Cell Therapy Products - Regulatory and Manufacturing Strategies - BIO 2005 - for pdf
细胞治疗药典参考目录(Gene and Cell Therapy Products)
1 Chapter Guide: Gene and Cell Therapy ProductsTo return to the Chapter Charts main list, click her e.Universal TestsIdentification•á11ñ USP Reference Standards•á1030ñ Biological Assay Chapters—Overview and Glossary•á1032ñ Design and Development of Biological Assays•á1033ñ Biological Assay Validation•á1034ñ Analysis of Biological Assays•á1044ñ Cryopreservation of Cells•á1102ñ Immunological Test Methods—General Considerations•á1103ñ Immunological Test Methods—Enzyme-Linked Immunosorbent Assay (ELISA)•á1104ñ Immunological Test Methods—Immunoblot Analysis•á1285ñ Preparation of Biological Specimens for Histologic and Immunohistochemical Analysis•á1285.1ñ Hematoxylin and Eosin Staining of Sectioned Tissue for Microscopic ExaminationAssay•á621ñ Chromatography•á1030ñ Biological Assay Chapters—Overview and Glossary•á1032ñ Design and Development of Biological Assays•á1033ñ Biological Assay Validation•á1034ñ Analysis of Biological Assays•á1044ñ Cryopreservation of Cells•á1102ñ Immunological Test Methods—General Considerations•á1103ñ Immunological Test Methods—Enzyme-Linked Immunosorbent Assay (ELISA)•á1430.1ñ Analytical Methodologies Based on Scattering Phenomena—Static Light Scattering Specific Tests1, 2Biocompatibility•á87ñ Biological Reactivity Tests, In Vitro•á88ñ Biological Reactivity Tests, In Vivo•á1031ñ The Biocompatibility of Materials Used in Drug Containers, Medical Devices, and Implants•á1184ñ Sensitization TestingMicrobial/Sterility Issues•á61ñ Microbiological Examination of Nonsterile Products: Microbial Enumeration Tests•á62ñ Microbiological Examination of Nonsterile Products: Tests for Specified Microorganisms•á63ñ Mycoplasma Tests•á71ñ Sterility Tests•á85ñ Bacterial Endotoxins Test•á151ñ Pyrogen Test•á161ñ Medical Devices—Bacterial Endotoxin and Pyrogen Tests•á1050ñ Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin•á1071ñ Rapid Microbial Tests for Release of Sterile Short-Life Products: A Risk-Based Approach•á1085ñ Guidelines on Endotoxins Test•á1113ñ Microbial Characterization, Identification, and Strain Typing•á1116ñ Microbiological Control and Monitoring of Aseptic Processing Environments•á1208ñ Sterility Testing—Validation of Isolator Systems•á1211ñ Sterility Assurance•á1227ñ Validation of Microbial Recovery from Pharmacopeial Articles•á1228ñ Depyrogenation•á1228.1ñ Dry Heat Depyrogenation•á1228.3ñ Depyrogenation by Filtration•á1228.4ñ Depyrogenation by Rinsing•á1228.5ñ Endotoxin Indicators for Depyrogenation•á1229ñ Sterilization of Compendial Articles•á1229.3ñ Monitoring of Bioburden•á1229.4ñ Sterilizing Filtration of Liquids2•á1229.14ñ Sterilization Cycle Development•á1229.15ñ Sterilizing Filtration of Gases•á1229.17ñ Mycoplasma Sterilization•á1229.18ñ Viral Clearance MethodsProduction Issues•á1ñ Injections and Implanted Drug Products (Parenterals)—Product Quality Tests•á90ñ Fetal Bovine Serum—Quality Attributes and Functionality Tests•á92ñ Growth Factors and Cytokines Used in Cell Therapy Manufacturing•á797ñ Pharmaceutical Compounding—Sterile Preparations•á1024ñ Bovine Serum•á1041ñ Biologics•á1043ñ Ancillary Materials for Cell, Gene, and Tissue-Engineered Products•á1044ñ Cryopreservation of Cells•á1046ñ Cell-based Advanced Therapies and Tissue-Based Products•á1047ñ Gene Therapy Products•á1074ñ Excipient Biological Safety Evaluation Guidelines•á1126ñ Nucleic Acid-Based Techniques—Extraction, Detection, and Sequencing•á1127ñ Nucleic Acid-Based Techniques—Amplification•á1229.16ñ Prion Inactivation•á1229.17ñ Mycoplasma Sterilization•á1229.18ñ Viral Clearance Methods•á1237ñ Virology Test Methods•á1285ñ Preparation of Biological Specimens for Histologic and Immunohistochemical Analysis•á1285.1ñ Hematoxylin and Eosin Staining of Sectioned Tissue for Microscopic Examination Product Issues•á381ñ Elastomeric Components in Injectable Pharmaceutical Product Packaging/Delivery Systems•á382ñ Elastomeric Component Functional Suitability in Parenteral Product Packaging/Delivery Systems•á1046ñ Cell-based Advanced Therapies and Tissue-Based Products•á1086ñ Impurities in Drug Substances and Drug Products•á1121ñ Nomenclature•á1151ñ Pharmaceutical Dosage Forms•á1229.17ñ Mycoplasma SterilizationEquipment•á31ñ Volumetric Apparatus•á41ñ Balances•á1051ñ Cleaning Glass Apparatus•á1228.4ñ Depyrogenation by Rinsing•á1229.13ñ Sterilization-in-Place•á1229.15ñ Sterilizing Filtration of Gases•á1229.16ñ Prion Inactivation•á1251ñ Weighing on an Analytical BalanceCharacterization•á111ñ Design and Analysis of Biological Assays•á507ñ Protein Determination Procedures•á621ñ Chromatography•á785ñ Osmolality and Osmolarity•á787ñ Subvisible Particulate Matter in Therapeutic Protein Injections•á788ñ Particulate Matter in Injections•á791ñ pH•á905ñ Uniformity of Dosage Units•á911ñ Viscosity—Capillary Methods•á912ñ Viscosity—Rotational Methods•á913ñ Viscosity—Rolling Ball Method•á1027ñ Flow Cytometry•á1030ñ Biological Assay Chapters—Overview and Glossary•á1032ñ Design and Development of Biological Assays•á1033ñ Biological Assay Validation•á1034ñ Analysis of Biological Assays•á1044ñ Cryopreservation of Cells•á1046ñ Cell-based Advanced Therapies and Tissue-Based Products3•á1048ñ Quality of Biotechnology Products: Analysis of the Expression Construct in Cells Used for Production of r-DNA Derived Protein Products•á1049ñ Quality of Biotechnological Products: Stability Testing of Biotechnological/Biological Products•á1052ñ Biotechnology Derived Articles—Amino Acid Analysis•á1053ñ Capillary Electrophoresis•á1054ñ Biotechnology Derived Articles—Isoelectric Focusing•á1055ñ Biotechnology Derived Articles—Peptide Mapping•á1056ñ Biotechnology Derived Articles—Polyacrylamide Gel Electrophoresis•á1057ñ Biotechnology Derived Articles—Total Protein Assay•á1084ñ Glycoprotein and Glycan Analysis—General Considerations•á1102ñ Immunological Test Methods—General Considerations•á1103ñ Immunological Test Methods—Enzyme-Linked Immunosorbent Assay (ELISA)•á1104ñ Immunological Test Methods—Immunoblot Analysis•á1126ñ Nucleic Acid-Based Techniques—Extraction, Detection, and Sequencing•á1127ñ Nucleic Acid-Based Techniques—Amplification•á1128ñ Nucleic Acid-Based Techniques—Microarray•á1129ñ Nucleic Acid-Based Techniques—Genotyping•á1130ñ Nucleic Acid-Based Techniques—Approaches for Detecting Trace Nucleic Acids (Residual DNA Testing)•á1237ñ Virology Test Methods•á1285ñ Preparation of Biological Specimens for Histologic and Immunohistochemical Analysis•á1285.1ñ Hematoxylin and Eosin Staining of Sectioned Tissue for Microscopic Examination•á1430.1ñ Analytical Methodologies Based on Scattering Phenomena—Static Light Scattering•á1776ñ Image Analysis of Pharmaceutical Systems•á1787ñ Measurement of Subvisible Particulate Matter in Therapeutic Protein Injections•á1788ñ Methods for the Determination of Subvisible Particulate Matter•á1788.1ñ Light Obscuration Method for the Determination of Subvisible Particulate Matter•á1788.2ñ Membrane Microscope Method for the Determination of Subvisible Particulate Matter•á1788.3ñ Flow Imaging Method for the Determination of Subvisible Particulate Matter。
6 FDA细胞与基因治疗制品早期临床试验设计考量行业指南
Guidance for Industry Considerations for the Design ofEarly-Phase Clinical Trials of Cellular and Gene Therapy ProductsDRAFT GUIDANCEThis guidance document is for comment purposes only.Submit one set of either electronic or written comments on this draft guidance by the date provided in the Federal Register notice announcing the availability of the draft guidance. Submit electronic comments to . Submit written comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852. You should identify all comments with the docket number listed in the notice of availability that publishes in the Federal Register.Additional copies of this guidance are available from the Office of Communication, Outreach and Development (OCOD), (HFM-40), 1401 Rockville Pike, Suite 200N, Rockville, MD 20852-1448, or by calling 1-800-835-4709 or 301-827-1800, or e-mail ocod@, or from the Internet at/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guida nces/default.htm.For questions on the content of this guidance, contact OCOD at the phone numbers or e-mail address listed above.U.