 128 coding for cellular therapy products was initially developed during the 1990s. Since that time, the field of cellular therapy has grown dramatically. Recognizing the need to expand and revise the existing coding system, an international advisory group, the Cellular Therapy Coding and Labeling Advisory Group (CTCLAG), was created to review and expand the standard. CTCLAG included representatives from the following organizations: AABB, American Society for Blood and Marrow Transplantation (ASBMT), American Society for Apheresis (ASFA), European Group for Blood and Marrow Transplantation (EBMT), Foundation for the Accreditation of Cellular Therapy (FACT), ICCBBA, International Society of Blood Transfusion (ISBT), International Society for Cellular Therapy (ISCT), ISCT Europe, Joint Accreditation Committee of ISCT and EBMT (JACIE), National Marrow Donor Program (NMDP), and the World Marrow Donor Association (WMDA). The US Food and Drug Administration (FDA) also provided a liaison to work with the group. These representatives developed the terminology and label design for cellular therapy products using ISBT 128 and published it in July 2007 (Ashford P, Distler P, et. al. Standards for the terminology and labeling of cellular therapy products. Transfusion 2007;47:1319-1327).Shortly after the publication of the international standard, a group of individuals representing US organizations met to define those elements left to national discretion. Organizations involved in this effort included AABB, ASBMT, ASFA, FACT, ICCBBA, and NMDP. Again, FDA provided a liaison. A variety of interested vendors also participated in these discussions. The output of that work is this document.3 ISBT 128 Data StructuresIn order for information about cellular therapy products to be transferred electronically (via bar codes, two-dimensional symbols, radio frequency tags, etc.), the information must first be coded into a format that makes electronic transfer easy. Data structures are this format.Data structures define the way in which information is presented in ISBT 128. There are many data structures, only some of which are used on product labels. Examples of data structures which encode information that does not appear on the label include Staff Member Identification Number and Patient Identification Number. Consult the ISBT 128 Standard TechnicalSpecification for a complete list of data structures.Each data structure consists of data identifiers and data content (see Figure 1, Page 13) and is very precisely defined in terms of its length and permissible characters.Figure 1 Data Structure3.1 ISBT 128 Data IdentifiersEach data structure begins with two characters, the data identifier. Data identifiersdefine the type of information the bar code contains.The first character will always be “=” or “&.” By international agreement these characters are reserved for ISBT 128 data structures.The second character distinguishes the type of ISBT 128 information to be conveyed. For example, the two characters “=%” at the beginning of a data structure indicate that the bar code carries information about the ABO/Rh Blood Groups whereas “=<” means the bar code carries information about the product code. Consult the ISBT 128 Standard Technical Specification for more information.3.2 Data ContentData content is the information to be conveyed. For example, the information to becommunicated is that the product is A Rh Positive. This information is encoded to allow it to be efficiently transferred electronically. For example, A Rh Positive is encoded as 6200. Internationally agreed upon reference tables are used to encode and decodeinformation. Some of these reference tables are found in the ISBT 128 StandardTechnical Specification ; others are databases and are found on the ICCBBA Website. Data Identifier Data ContentThe data content appears in an eye-readable form beneath a linear bar code on an ISBT 128 label.Figure 2 Example of Data Content on a LabelData characters are the individual ASCII characters that make up the data content.© 1997–2009 ICCBBA All rights reserved 4 ConcatenationConcatenation is the scanning of two bar codes as a single message (see ISBT 128 Standard Technical Specification for specific details). It requires that the bar codes be placed side by side with the right edge of the bar code on the left within a specific distance (9 mm +/- 4mm) of the left edge of the bar code on the right. The design of a 100 mm by 100 mm ISBT 128 label allows concatenation of two pairs of bar codes: The Donation Identification Number and the ABO/Rh; and the Product Code and the Expiration Date (see Figure 3).Figure 3 Label Showing Placement of Bar Codes for Concatenation1 Donation Identification Number2 ABO/Rh3 Product Code4 ExpirationDateConcatenation can provide better process control. By concatenating pairs of bar codes, it can be assured that information is being read from the same label. In some situations one type of data is a function of another. For example, the expiration date is a function of the product code. In this situation, concatenation may be used to ensure the expiration date/time is changed if the product code is changed.The following is a list of bar code pairs that are commonly concatenated. The list is not exhaustive and it must be emphasized that the Standard allows any pair of ISBT 128 codes to be concatenated. Reference to the corresponding data structure is given in parentheses.•Donation Identification Number (001) and Blood Groups [ABO and RhD] (002);•Product Code (003) and Expiration Date and Time (005);•Donation Identification Number (001) and Product Code (003);•Donation Identification Number (001) and Donor Identification Number (019);•Container Manufacturer and Catalog Number (017) and Container Lot Number (018);•Manufacturer and Catalog Number: Items Other Than Containers (021) and Lot Number: Items Other Than Containers (022):•Patient Birth Date (024) and Patient Hospital Identification Number (025)It is possible to concatenate other pairs of ISBT 128 bar codes and these can be specified within some scanner systems (see Technical Bulletin 5 found on the ICCBBA Website at ).