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Biologics Evaluation and ResearchJuly 2013Table of ContentsI.INTRODUCTION (1)II.BACKGROUND (2)III.FEATURES OF CGT PRODUCTS THAT INFLUENCE CLINICAL TRIAL DESIGN (3)A.Product Characteristics (3)B.Manufacturing Considerations (5)C.Preclinical Considerations (5)IV.CLINICAL TRIAL DESIGN (6)A.Early-Phase Trial Objectives (6)B.Choosing a Study Population (7)C.Control Group and Blinding (10)D.Dose Selection (11)E.Treatment Plan (12)F.Monitoring and Follow-up (14)V.MEETINGS WITH OCTGT (18)VI.GUIDANCE ON SUBMITTING AN IND (18)V.REFERENCES (21)Guidance for IndustryConsiderations for the Design of Early-Phase Clinical Trials ofCellular and Gene Therapy ProductsI.INTRODUCTIONThe Center for Biologics Evaluation and Research (CBER)/Office of Cellular, Tissue, and Gene Therapies (OCTGT) is issuing this guidance to assist sponsors of Investigational New Drug Applications (INDs) for cellular therapy (CT) and gene therapy (GT) products. CT and GT products will be referred to collectively as CGT products. This guidance provides recommendations to assist in designing early-phase clinical trials of CGT products. When this guidance is finalized, we believe it will clarify OCTGT’s current expectations regarding clinical trials in which the primary objectives are the initial assessments of safety, tolerability, or feasibility of administration of investigational products. Such trials include most Phase 1 trials, including the initial introduction of an investigational new drug into humans, and some Phase 2 trials of CGT products.The scope of this guidance is limited to products for which OCTGT has regulatory authority. CGT products within the scope of this guidance meet the definition of “biological product” in section 351(i) of the Public Health Service (PHS) Act (42 U.S.C. 262(i)). This guidance does not apply to those human cells, tissues, and cellular-and tissue-based products (HCT/Ps) regulated solely under section 361 of the PHS Act (42 U.S.C. 264), as described in Title 21 Code of Federal Regulations (CFR) Part 1271 (21 CFR Part 1271), to products regulated as medical devices under the Federal Food, Drug, and Cosmetic Act, or to therapeutic biological products for which the Center for Drug Evaluation and Research (CDER) has regulatory responsibility. There is increasing interest and activity in the development of CGT products because of their potential to address unmet medical needs. This guidance is intended to facilitate such development by providing recommendations regarding selected aspects of the design of early-phase clinical trials of these products. This guidance does not provide detailed information about the preclinical and chemistry, manufacturing, and controls (CMC) components of an IND, as we have previously provided recommendations in connection with these components (Refs. 1, 2)(Ref. 3, when finalized, will reflect our current thinking on that topic). When finalized, this guidance is intended to complement the information in those guidances.FDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the FDA’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in FDA’s guidances means that something is suggested or recommended, but not required.II.BACKGROUNDThe design of early-phase clinical trials of CGT products often differs from the design of clinical trials for other types of pharmaceutical products. Differences in trial design are necessitated by the distinctive features of these products, and also may reflect previous clinical experience. Early experiences with CGT products indicate that some CGT products may pose substantial risks to subjects. These experiences include multi-organ failure and death of a subject who received a GT product for ornithine transcarbamylase deficiency (Ref. 4), late-onset T-cell leukemia in subjects who received a GT product for X-linked severe combined immunodeficiency (X-SCID) (Ref. 5), and development of tumors in the brain and spinal cord of a patient who received intrathecal allogeneic stem cells for ataxia telangiectasia (Ref. 6). These events illustrate that the nature of the risks of CGT products can be different from those typically associated with other types of pharmaceuticals.Features of some CGT products that may contribute to their risks include the potential for prolonged biological activity after a single administration, a high potential for immunogenicity, or the need for relatively invasive procedures to administer the product. Unlike many small molecule pharmaceuticals, the logistics and feasibility of manufacturing a CGT product sometimes influence the design of the clinical trials. In addition, the preclinical data generated for CGT products may not always be as informative as for small molecule pharmaceuticals, particularly since it usually is not feasible to conduct traditional preclinical pharmacokinetic (PK) studies with CGT products.Thus, the design of early-phase clinical trials of CGT products often involves consideration of clinical safety issues, preclinical issues, and CMC issues that are encountered less commonly or not at all in the development of other pharmaceuticals. Section III of this guidance describes some distinctive features of CGT products and their development. Section IV discusses specific aspects of the design of early-phase trials of CGT products, based on consideration of the issues presented in Section III. Therefore, Section IV focuses on elements of trial design that may be different for CGT products than for other types of pharmaceuticals. Finally, Sections V and VI offer brief recommendations regarding IND submissions and meetings with OCTGT.III.FEATURES OF CGT PRODUCTS THAT INFLUENCE CLINICAL TRIAL DESIGNThe design of early-phase clinical trials of CGT products is influenced by their many distinctive features. These features include product characteristics and manufacturing considerations, some of which are unique to CGT products, and these can dictate critical elements of the clinical trial design. In addition, the preclinical studies conducted in support of the clinical trial design are often different from those for other types of products.A.Product Characteristics1.Characteristics of both CT and GT ProductsIn contrast with some well-studied classes of small molecules, there is a relative lackof clinical experience with some CGT products. In the absence of substantialexperience across a broad population, there can be considerable uncertainty about thenature and frequency of safety problems that might be associated with specific typesof CGT products.Also, some CGT products can persist in humans for an extended period after a singleadministration, or have an extended duration of effect even after the product itself isno longer present. The effects of the product might evolve over time (e.g., stem cellsthat proliferate and differentiate). Therefore, evaluation of safety might requireobservation of subjects for a substantial period of time to understand the safetyprofile.CGT products may require surgery or other invasive procedures for delivery to thetarget site. The risks added by the use of an invasive procedure might be a substantialcomponent of the overall risk of treatment, particularly when the product isadministered into a relatively sensitive site. In some cases, product delivery mayrequire use of an investigational device. The use of an existing, legally marketeddevice for administering a CGT product may be investigational, as well, and, asindicated in Section V of this guidance, it is appropriate to discuss clinical issuesrelated to this usage in the pre-IND meeting. Furthermore, when surgery or otherinvasive procedures are required, the training of those responsible for administeringthe product might affect the safety and reliability of the administration procedure, andwe refer you to Section IV.E.4. of this guidance in connection with this issue.Allogeneic CT products, GT vectors, and proteins that might be produced by CGTproducts have the potential to elicit an immune response (immunogenicity).Immunogenicity may be significant in one of the two following ways. First, pre-existing antibodies, or antibodies that develop after administration of the product,could reduce or extinguish a beneficial effect, cause an adverse reaction (e.g., anautoimmune syndrome), or influence safety or efficacy if there are any subsequentadministrations. Second, in patients who have a condition that could be treated with acellular, tissue, or organ transplant in the future, the development of antibodies to an allogeneic CGT product might jeopardize the prospect for successful transplantation.2.Characteristics of CT ProductsCT products have unique complexities due to the dynamic nature of living cells. For example, cells may present a variety of molecules on their membranes and express a variety of factors. These molecules and factors may be affected by the microenvironment and change over time. Cells may differentiate in vivo into undesired cell types. Cells might also develop undesired autonomous functions, such as cells with the characteristics of cardiomyocytes forming a focus that generates electrical activity uncoordinated with the rest of the heart (Ref. 7). Stem cells, which have the potential to develop into a variety of mature tissue types, may undergo transformation and begin forming tumors. In addition, a CGT product may include a variety of cell types, and it may be unclear which cell type or types are responsible for any specific toxicity or therapeutic effect.Another distinctive feature of cells is the ability to migrate. Systemic delivery of CT products may result in cells being distributed to a variety of tissues in the body; even cells delivered to a specific tissue or organ may migrate to unintended locations (Ref.8).The source of the cells or tissue may be the subject to be treated (autologous), or another individual (allogeneic). In some cases, the donor may receive a treatment prior to the harvest of source material. If the donor is also the trial subject, such pre-treatment may add to the overall risk to the subject.3.Characteristics of GT ProductsSeveral characteristics of GT products can influence trial design. For example, expression of a delivered gene may be uncontrolled and interfere with normal function of a critical enzyme, hormone, or other biological process in the recipient. Some GT products are designed to integrate into the DNA of the recipient’s cells to allow for long-term expression of the integrated genes. This genomic alteration could cause activation or inactivation of neighboring genes and give rise to benign or malignant tumors. In addition, GT products present the possibility of viral or bacterial shedding, i.e., excretion/secretion of viral particles or bacteria that could be transmitted to other individuals.4.Characteristics of Gene-Modified Cellular ProductsGene-modified cells, or ex vivo GT products, are products in which a gene is introduced into cells ex vivo, and then the modified cells are administered to the subjects. Products of this type have features, and potential risks, of both GT and CTproducts. Therefore, clinical trial design considerations of both GT and CT products apply to gene-modified cells.B.Manufacturing ConsiderationsThe scientific or logistical complexities of manufacturing CGT products may impose practical limits on the dose of the product that can be produced, or may limit the concentration or volume of product that can be delivered. These factors might therefore restrict the range of doses that are feasible in an early-phase trial. In addition, cell viability and potency may decline rapidly from the time of formulation. Therefore, “fresh” cells that are not cryopreserved may need to be administered within hours of manufacturing.For autologous products or patient-specific allogeneic donor products, unique product lots are manufactured for each subject, and potentially for each dose a subject receives. For such products, the inability to control factors such as subject-to-subject variability can contribute to product complexity. Some CGT products may take several weeks to months to produce. A failure or delay in manufacturing could prevent a subject from being treated as intended.C.Preclinical ConsiderationsPreclinical in vitro and in vivo proof-of-concept (POC), pharmacology, and toxicology studies are conducted to characterize the safety profile of investigational products. These studies also provide the scientific basis to support the conclusion that it is reasonably safe to conduct the proposed clinical investigations (21 CFR 312.23(a)(8)). Due to the diverse biology and scientific issues associated with CGT products, it is important to conduct a careful risk-benefit analysis, performed in the context of the particular clinical indication under study. Preclinical data generated from studies conducted in appropriate animal species and animal models of disease contribute to defining reasonable risk for the investigational CGT product.The extrapolation of a potentially safe and possibly bioactive starting clinical dose from the animal data can depend on various factors, such as the animal models used, the anatomic site of product administration, the biodistribution profile, and any immune response to the administered CGT product. However, traditional PK study designs are generally not feasible for CGT products; thus, such data are not available to guide clinical trial design. Due to various issues, such as species specificity and immunogenicity, extrapolation from a CGT product dose administered in animals to a clinical dose can be less reliable than the customary allometric scaling typically used for small molecule pharmaceuticals. These issues can limit the ability of the preclinical data to guide various aspects of the design of the early-phase clinical trial.For additional information about preclinical program objectives, selection of suitable animal species and animal models of disease, and overall considerations for the design ofpreclinical studies to support early-phase clinical trials, we note that FDA has published the draft guidance entitled “Guidance for Industry: Preclinical Assessment ofInvestigational Cellular and Gene Therapy Products”(dated November 2012) (Ref. 3).This guidance, when finalized, will represent FDA’s current thinking on this topic.IV.CLINICAL TRIAL DESIGNThis section describes specific elements of the design of an early-phase trial for a CGT product. For the most part, this guidance does not discuss elements of the trial design, such as efficacy endpoints and the analysis plan, that are generally the same for CGT products and other types of products. Instead, the discussion focuses on aspects of early-phase clinical trial design that are often different for CGT products than for other types of products.A.Early-Phase Trial ObjectivesThe IND regulations in 21 CFR Part 312 emphasize the importance of the assessment of trial risks and the safeguards for trial subjects. For early-phase clinical trials, especially first-in-human trials, the primary objective should be an evaluation of safety (21 CFR312.21). Safety evaluation includes an assessment of the nature and frequency ofpotential adverse reactions and an estimation of the relationship to dose. For CGTproducts, these early-phase trials often assess not only safety of specific dose levels, but also other issues, such as feasibility of administration and pharmacologic activity.1.Dose ExplorationFor some products and indications, including many uses of CGT products for life-threatening diseases, some toxicities may be expected and acceptable. In thesesituations, a major trial objective might be to identify the maximum tolerated dose(MTD), the highest dose that can be given with acceptable toxicity. To achieve thisobjective, some trials use a well-defined dose-escalation protocol.For some CGT products, toxicity is not expected to be substantial in the predictedtherapeutic range. In this situation, the objective of dose exploration may be todetermine the range of biologically active or optimal effective doses. In some cases,indicators of potential benefit may plateau above a certain dose, so that further doseescalation to reach an MTD may be unnecessary.For many CGT products, there are significant practical limits on the dose of theproduct that can be produced or delivered. In such cases, the trial objectives mayfocus on characterizing the safety profile of the feasible dose or doses, rather thanfinding the MTD.2.Feasibility AssessmentsCGT products sometimes require specialized devices or novel procedures foradministration, customized preparation of products, special handling of products (e.g., very short expiration time), or adjunctive therapy. In these cases, sponsors should consider designing early-phase trials to identify and characterize any technical or logistic issues with manufacturing and administering the product. Such issues may need to be addressed before proceeding with further product development.3.Activity AssessmentsA common secondary objective of early-phase trials is to obtain preliminaryassessments of product activity, using either short-term responses or longer-termoutcomes that could suggest potential for efficacy. For CGT products, theseoutcomes might include specialized measures such as gene expression, cellengraftment, or morphologic alterations, as well as more common measures such as changes in immune function, tumor shrinkage, or physiologic responses of various types.B.Choosing a Study PopulationChoice of the subjects to include in the trial depends on the expected risks and potential benefits, recognizing that there will be considerable uncertainty about those expectations in an early-phase trial. Expected risks may be estimated by the nonclinical data and any previous relevant human experience, but the clinical significance of those risks can depend on the population that receives the product. Similarly, the potential for benefit might depend on the choice of study population. In addition, the choice of study population may affect the ability to detect the product’s activity, either adverse or beneficial. For example, a biomarker that may be indicative of risk or benefit might be more sensitive, meaningful, or interpretable in one population versus another. Some populations may offer advantages (e.g., higher cell numbers or viability) as sources for autologous products. The objective is to select a trial population with an acceptable balance between the anticipated risks and potential benefits for the study subjects, while also achieving the study’s scientific objectives. As discussed below in Section IV.E.5 of this guidance, there are special considerations regarding selection of the study population for patient-specific products.1.Healthy VolunteersStudy of healthy adult volunteers may be reasonable for an early-phase trial forproducts with short duration of action or in a class with a well understood safetyprofile. However, the risks of most CGT products include the possibility of persistent or permanent effects, along with the risks of any invasive procedures necessary for product administration. Therefore, for most CGT trials, the risk-benefit profile is not acceptable for healthy volunteers.2.Disease Stage or SeveritySelection of the most appropriate study population for an early-phase trial involves several considerations, including not only the potential risks, but also the potential benefits and the ability of the study population to provide interpretable data. Subjects with more severe or advanced disease may be more willing to accept the risks of an investigational CGT product, or they may be in a situation where the risks can be more readily justified. Therefore, sponsors sometimes propose to limit enrollment in early-phase