© 1997–2009 ICCBBA All rights reserved 5 Delivery SystemsISBT 128 data structures can be delivered using a number of different technologies including Code 128 bar codes, Electronic Data Interchange (EDI) messages, two-dimensional (2-D) and Reduced Space Symbology (RSS) bar codes, and wireless radio frequency identification transponders (RFID tags). This makes ISBT 128 highly flexible for the unique requirements of cellular therapy products.Rules for uses of ISBT 128 data structures will depend on the delivery mechanism.5.1 Linear bar codes (Code 128 required)Code 128 is the only linear bar code format approved for ISBT 128. The code mustcomply with the industry standard ISO/IEC 15417: 2007(E): Information technology—Automatic identification and data capture techniques—Code 128 bar code symbologyspecification. Additional rules regarding Code 128 bar codes used to deliver ISBT 128 data structures are given in the ISBT 128 Standard Technical Specification.5.2 Two-dimensional bar codes (Data MatrixRecommended)Two-dimensional (2-D) barcodes are very useful when space is limited. In Figure 4, the amount of data in the Data Matrix symbol on the left is equal to that found in the fivelinear bar codes on the right.Figure 4 Comparison of 2-D and Linear Bar Codes© 1997–2009 ICCBBA All rights reserved While many 2-D symbologies are available, ICCBBA recommends Data Matrix (ECC 200) as the 2-D symbology for ISBT 128. The ISO/IEC 16022 Information technology—International symbology specification—Data Matrix should be followed.This does not preclude the use of other symbologies. Use must comply with theappropriate industry standard. Implementers wishing to use other symbologies or novel technologies should contact ICCBBA for advice before proceeding.5.3 RFIDICCBBA has not as yet specified additional requirements for using RFID technologies,but these will be required in order to provide an adequate level of standardization. The ISBT Working Party on Information Technology is currently evaluating issues related to the application of RFID to transfusion medicine. When available, ICCBBA will consider these recommendations for inclusion in the ISBT 128 Standard. In the interim,implementers wishing to use these or any other novel technologies should contactICCBBA for advice before proceeding. Use must comply with the appropriate industrystandard.5.4 EDI MessagesRules for incorporating ISBT 128 data structures into EDI messages will normally bespecified by the body responsible for the message standard. The only restriction placed by ICCBBA is that data identifier characters are a required part of the data field unless the message standard provides an alternative means of unambiguously identifying adata field as containing a specific ISBT 128 data structure. In this case, data identifiers may be omitted.© 1997–2009 ICCBBA All rights reserved 6 ISBT 128 Data StructuresThis document reviews those data structures for which there are US-specific instructions and those data structures which have unique applications for cellular therapy products.6.1 Donation Identification Number (Data Structure001)This data structure provides for the unique identification of any donation or collectionworldwide for a one hundred year period. It has 13 data characters:αppppyynnnnnnwhere:αpppp designates the collection facility or registry. In the case of cord bloodcollections where the processing laboratory is administratively responsiblefor the collection, this number may reflect the processing laboratory;yy designates the year in which the donation or collection was made;nnnnnn is a serial number associated with the donation or collection.Other characters incorporated into this bar code are “flag” characters. These may beused to assist in process control (such as identifying materials used in the collectionprocess — container 1, container 2, tube 1, tube 2, etc. — permitting verification that the correct bar code has been scanned, i.e., the bar code actually attached to container 1,etc.) or to support additional checks for accurate data transmission. Flag characters are printed in a way that identifies their special role, either rotated 90 degrees clockwise (i.e., vertically rather than horizontally) or in “pictorial” or “iconized” format. Flag charactersare the last two characters of the Donation Identification Number data structure. Theyare not part of the Donation Identification Number itself. Flag characters are to be usedin process control; it is not intended that they be recorded as part of the DonationIdentification Number.An additional check character (not the same character that is integral to every Code 128 bar code) calculated on the entire 13 data characters (αppppyynnnnnn) will be printed,enclosed in a box, to the right of the Donation Identification Number (DIN) (see Figure12, page 50). The ISO modulo 37,2 method will be used to compute this checkcharacter. This check character can be used to ensure the accuracy of keyboard dataentry when supported by the appropriate computer software.© 1997–2009 ICCBBA All rights reserved 6.1.1 US SpecificationUsage: The Donation Identification Number is required to be both machine andeye readable.6.1.1.1 Applying the DINUsually, the Donation Identification Number should be the first labelapplied to product containers. It is applied before a product is collectedand should not afterwards be removed or defaced. To prevent potentialerrors, it is recommended that the Donation Identification Number not beover-labeled during processing of the product. However, with extremelysmall labels this may be unavoidable. Should it become necessary toover-label the DIN, mechanisms must be in place to ensure that the DINon the new label matches the DIN on the original label.6.1.1.2 Facility IdentificationCord Blood Facilities: In the situation of cord blood facilities, a processinglab may be administratively responsible for collections and assignment ofDINs. If the DIN is not affixed until the donation reaches the processinglaboratory, it is essential that suitable mechanisms be in place to ensurethe accurate identification and traceability of the product prior to theapplication of the DIN.Registry Collections: In some countries, the DIN may be assigned by theRegistry for collections being shipped through the Registry. In this case,the FIN and the text beneath it will correspond to the Registry. The finaldecision on who (facility or the Registry) will assign the DIN in the US hasnot been made. When the decision is made, a new version of thisdocument will be published6.1.1.3 Data CharactersIn the US the data characters should appear as follows:W0000 08 123456The Donation Identification Number is divided into three parts in its eye-readable form for ease in reading. This should facilitate reading,checking, and recording identification numbers.No special emphasis (e.g., font, size, or color) should be given to anycharacter(s) within the 13-character DIN.© 1997–2009 ICCBBA All rights reserved 。

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