trials to subjects with more severe or advanced disease. However, in some cases, selection of patients with less advanced or more moderate disease may be more appropriate.Subjects with minimal reserve of physiological function due to severe or advanced disease may be less able than subjects with less severe disease to tolerate additional loss, which could leave them with no function. For example, the risk of a decrease in visual acuity might be more acceptable in a subject with some visual reserve than in a subject for whom that same decrement might result in loss of all functional vision. Similarly, a risk of pulmonary or cardiovascular toxicity might be more acceptable in a subject with early lung disease than in a subject with more advanced disease and less pulmonary reserve. Thus, the decision about the severity of disease to be studied in an early-phase trial should be made only after considering the estimated nature and magnitude of the risks to the subjects, and the implications of those risks, for various stages or severity of the disease.In addition to considerations regarding risks, assessment of the overall risk-benefit profile should take into account any potential for individual subject benefit. In some situations, such as trials in children or trials that involve high-risk procedures, the prospect for individual benefit may be an important factor in making the risk-benefit assessment for the selected study population. The estimated prospect for benefit may depend on the severity or stage of disease. Although subjects with more severe or advanced disease may have the greatest need for benefit, there can be situations in which a greater potential for benefit might be expected for subjects who are less severely affected. Further, the ability to detect evidence of any benefit could depend on the severity or stage of disease in the study population, and the anticipated effects of the product might be more clearly discernible in subjects with milder disease. This could be a significant consideration if detecting evidence of treatment activity is important to the objectives of the study.Also, the study population should be chosen with consideration of the potential interpretability of study outcomes. Subjects with severe or advanced disease might have confounding adverse events, due to underlying disease, that could make the safety or effectiveness data difficult to interpret. If the ultimate target population is patients with milder disease, a trial in severe or advanced disease could be essentiallyuninformative regarding relevant safety information and might also have a smaller prospect for benefit to offset risks.Thus, while severely affected subjects are often included in early-phase CGT trials, they should not be an automatic choice. Several factors should be taken into account when selecting the appropriate subjects to include in the study for a specific indication. The study population should be chosen in light of the above considerations, and the choice should be discussed and justified in the IND submission.ck of Other Treatment OptionsEarly-phase studies of CGT products typically present significant risks and an uncertain potential for benefits. Therefore, for any specific target indication, early-phase CGT trials sometimes enroll only the subset of subjects who have not had an adequate response to available medical treatment or who have no treatment options. When subjects are selected because no other treatment options are available or tolerable, the trial should include procedures to ensure that the lack of treatment options is adequately evaluated, and the protocol should be designed to capture the pertinent information regarding that evaluation.4.Pediatric SubjectsSome CGT products are developed specifically for pediatric indications. For example, GT products might be intended to correct childhood genetic diseases by replacing a defective or missing gene. CT products might be intended as regenerative medicine to correct congenital deformities or as treatments for genetic diseases, such as hematologic or immunologic disorders, that result in abnormal cellular function. Title 21 CFR Part 50, Subpart D provides additional safeguards to children in clinical investigations. A discussion of the individual provisions of Subpart D is beyond the scope of this guidance, and FDA directs you to other documents for this purpose. (Refs. 9, 10) We highlight the following principles for sponsors who wish to conduct studies of CGT products in pediatric subjects.Before a trial may proceed, Subpart D requires an assessment of the level of risk that the clinical trial would pose to pediatric subjects (minimal risk, slightly more than minimal risk, or greater than minimal risk) and of the outcome or consequence of the trial (the prospect of direct benefit to subjects, the development of generalizable knowledge about the subjects’ disorder or condition, or an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children). Under 21 CFR 50.50, an Institutional Review Board (IRB) is authorized to approve a clinical trial in children only after assessing the risks and outcome of the planned trial, and finding that the trial meets the requirements of Subpart D. In someinstances, an IRB may determine that additional data from studies in animals or inadults are needed, either as safety data or to support a prospect of direct benefit,before the study may be conducted in children consistent with Subpart D.1FDA also has a responsibility to determine whether the study presents anunreasonable risk to subjects (21 CFR 312.42(b)(1)(i) and (b)(2)(i)). When reviewingstudies of CGT products proposed to be conducted in pediatric subjects, we intend toassess the reasonableness of the risks presented within the context of the Subpart Dsafeguards. Accordingly, the investigational plan submitted under 21 CFR 312.23should provide adequate information to permit FDA to make this assessment. Forexample, when the study would present greater than minimal risk to pediatricsubjects, the sponsor should submit to the IND the proof-of-concept data used insupport of the prospect of direct benefit. Evidence of a prospect of direct benefitmight come from studies in animal models of the disease or condition, or from initialclinical studies in adults.C.Control Group and BlindingIn early phases of clinical development, a control group can be useful to facilitateinterpretation of the safety data and provide a comparator for preliminary assessments of activity. A concurrent control group may be particularly valuable for CGT trials indiseases for which the natural history is not well-characterized or for trials that enrollsubjects with a wide range of disease severity. For trials that include a concurrent control group, blinding of subjects, investigators, and assessors can be useful to minimize the risk of bias in the study results.However, some CGT products require invasive procedures for administration or forcollection of starting materials. In such cases, rigorous blinding in early-phase trials may not be desirable if it cannot be done simply and with minimal risk to control subjects.The primary objective for an early-phase trial should be preliminary assessment of safety, for which rigorous inference regarding comparison to placebo is not usually necessary.Conclusions about efficacy, if any are to be made, are at best exploratory. Therefore, in early-phase trials, blinding is generally not as critical as for a confirmatory efficacy trial.For example, an invasive procedure such as cardiac catheterization may be required toadminister the investigational product. Using a similar invasive procedure to administera placebo to the control group for purposes of blinding could represent an unacceptablerisk for an early-phase trial, even if it might be considered for a later confirmatory trial.The risk of the administration procedure is also an aspect of the overall treatment thatneeds to be evaluated, so a noninvasive control group might be more appropriate in early-1 If an IRB cannot conclude that a study meets the requirements of 21 CFR Part 50, specifically 21 CFR 50.51, 50.52, or 50.53, under certain circumstances, the IRB may refer the clinical protocol to FDA’s Office of Pediatric Therapeutics for review under 21 CFR 50.54. For additional information on this issue, please refer to the FDA guidance entitled “Guidance for Clinical Investigators, Institutional Review Boards and Sponsors - Process for Handling Referrals to FDA Under 21 CFR 50.54 - Additional Safeguards for Children in Clinical Investigations”; dated December 2006, /RegulatoryInformation/Guidances/ucm127541.htm。
FDA生物制品评价和研究中心(CBER)组织机构和主要职位清单
Division of Viral Products（病毒制品处）
Deputy Director（副主任）
Laboratory of Hepatitis Viruses（肝炎病毒实验室）
Deputy Director（副主任）
Blood and Plasma Branch（血液和血浆科）
Regulatory Project Management Branch（项目监管科）
Devices Review Branch（器械审查科）
七、OFFICE OF VACCINES RESEARCH AND REVIEW（疫苗研究和审查办公室）
Laboratory of Respiratory & Special Pathogens（呼吸系统和特殊病原体实验室）
Laboratory of Bacterial Toxins（细菌毒素实验室）
Lab. of Enteric & Sexually Transmitted Diseases（肠道和性传播疾病实验室）
Laboratory of Biophysics（生物物理学实验室）
Laboratory of Bacterial Polysaccharides（细菌多糖类实验室）
Laboratory of Mycobacterial Diseases & Cellular Immunology（分歧杆菌疾病和细胞免疫学实验室）
Division of Bacterial, Parasitic & Allergenic Products（细菌、寄生和变应原产品处）
自体细胞治疗Autologous Cellular Therapies
Types of Autologous Products
• • • • • • Hematopoietic progenitor cells Non-hematopoietic progenitor cells Cytotoxic cells - T lymphocytes Regenerative cells - Mesenchymal stromal cells Antigen-presenting cells - Dendritic cells Tumor vaccines – modified autol. tumor or Agloaded APC • Etc.
Pre-prepared, third party, off-the-shelf, easy to store and deliver
Role for Autologous Cellular Therapy?
FDA Definition of Autologous Use
The implantation, transplantation, infusion, or transfer of human cells or tissue back into the individual from whom the cells or tissue were recovered
21 CFR 1271.3
Advantages of Autologous Products
• The donor is immediately available • No HLA matching is required
– Reduced rejection – Reduced Graft-versus-Host disease but no Graftversus-Disease effect (alloreactivity) – No immunosuppression required
Stem Cell Biology and Regenerative Medicine
Stem Cell Biology and Regenerative Medicine Stem cell biology and regenerative medicine are fields that have gained significant attention in recent years. Stem cells are unique cells that have the ability to differentiate into various cell types and have the potential to regenerate damaged tissues. The field of regenerative medicine aims to use stem cells to replace or repair damaged tissues and organs in the body. While the potential benefits of stem cell research and regenerative medicine are vast, there are also ethical concerns and challenges that need to be addressed.One of the main ethical concerns surrounding stem cell research is the use of embryonic stem cells. Embryonic stem cells are derived from embryos that are typically discarded after in vitro fertilization. Some individuals argue that using these embryos for research purposes is unethical and violates the sanctity of human life. Others argue that the potential benefits of stem cell research outweigh these concerns and that the embryos used for research would have been discarded anyway.Another ethical concern is the potential for the commercialization of stem cells. As stem cell research continues to advance, there is a growing market for stem cell therapies. Some companies are already offering stem cell treatments for various conditions, despite the lack of sufficient clinical trials and regulatory oversight. This raises concerns about the safety and efficacy of these treatments, as well as the potential for exploitation of vulnerable patients.In addition to ethical concerns, there are also scientific and technical challenges that need to be addressed in the field of regenerative medicine. One major challenge is the ability to control the differentiation of stem cells into specific cell types. While stem cells have the potential to differentiate into any cell type, directing them to differentiate into a specific cell type can be difficult. This can limit the effectiveness of stem cell therapies and increase the risk of complications.Another challenge is the potential for immune rejection of transplanted stem cells. Since stem cells can differentiate into any cell type, they can potentially be used to replace damaged tissues and organs. However, the immune system may recognize thesetransplanted cells as foreign and mount an immune response, leading to rejection of the transplanted cells. This can limit the effectiveness of stem cell therapies and increase the risk of complications.Despite these challenges, the potential benefits of stem cell research and regenerative medicine are vast. Stem cells have the potential to revolutionize the treatment of a wide range of conditions, including cancer, heart disease, and neurological disorders. Stem cell therapies could also reduce the need for organ transplants and improve the quality of life for millions of people around the world.In conclusion, stem cell biology and regenerative medicine are fields that hold great promise for the future of medicine. While there are ethical concerns and scientific challenges that need to be addressed, the potential benefits of these fields are vast. As research in these areas continues to advance, it is important to ensure that ethical considerations are taken into account and that the safety and efficacy of stem cell therapies are rigorously tested. With careful consideration and continued research, stem cell biology and regenerative medicine could transform the way we treat a wide range of conditions and improve the lives of millions of people around the world.。
胰岛移植即刻经血液介导的炎症反应应对策略
第14卷 第3期2023年5月Vol. 14 No.3May 2023器官移植Organ Transplantation ·移植前沿·胰岛移植即刻经血液介导的炎症反应应对策略杨玉伟 张婷 李万里 陈继冰 高宏君【摘要】 胰岛移植作为治疗1型糖尿病和终末期2型糖尿病的有效手段，可以使患者获得较好的血糖控制能力。
即刻经血液介导的炎症反应（IBMIR ）是胰岛移植早期出现的非特异性炎症反应，发生后可迅速出现凝血级联和补体系统激活、炎症细胞聚集等，造成大量移植胰岛丢失，严重影响胰岛移植的疗效。
如何减轻IBMIR 对胰岛造成损伤是目前胰岛移植的研究热点，临床推荐的治疗胰岛移植IBMIR 的药物有肝素和肿瘤坏死因子-α抑制剂依那西普。
新近研究表明多种方法和药物可以减轻IBMIR 对胰岛的损伤，本文就这些临床研究成果和临床前研究成果进行综述，以期为胰岛移植IBMIR 的应对提供参考。
【关键词】 胰岛移植；糖尿病；即刻经血液介导的炎症反应（IBMIR ）；炎症反应；胰岛丢失；胰岛保护；胰岛封装；凝血【中图分类号】 R617，R587 【文献标志码】A 【文章编号】 1674-7445（2023）03-0005-06【Abstract 】 As an effective procedure for type 1 diabetes mellitus and end-stage type 2 diabetes mellitus, islet transplantation could enable those patients to obtain proper control of blood glucose levels. Instant blood-mediated inflammatory reaction (IBMIR) is a nonspecific inflammation during early stage after islet transplantation. After IBMIR occurs, coagulation cascade, complement system activation and inflammatory cell aggregation may be immediately provoked, leading to loss of a large quantity of transplant islets, which severely affects clinical efficacy of islet transplantation. How to alleviate the islet damage caused by IBMIR is a hot topic in islet transplantation. Heparin and etanercept, an inhibitor of tumor necrosis factor-α, are recommended as drugs for treating IBMIR following islet transplantation. Recent studies have demonstrated that multiple approaches and drugs may be adopted to mitigate the damage caused by IBMIR to the islets. In this article, the findings in clinical and preclinical researches were reviewed, aiming to provide reference for the management of IBMIR after islet transplantation.【Key words 】 Islet transplantation; Diabetes mellitus; Instant blood-mediated inflammatory reaction (IBMIR); Inflammation; Islet loss; Islet protection; Islet encapsulation; CoagulationTherapeutic strategy for instant blood-mediated inflammatory reaction after islet transplantation Yang Yuwei *, Zhang Ting, Li Wanli, Chen Jibing, Gao Hongjun.*Graduate School of Guangxi University of Chinese Medicine, Nanning 530001, China Correspondingauthor:GaoHongjun,Email:***************DOI: 10.3969/j.issn.1674-7445.2023.03.005基金项目：广西科技基地和人才专项（桂科AD22035122）；广西研究生教育创新计划项目（YCSW2022355、YCXJ2021091）作者单位：530001 南宁，广西中医药大学研究生院（杨玉伟、李万里）；广西中医药大学附属瑞康医院（张婷、陈继冰、高宏君）作者简介：杨玉伟（ORCID ：0009-0000-2017-8883），硕士研究生，住院医师，研究方向为器官移植，Email ：*****************通信作者：高宏君（ORCID ：0000-0003-1451-0725），博士，主任医师，研究方向器官移植与胰岛移植，Email ：***************对于疗效欠佳的1型糖尿病和伴有胰岛功能衰竭的2型糖尿病，胰岛移植已成为理想的治疗方法。
干细胞扩增的原理
干细胞扩增的原理Stem cell expansion is an essential process in regenerative medicine and tissue engineering. 干细胞扩增是再生医学与组织工程中至关重要的过程。
It involves the growth and multiplication of stem cells in culture to obtain a larger population of cells for various applications. 它涉及在培养中的干细胞的生长和增殖，以获得更多细胞用于不同的应用。
The principle behind stem cell expansion lies in the ability of stem cells to self-renew and differentiate into specialized cell types. 干细胞扩增的原理在于干细胞具有自我更新和分化成特定细胞类型的能力。
There are several methods and techniques used for stem cell expansion, each with its advantages and limitations. 干细胞扩增有几种方法和技术，每种都有其优点和局限性。
One of the primary methods for stem cell expansion is the use of growth factors and cytokines. 干细胞扩增的主要方法之一是使用生长因子和细胞因子。
These are signaling molecules that regulate the growth and differentiation of stem cells in culture. 这些是在培养中调节干细胞生长和分化的信号分子。
CAR-T细胞治疗产品中复制型病毒的风险分析及控制
中 图分 类号 ： Ｒ３９２—３３ 文献标 识码 ：Ａ 文章 编号 ：１００２—７７７７（２０１８）０７—０８７９—０７ ｄｏｉ：１０．１６１５３￣．１００２—７７７７．２０１８．０７．００６
８８０
中国药 事 ２０１８年 ７月 第 ３２卷 第 ７期
ｏｆ ｒｅｐｌｉｃａｔｉｏｎ ｃｏｍ ｐｅｔｅｎｔ ｖｉｒｕｓ ｄｅｔｅｃｔｉｏｎ ａｎｄ ｔｈｅ ｄｅｔｅｃｔｉｏｎ ｍｅｔｈｏｄｓ，ａｎｄ ｐｕｔｔｉｎｇ ｆｏｒｗａｒｄ ｔｈｅ ｃｏｎｓｉｄｅｒａｔｉｏｎ ｆｏｒ ｃｏｎｔｒｏｌｌｉｎｇ ＲＣＲ／ＲＣＬ ｉｎ ｔｈｅ ｐｒｏｃｅｓｓ ｏｆ ＣＡＲ—Ｔ ｃｅｌｌ ｐｒｏｄｕｃｔｉｏｎ ｆ ｏｒ ｒｅｆｅｒｅｎｃｅ ｂｙ ＣＡＲ—Ｔ ｃｅｌｌ ｐｒｏｄｕｃｔ ｄｅｖｅｌｏｐｅｒｓ．
摘 要 ：嵌 合 抗 原 受体Ｔ细胞 （ＣＡＲ—Ｔ细 胞 ）因其 在 血 液肿 瘤 中的显 著疗 效 已成 为 肿瘤 免疫 治 疗领域 中的 国际研 究新热点，成为肿瘤治愈新的希望。 目前 ，在ＣＡＲ—Ｔ细胞产品的生产中，通常是利用逆转录病毒 载体或慢病毒载体将ＣＡＲ基 因高效地导入Ｔ细胞 中，但在使用这些病毒载体的同时也带来了ＣＡＲ—Ｔ产品 污染复制型逆转录病毒 （ＲＣＲ ）或复制型慢病毒 （ＲＣＬ）的潜在风险。虽然随着病毒载体设计及生产体 系的不 断 改进 ，这种 风 险 已大 大降低 ，但 仍 不 能 完全排 除 。 因此 ，监 管机 构要 求对 于临床 使 用 的慢病 毒 或逆 转 录病毒 载体 、转 导 的ＣＡＲ—Ｔ细胞 产品 以及 患者 均要进 行 复制 型病 毒 的检 测 。本 文主要 通过 分析 复 制型病毒污染检测的必要性、降低复制型病毒污染风险的措施、复制型病毒检测的阶段 以及检测方法等 方 面 ，提 出在 ＣＡＲ—Ｔ细胞 生 产过程 中控 制ＲＣＲ／ＲＣＬ的策略 ，以供 ｃＡＲ—Ｔ细胞 产 品研 发 者参 考 。
基因修饰细胞治疗产品及欧盟监管法规介绍
修饰细胞的质量，非临床研究，安全性和功效要求。质
EMA 对基因修饰细胞治疗产品的监管法规主要包括
量部分主要针对目标细胞群体的基因修饰过程和基因修 《人体细胞药物产品指南》（EMEA/CHMP/410869/2006）、
饰的细胞产品工业化的质量要求。非临床部分涉及评估 《含基因修饰细胞药品的质量、非临床和临床研究指南》
这次修订是基于 EMA 在包括 CAR-T 细胞、诱导性 多能干细胞和基因编辑等新技术方面的经验。EMA 在新 指南中表示 ：“EMA 已经认识到，这是一个不断发展的 领域，该指南应可以在合适的情况下应用于该领域的任
上海医药 2021年 第42卷 第13期 （7月上）
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·专家论坛·
何新产品。”
此外，人源细胞的捐赠、采购和测试必须符合指令
CAR-T 细胞免疫治疗技术的开创和成功应用为肿瘤 的治疗甚至治愈带来了希望。为了提高 CAR-T 细胞免疫 疗法的特异性、安全性和通用性，使用基因编辑技术改 造 CAR-T 细胞已变得至关重要。原代免疫细胞由于增殖 能力有限一定程度上降低了基因编辑效率。
1.2.2 TCR-T
间 充 质 干 细 胞（MSC） 以 及 多 能 干 细 胞， 如 人 类 胚 胎 干细胞（hESC）和诱导多能干细胞（iPSCs）。ESCs 和 iPSCs 具有无限增殖和分化成其他类型细胞的能力。将 ESCs 或 iPSCs 分化为 NK 细胞、巨噬细胞或 T 细胞等免 疫细胞可以为癌症的细胞免疫治疗提供不竭的细胞来源。 随着基因修饰技术的出现，经过改造的干细胞衍生物作 为新一代干细胞，其功能、特异性和反应性都比天然细 胞更好。拥有无限增殖能力和 T 细胞分化能力的多能干 细胞（PSCs），尤其是不涉及伦理问题的 iPSCs 成为基 因修饰和无限产生 T 细胞的理想选择 [4]。
natural killer cell therapy
Prospects for adoptive natural killer cell therapyAbstract: Natural killer (NK) cells are cytotoxic and cytokine-producing lymphocytes, involved in the immune defense against viral infections and tumors. Their effector function is regulated by cytokines and membrane associate receptors able to inhibit or activate cellular programs. NK cells are able to discriminate self from non-self through MHC class I-binding inhibitory receptor. When NK cells are faced with allogeneic targets which do not express the inhibiting class I ligand(s), NK cells may mediate alloreactions (―missing self‖recognition). NK cells are emerging to apply as therapeutic agents against many types of cancers. NK cell alloreactivity has been demonstrated to enhanced control of acute myeloid leukemia (AML) relapse and no risk of graft-versus-host disease (GVHD) in HLA haplotype-mismatched hematopoietic transplantation, and have been explored as tools for adoptive immunotherapy for poor prognosis AML patients. Future larger clinical trials are required to determine the usefulness of NK cells as adoptive immunortherapy, optimal NK cell doses, and timing of administration. It is hoped that allogeneic NK cell infusions will become a safe and effective form of adoptive immunotherapy of cancer.Introduction: Natural killer (NK) cells comprise 10-20% of human peripheral blood lymphocytes and have the morphology of large granular lymphocytes defined by the expression of CD56 or CD16 and the absence of CD3[1]. They play a role in innate immune system by defending against invading infectious pathogens and malignant transformation through elaboration of cytokines and cytolytic activity [2, 3]. Natural Killer (NK) cells are important effector cells in the immune system where they act as a bridge between the innate and acquired immune responses [4]. NK cells have some surface markers in common with T cells, and they are also functionally similar to cytotoxic T lymphocytes (CTL's). Like CTL's, NK cells are particularly important in the killing of tumor cells. Unlike CTL's, however, the killing by NK cells is nonspecific, they do not need to recognize antigen/MHC on the target cell.NK cells recognize targetsUnlike T cells and B cells, NK cells are preprogrammed to recognize their targets and have no need to develop into a clone of identical cells. NK cells mainly recognize their target cells via their own receptors that bind to MHC class I or class I-like molecules or targets that regulate whether NK cells will be activated or inhibited[5,6]. The activity of NK cells is determined by a delicate balance between positive signals that initiate NK effector function and negative signals that prevent cytolysis through activating and inhibitory receptors. There are several NK receptors identified: killer cell inhibitory receptors (KIRs), C-lectins, natural cytotoxicity receptors (NCR), and other activatingco-receptors. KIRs (Killer-cell Immunoglobulin-like Receptors) are type I membrane glycoproteins belonging to the immunoglobulin superfamily, coded for by a family of genes located on chromosome 19 which produce at least 12 different proteins, each of which presumably has allelic specificity for HLA-A, -B, or -C[7,8]. KIRs bind to alpha1 and alpha2 domains of class I MHC. Inhibitory KIRs have long cytoplasmic tails containing 2 ITIM motifs whereas activating KIRs have short cytoplasmic tails, lack ITIMs, and possess charged transmembrane amino acid residues which allow association with DAP12. DAP12 is a disulfide-bonded homodomer containing an immunoreceptor tyrosine-based activation motif (ITAM). Once DAP12 is phosphorylated by protein tyrosine kinases, it recruits ZAP70 and syk protein tyrosine kinase for activating signal transduction [9].NKG2D is the best characterized activating receptor described on NK cells. It is a member of the C-type lectin family expressed by most human NK cells, encoded within the NK gene complex on human chromosome 12[10, 11]. Its ligands are MICA and MICB, which are encoded by a distinct family of genes stationed along the entire MHC class I region on human chromosome 6, and certain cytomegalovirus proteins[12, 13]. MICA and MICB have conserved alpha1 and alpha2 domains but do not require ß2 microglobulin or peptide for stable surface expression[14]. MICA and MICB expression is induced by cellular stress or neoplastic transformation. MICA and MICB are generally either absent or present at low levels on normal cells, but their expression is up-regulated on many human primary tumors of epithelial origin and leukemic cells [15, 16].The Natural cytotoxic receptors (NCR) are NK activating receptors without apparent specificity for MHC class I molecules. NCRs, which include NKp30, NKp44, NKp46, NKp80 are all members of the immunoglobulin superfamily, and with the exception of NKp80 (also expressed on a T cell subset) are selectively expressed on human NK cells [16, 17]. The ligands for NKp44 and NKp46 are the influenza and sendai virus hemagglutinins. They do not themselves have signal transducing capability. Their cytoplasmic domain lacks ITAMs but binds to various adaptor signaling molecules via a charged residue in the transmembrane domain: NKp30 associates with the CD3 zeta chain; NKp44 associates with DAP12; NKp46 is coupled to the CD3 zeta chain and FCRIgamma chain, both of which are able to recruit ZAP-70 and syk protein tyrosine kinases [18, 19, 20].NK p46 and NKp30 precisely identify resting and activated NK cells, while NKp44 is expressed only by activated NK cells. This may explain the higher levels of cytolytic activity against tumors displayed by NK cells that had been cultured in IL-2 [21].There are other NK co-receptors which appear to activate NK cells after initial NKR binding, and they include CD16, CD2, LFA-1, NKp80, and CD40 ligand [22]. CD16 is important for NK cell-mediated ADCC and cytokine production. Src-family and Syk-family protein tyrosine kinases are involved in CD16 signaling [23].NK cells can be activated by various cytokines such asinterferon-γ (IFN-γ), IL-2, IL-12, IL-15, or IL-18. This is probably related to the change in cytokine environment that can induce specific molecules on both NK as well as target cells to support cell adhesion and to mediate cytolysis of NK cell-resistant targets [24].Autologous NK cell therapyNatural killer (NK) cells are well known for their ability to kill certain tumors. An NK cell kills a target cell by releasing perforin and granzymes which damages the target cell membrane leading to death [25]. NK cells also cause death by inducing apoptosis in the target. Based in laboratory observations that IL-2 enhances NK cell activity, Rosenberg et al. reported the first clinical trial in humans [26]. Subsequent studies showed that nearly 20-30% response rates were seen when IL-2 and LAK (lymphokine-activated killer) cells were administered to patients with metastatic cancers, including renal cell carcinoma, melanoma, colorectal cancer, lung adenocarcinoma, and non-Hodgkin lymphoma[27,28,29]. But therapy with high amounts of IL-2 is associated with toxicity [26]. Although the regimen of low-dose IL-2 was well tolerated in patients with leukemia and solid tumors [30, 31], the clinical results were disappointing. There were on consistent efficacy of autologous NK-cell therapy could be detected in cancer patients when compared with cohorts of matched controls [32]. The efficacy of IL-2 administration targeting the in vivo expansion and activation of NK cells remains uncertain. The low-dose IL-2 may activate regulatory T cells, which may promote tolerance and hamper NK cell activity [33]. Taking all of these studies into account, although clinical responses can occur, it has been difficult to convincingly demonstrate a clinical benefit of autologous NK-cell therapy for most tumors.Autologous NK cells are self-tolerant through MHC class I-binding inhibitory receptors. In an autologous setting, the NK-mediated lysis of self-cells occurs only when the latter have lost HLA class I molecules. Tumor KIR ligands are always matched to NK cell KIR, autologous NK cells would be inhibited by MHC class I-expressing tumors, even in the presence of activating ligands [34]. The inactivation of NK cells by self-HLA molecules might be a mechanism permitting tumor cells to evade NK cell-mediated immunity. This may in part explain the failure of adoptively transfused autologous NK [35] or LAK cells to mediate antitumor effects against most metastatic solid tumors [27].NK cell alloreactivity on hematopoietic transplantationAllogeneic haematopoietic cell transplantation cures leukemia through alloreactions mediated by donor T cells in the graft that promote engraftment, eradicate leukemia and reconstitute immunity [36]. Unfortunately, they also mediate graft-versus-host disease (GVHD). The potential benefit of NK cells has been demonstrated in allogeneic hematopoietic cell transplantation. NK cells can detect the absence of self epitopes. In an allogeneic setting, NK cells sense the missing expression of self-MHC class I molecules and mediatealloreactions (―missing self‖ recognition) [37]. NK cells exhibit alloreactions through KIRs as inhibitory receptors for self-HLA class I. [38-42]. Inhibitory KIRs recognize HLA class I allotypes by amino acids. KIR2DL1 recognizes HLA-C alleles characterized by a Lys80 residue (HLA-Cw4 and related, ―group 2‖ alleles). KIR2DL2 and KIR2DL3 recognize HLA-C with an Asn80 residue (HLA-Cw3 and related, ―group1‖ alleles). KIR3DL1 is the receptor for HLA-B alleles sharing the Bw4 supertypic specificity [38, 43]. NK cell alloreactions are generated only between individuals who are ―KIR ligand-mismatched‖. KIRs are polymorphic so that the repertoire of KIR differs from person to person.Murine transplant model illustrated the potential beneficial role of NK cells in haploidentical stem cell transplant[44-46] probably through the following theoretical mechanisms: (1) targeting host T lymphocytes that may improve engraftment of the MHC-mismatched bone marrow; (2) targeting host dendritic cells resulting in decrease antigen presentation by host dendritic cells and hence preventing from T cell-mediated GVHD; (3) targeting leukemic cells which may initiate GVL effect and decrease relapse; and (4) improving immune reconstitution which may decrease the risk of opportunistic infections [47-49].In the hybrid mouse transplant model, alloreactive NK cells did not themselves cause GVHD, which indicates that tissues may lack ligands for activating NK cell receptors.Ruggeri et al [46, 50], reported surprisingly good clinical results that high-risk AML patients received haploidentical transplants from NK-alloreactive had a significantly lower relapse rate. They also reported that donor-versus-recipient alloreactive NK cell clones were isolated prior to transplantation in all tested donor-recipient pairs KIR epitope-mismatched in the GVH direction [51]. Following transplantation of T-cell-depleted stem cells, the engrafted stem cells quickly gave rise to an NK cell wave which reproduced the same NK repertoire as was originally present in the donor, including the alloreactive NK clones. This occurred without GVHD. Importantly, the donor repertoire became ―educated‖to the host MHC and the alloreactive NK clones were no longer found beyond 4 months after transplantation [51]. An updated analysis of 93 advanced AML stage AML patients transplanted from haploidentical donors from 1993 to 2003, confirms that grafts from NK alloreactive donors enhance engraftment, indeed appear to protect from GVHD, control leukemia relapse and improve disease-free survival [52].Some results from retrospective studies have shown no advantage of transplantation from unrelated donors with the potential to exert NK cell alloreactivity [53-55].Common to these reports lacked functional assessment of donor-versus-recipient NK cell alloreactivity, heterogeneous transplant protocols which differ from the haploidentical, immunosuppressive therapy, and infused smaller stem cell doses. However, other studies have documented an increased GVL effect in transplants from unrelated donors [56-60]. The Eurocord-Netcord and Acute Leukemia Working Party of the EBMT assessed NK cell alloreactivity in unrelated cord blood transplantation in 218 acuteleukemia patients and found it was associated with a significantly reduced incidence of relapse (P = 0.05) and better leukemia-free survival (73% versus 38%, P = 0.0016). (R Willemze et al., Van Bekkum Award, Annual EBMT Meeting. Florence, Italy, 30 March–2 April 2008) [43].Interestingly, one recent study demonstrated NK cell alloreactivity provided a dramatic GVL effect to protect from leukemia relapse in children who received transplantation from maternal donors (as opposed to any other donor-recipient family relationship) [61]. The reason probably is fetal antigens are exposured to maternal immune system during pregnancy and ensuing memory T-cell immunity against the child‘s paternal HLA haplotype.Donor NK cell adoptive immunotherapyDonor lymphocyte infusion is a promising therapy for leukemia patients relapsing after allogeneic transplantation. However, it is limited by the complication such as acute and chronic GVHD, pancytopenia, which has been associated with significant morbidity and mortality. Some groups have studied the preparation and infusion of donor NK lymphocytes to consolidate engraftment and induce GVL effects in patients after hematopoitic stem cell transplantation (HSCT). A recent study demonstrate that adoptively transferred human NK cells derived from haploidentical related donors can be expanded in vivo in a nontransplantation setting [62]. Expansion was induced only by a high-dose cyclophosphamide plus fludarabine preparative regimen, which caused lymphopenia and high endogenous concentrations of interleukin 15(IL-15). IL-15 is essential for in vivo expansion and survival of NK cells [63]. The study shows that in vivo NK cell infusion/expansion does not cause GVHD.5 of 19 poor prognosis AML patients achieved complete remission and, interestingly, 4/5 remissions occurred when KIR ligand mismatched (i.e. potentially NK cell alloreactive) donors were used. Larger clinical trials are required to determine the usefulness of NK cells as adoptive immunortherapy, optimal NK cell doses, and timing of administration. It is hoped that allogeneic NK cell infusions will become a safe and effective form of adoptive immunotherapy of cancer.ConclusionNK cell is a critical component of tumor-mediated cytotoxicity. NK cell function is regulated by competing signals mediated through inhibitory and activating receptors. 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常用的医学英语用词
1. pausimenia: 绝经2. presumptive [prɪ'zʌm(p)tɪv] adj. 假定的；根据推定的3. Postgraduate Degree: 硕士学位| 研究生学位4. mycophenolate 麦考酚酯，霉酚酸酯(免疫抑制剂)5. cold intolerance: 寒冷耐受不良| 严寒耐受不良6. gastrointestinal disorders: 肠胃功能紊乱7. Crohn's disease 节段性回肠炎；克罗恩氏病8. hysterectomy [,hɪstə'rektəmɪ] n. [妇产] 子宫切除9. shingle ['ʃɪŋg(ə)lz] n. 木瓦；屋顶板Chongqing Publishing Group hangs out shingle 重庆出版集团挂牌10. birth control: 生育控制| 计划生育| 节育11. endocrine ['endə(ʊ)kraɪn] disorder 内分泌紊乱12. Diabetes mellitus type: 型糖尿病mellitus蜜剂13. Metabolism [mə'tæbə.lɪz(ə)m] and Nutrition: 代谢和营养14. vascular disorders: 血管疾病| 脑血管疾病| 心血管疾病15. hemicolectomy [,hemikə'lektəmi] n. 部分结肠切除术colectomy 结肠切除术；hemi 半16. aseptic [e'septɪk] meningitis [.menɪn'dʒaɪtɪs] 无菌性脑膜炎17. hair loss 脱发18. heartburn ['hɑːtbɜːn] n. 心痛，妒忌；[内科] 胃灼热；烧心19. mammogram ['mæməgræm] n. 乳房X线照片20. colonoscopy [,kəʊlə'nɒskəpɪ] n. 结肠镜检查21. aseptic [eɪ'septɪk] n. [助剂] 防腐剂；adj. 无菌的；防腐性的。
开启片剂完整性的窗户(中英文对照)
开启片剂完整性的窗户日本东芝公司，剑桥大学摘要：由日本东芝公司和剑桥大学合作成立的公司向《医药技术》解释了FDA支持的技术如何在不损坏片剂的情况下测定其完整性。
太赫脉冲成像的一个应用是检查肠溶制剂的完整性，以确保它们在到达肠溶之前不会溶解。
关键词：片剂完整性，太赫脉冲成像。
能够检测片剂的结构完整性和化学成分而无需将它们打碎的一种技术，已经通过了概念验证阶段，正在进行法规申请。
由英国私募Teraview公司研发并且以太赫光（介于无线电波和光波之间）为基础。
该成像技术为配方研发和质量控制中的湿溶出试验提供了一个更好的选择。
该技术还可以缩短新产品的研发时间，并且根据厂商的情况，随时间推移甚至可能发展成为一个用于制药生产线的实时片剂检测系统。
TPI技术通过发射太赫射线绘制出片剂和涂层厚度的三维差异图谱，在有结构或化学变化时太赫射线被反射回。
反射脉冲的时间延迟累加成该片剂的三维图像。
该系统使用太赫发射极，采用一个机器臂捡起片剂并且使其通过太赫光束，用一个扫描仪收集反射光并且建成三维图像(见图)。
技术研发太赫技术发源于二十世纪九十年代中期13本东芝公司位于英国的东芝欧洲研究中心，该中心与剑桥大学的物理学系有着密切的联系。
日本东芝公司当时正在研究新一代的半导体，研究的副产品是发现了这些半导体实际上是太赫光非常好的发射源和检测器。
二十世纪九十年代后期，日本东芝公司授权研究小组寻求该技术可能的应用，包括成像和化学传感光谱学，并与葛兰素史克和辉瑞以及其它公司建立了关系，以探讨其在制药业的应用。
虽然早期的结果表明该技术有前景，但日本东芝公司却不愿深入研究下去，原因是此应用与日本东芝公司在消费电子行业的任何业务兴趣都没有交叉。
这一决定的结果是研究中心的首席执行官DonArnone和剑桥桥大学物理学系的教授Michael Pepper先生于2001年成立了Teraview公司一作为研究中心的子公司。
TPI imaga 2000是第一个商品化太赫成像系统，该系统经优化用于成品片剂及其核心完整性和性能的无破坏检测。
ICH-Q7（中英文对照）
ICH-Q7（中英⽂对照）Q7a（中英⽂对照）FDA原料药GMP指南Table of Contents ⽬录1. INTRODUCTION 1. 简介1.1 Objective 1.1⽬的1.2 Regulatory Applicability 1.2法规的适⽤性1.3 Scope 1.3范围2. QUALITY MANAGEMENT 2.质量管理2.1 Principles 2.1总则2.2 Responsibilities of the Quality Unit(s) 2.2质量部门的责任2.3 Responsibility for Production Activities 2.3⽣产作业的职责2.4 Internal Audits (Self Inspection) 2.4内部审计（⾃检）2.5 Product Quality Review 2.5产品质量审核3. PERSONNEL 3. ⼈员3.1 Personnel Qualifications 3.⼈员的资质3.2 Personnel Hygiene 3.2 ⼈员卫⽣3.3 Consultants 3.3 顾问4. BUILDINGS AND FACILITIES 4. 建筑和设施4.1 Design and Construction 4.1 设计和结构4.2 Utilities 4.2 公⽤设施4.3 Water 4.3 ⽔4.4 Containment 4.4 限制4.5 Lighting 4.5 照明4.6 Sewage and Refuse 4.6 排污和垃圾4.7 Sanitation and Maintenance 4.7 卫⽣和保养5. PROCESS EQUIPMENT 5. ⼯艺设备5.1 Design and Construction 5.1 设计和结构5.2 Equipment Maintenance and Cleaning 5.2 设备保养和清洁5.3 Calibration 5.3 校验5.4 Computerized Systems 5.4 计算机控制系统6. DOCUMENTATION AND RECORDS 6. ⽂件和记录6.1 Documentation System andSpecifications6.1 ⽂件系统和质量标准6.2 Equipment cleaning and Use Record 6.2 设备的清洁和使⽤记录6.3 Records of Raw Materials, Intermediates, API Labeling and Packaging Materials 6.3 原料、中间体、原料药的标签和包装材料的记录6.4 Master Production Instructions (MasterProduction and Control Records)6.4 ⽣产⼯艺规程（主⽣产和控制记录）6.5 Batch Production Records (BatchProduction and Control Records)6.5 批⽣产记录（批⽣产和控制记录）6.6 Laboratory Control Records 6.6 实验室控制记录6.7 Batch Production Record Review 6.7批⽣产记录审核7. MATERIALS MANAGEMENT 7. 物料管理7.1 General Controls 7.1 控制通则7.2 Receipt and Quarantine 7.2接收和待验7.3 Sampling and Testing of IncomingProduction Materials7.3 进⼚物料的取样与测试7.4 Storage 7.4储存7.5 Re-evaluation 7.5复验8. PRODUCTION AND IN-PROCESSCONTROLS8. ⽣产和过程控制8.1 Production Operations 8.1 ⽣产操作8.2 Time Limits 8.2 时限8.3 In-process Sampling and Controls 8.3 ⼯序取样和控制8.4 Blending Batches of Intermediates orAPIs8.4 中间体或原料药的混批8.5 Contamination Control 8.5 污染控制9. PACKAGING AND IDENTIFICATIONLABELING OF APIs ANDINTERMEDIATES9. 原料药和中间体的包装和贴签9.1 General 9.1 总则9.2 Packaging Materials 9.2 包装材料9.3 Label Issuance and Control 9.3 标签发放与控制9.4 Packaging and Labeling Operations 9.4 包装和贴签操作10. STORAGE AND DISTRIBUTION 10.储存和分发10.1 Warehousing Procedures 10.1 ⼊库程序10.2 Distribution Procedures 10.2 分发程序11. LABORATORY CONTROLS 11.实验室控制11.1 General Controls 11.1 控制通则11.2 Testing of Intermediates and APIs 11.2 中间体和原料药的测试11.3 Validation of Analytical Procedures 11.3 分析⽅法的验证11.4 Certificates of Analysis 11.4 分析报告单11.5 Stability Monitoring of APIs 11.5 原料药的稳定性监测11.6 Expiry and Retest Dating 11.6 有效期和复验期11.7 Reserve/Retention Samples 11.7 留样12. V ALIDATION 12.验证12.1 Validation Policy 12.1 验证⽅针12.2 Validation Documentation 12.2 验证⽂件12.3 Qualification 12.3 确认12.4 Approaches to Process Validation 12.4 ⼯艺验证的⽅法12.5 Process Validation Program 12.5 ⼯艺验证的程序12.6 Periodic Review of Validated Systems 12.6验证系统的定期审核12.7 Cleaning Validation 12.7 清洗验证12.8 Validation of Analytical Methods 12.8 分析⽅法的验证13. CHANGE CONTROL 13.变更的控制14. REJECTION AND RE-USE OFMATERIALS14.拒收和物料的再利⽤14.1 Rejection 14.1 拒收14.2 Reprocessing 14.2 返⼯14.3 Reworking 14.3 重新加⼯14.4 Recovery of Materials and Solvents 14.4 物料与溶剂的回收14.5 Returns 14.5 退货15. COMPLAINTS AND RECALLS 15.投诉与召回16. CONTRACT MANUFACTURERS(INCLUDING LABORATORIES)16.协议⽣产商（包括实验室）17. AGENTS, BROKERS, TRADERS, DISTRIBUTORS, REPACKERS, AND RELABELLERS 17.代理商、经纪⼈、贸易商、经销商、重新包装者和重新贴签者17.1 Applicability 17.1适⽤性17.2 Traceability of Distributed APIs andIntermediates17.2已分发的原料药和中间体的可追溯性17.3 Quality Management 17.3质量管理17.4 Repackaging, Relabeling, and Holding of APIs and Intermediates 17.4原料药和中间体的重新包装、重新贴签和待检17.5 Stability 17.5稳定性17.6 Transfer of Information 17.6 信息的传达17.7 Handling of Complaints and Recalls 17.7 投诉和召回的处理17.8 Handling of Returns 17.8 退货的处理18. Specific Guidance for APIs Manufactured by Cell Culture/Fermentation 18. ⽤细胞繁殖/发酵⽣产的原料药的特殊指南18.1 General 18.1 总则18.2 Cell Bank Maintenance and RecordKeeping18.2细胞库的维护和记录的保存18.3 Cell Culture/Fermentation 18.3细胞繁殖/发酵18.4 Harvesting, Isolation and Purification 18.4收取、分离和精制18.5 Viral Removal/Inactivation steps 18.5 病毒的去除/灭活步骤19.APIs for Use in Clinical Trials 19.⽤于临床研究的原料药19.1 General 19.1 总则19.2 Quality 19.2 质量19.3 Equipment and Facilities 19.3 设备和设施19.4 Control of Raw Materials 19.4 原料的控制19.5 Production 19.5 ⽣产19.6 Validation 19.6 验证19.7 Changes 19.7 变更19.8 Laboratory Controls 19.8 实验室控制19.9 Documentation 19.9 ⽂件20. Glossary 20. 术语Q7a GMP Guidance for APIs Q7a原料药的GMP指南1. INTRODUCTION 1. 简介1.1 Objective 1.1⽬的This document is intended to provide guidance regarding good manufacturing practice (GMP) for the manufacturing of active pharmaceutical ingredients (APIs) under an appropriate system for managing quality. It is also intended to help ensure that APIs meet the quality and purity characteristics that they purport, or are represented, to possess. 本⽂件旨在为在合适的质量管理体系下制造活性药⽤成分（以下称原料药）提供有关优良药品⽣产管理规范（GMP）提供指南。
小剂量丙种球蛋白辅助治疗对重症ITP患儿Th17
- 115 -①龙岩市第一医院 福建 龙岩 364000小剂量丙种球蛋白辅助治疗对重症ITP患儿Th17/Treg平衡及血小板功能的影响李丽雯① 张丽萍① 邱雪文①【摘要】 目的：研究小剂量丙种球蛋白辅助治疗对重症原发免疫性血小板减少症（ITP）患儿辅助性T 细胞17（Th17）/调节性T 细胞（Treg）平衡及血小板功能的影响。
方法：选取2020年5月—2021年3月在龙岩市第一医院进行治疗的80例重症ITP 患儿作为研究对象，采用随机数表法分为观察组和对照组，各40例。
对照组采用常规激素治疗，观察组采用常规激素联合小剂量丙种球蛋白治疗。
观察比较两组治疗前后Th17/Treg 平衡、血小板压积（PCT）、血小板体积分布宽度（PDW）、血小板计数（PLT）水平，记录治疗不良反应发生率。
结果：治疗前，两组Th17、Treg 及Th17/Treg 比较，差异无统计学意义（P >0.05）；治疗4周后，两组Th17、Th17/Treg 均低于治疗前，Treg 高于治疗前，且观察组Th17、Th17/Treg 低于对照组，Treg 高于对照组，差异有统计学意义（P <0.05）。
治疗前，两组PCT、PDW、PLT 水平比较，差异无统计学意义（P >0.05）；治疗4周后，两组PCT、PLT 水平均高于治疗前，PDW 水平均低于治疗前，且观察组PCT、PLT 水平高于对照组，PDW 水平低于对照组，差异有统计学意义（P <0.05）。
治疗过程中，两组均未出现出血、头痛、发热、感染等不良反应。
结论：采用常规治疗联合小剂量丙种球蛋白治疗对重症ITP 患儿Th17/Treg 平衡及改善血小板功能具有一定作用。
【关键词】 Th17/Treg 平衡 丙种球蛋白 血小板功能 重症原发免疫性血小板减少症 doi：10.14033/ki.cfmr.2023.31.029 文献标识码 B 文章编号 1674-6805（2023）31-0115-04 Effect of Low-dose Gamma Globulin Adjuvant Therapy on Th17/Treg Balance and Platelet Function in Children with Severe ITP/LI Liwen, ZHANG Liping, QIU Xuewen. //Chinese and Foreign Medical Research, 2023, 21(31): 115-118 [Abstract] Objective: To investigate the effect of low-dose Gamma Globulin adjuvant therapy on the balance of helper T cell 17 (Th17)/regulatory T cell (Treg) and platelet function in children with severe primary immune thrombocytopenia (ITP). Method: A total of 80 children with severe ITP treated in Longyan First Hospital from May 2020 to March 2021 were selected as the study objects and divided into observation group and control group by random number table method, with 40 cases in each group. The control group was treated with conventional hormone therapy, and the observation group was treated with conventional hormone combined with low-dose Gamma Globulin. Th17/Treg balance, platelet accumulation (PCT), platelet volume distribution width (PDW) and platelet count (PLT) levels before and after treatment were observed and compared between the two groups, and the incidence of adverse reactions was recorded. Result: Before treatment, there were no significant differences in Th17, Treg and Th17/Treg between the two groups (P >0.05). After 4 weeks of treatment, Th17 and Th17/Treg in both groups were lower than those before treatment, and Treg were higher than those before treatment, and Th17 and Th17/Treg in observation group were lower than those in the control group, and Treg was higher than that in the control group, the differences were statistically significant (P <0.05). Before treatment, there were no significant differences in PCT, PDW and PLT levels between the two groups (P >0.05). After 4 weeks of treatment, PCT and PLT levels in both groups were higher than those before treatment, and PDW levels were lower than those before treatment, and PCT and PLT levels in observation group were higher than those in the control group, and PDW levels was lower than that in the control group, the differences were statistically significant (P <0.05). During the treatment, there were no adverse reactions such as bleeding, headache, fever, infection in both groups. Conclusion: The combination of conventional therapy and low-dose Gamma Globulin therapy can improve Th17/Treg balance and platelet function in children with severe ITP. [Key words] Th17/Treg balance Gamma Globulin Platelet function Severe primary immune thrombocytopenia First-author's address: Longyan First Hospital, Longyan 364000, China 原发免疫性血小板减少症（ITP）是一种以皮肤黏膜出血为主要临床表现的免疫性综合出血性疾病，占出血性疾病的1/3，儿童为主要易患人群，其中重症ITP 患儿指血小板计数（PLT）<10×109/L的ITP 类型，其发病机制尚不明确，以血液循环中出现抗血小板抗体、血小板破坏过多或生成减少为特点，救治难度比较大，病情严重者甚至会引发颅内出血，严重威胁患儿的生命安全[1-3]。
利用大肠杆菌全细胞催化赖氨酸发酵液生产1,5-戊二胺
2017年第36卷第5期 CHEMICAL INDUSTRY AND ENGINEERING PROGRESS·1843·化 工 进展利用大肠杆菌全细胞催化赖氨酸发酵液生产1,5-戊二胺齐雁斌，马伟超，陈可泉（南京工业大学生物与制药工程学院，江苏 南京 211816）摘要：1,5-戊二胺是一种具有生物活性的生物胺。
赖氨酸脱羧酶可以催化L-赖氨酸生产1,5-戊二胺。
为了减少生产成本，本文利用大肠杆菌AST1以赖氨酸发酵液作为底物进行全细胞催化生产1,5-戊二胺。
研究转化pH 、菌体浓度、转化温度、磷酸吡哆醛（PLP ）添加量以及不同酸种类对转化的影响，并对菌体的重复利用性进行了研究。
在最优条件下：pH6.8、转化温度37℃、PLP 添加量0.1mmol/L 、菌体浓度（DCW ）2.5g/L ，用乙酸来调节转化过程pH ，可以转化含有赖氨酸123.8g/L 的发酵液，得到含有86.18g/L 戊二胺的转化液，转化率可达到99.61%。
并且菌体在赖氨酸发酵液中重复利用5次的情况下转化率可以达到50%以上，重复利用性明显比在赖氨酸溶液中转化时强，这极大程度地节约了生产成本，为1,5-戊二胺连续工业化生产打下了基础。
关键词：1,5-戊二胺；赖氨酸发酵液；全细胞转化；工业化生产中图分类号：TQ033 文献标志码：A 文章编号：1000–6613（2017）05–1843–05 DOI ：10.16085/j.issn.1000-6613.2017.05.0361,5-pentanediamine production by using Escherichia coli whole-cellbiocatalysis lysine fermentation liquidQI Yanbin ，MA Weicao ，CHEN Kequan（Biotechnology and Pharmaceutical Engineering ，Nanjing University of Technology ，Nanjing 211816，Jiangsu ，China ）Abstract:1,5-pentanediamine is a bioactive biogenic amine. L-lysine decarboxylase can catalyze with L-lysine to produce 1,5-pentanediamine. To reduce the production cost ，whole cell catalytic production of 1,5-pentanediamine was outperformed using Escherichia coli AST1 and with lysine fermentation broth as the substrate. The effects of transformation pH ，cell concentration ，transformation temperature ，PLP addition amount ，and different kinds of acid on the transformation and the reusability of the cells were investigated. At the optimal condition ，0.1mmol/L PLP ，2.5g/L DCW and pH as 6.8，37℃，86.18g/L of 1,5-pentanediamine was obtained by transforming the fermentation broth containing 123.8 g/L L-lysine ，and adjusting the pH using the acetic acid during conversion process. Furthermore ，the cells can be reused five times and the substrate conversion rate maintained above 50% in the lysine fermentation broth. The reusability was better than that in the lysine solution ，which greatly reduces the production cost and lays a foundation for 1,5-pentanediamine commercial production. Key words ：1,5-pentanediamine ；lysine fermentation liquid ；whole-cell biocatalysis ；commercial process1,5-戊二胺（1,5-pentanediamine ，简称戊二胺），即尸胺，是生物体内广泛存在的具有生物活性的含氮碱，为蛋白质腐败时赖氨酸在脱羧酶作用下发生脱羧反应时生成的产物。
司库奇尤单抗的用法英语
司库奇尤单抗的用法英语The Utilization of Sotorasib in Clinical PracticeSotorasib, also known as AMG 510, is a novel targeted therapy that has garnered significant attention in the field of oncology. As a selective and irreversible inhibitor of the KRAS G12C mutation, sotorasib represents a groundbreaking advancement in the treatment of certain types of cancer. This article will delve into the clinical applications and practical considerations surrounding the use of sotorasib in the management of cancer patients.The KRAS gene is a critical player in the regulation of cellular growth and proliferation. Mutations in this gene, particularly the G12C subtype, are frequently observed in various malignancies, including non-small cell lung cancer (NSCLC), colorectal cancer, and pancreatic cancer. Historically, KRAS mutations have been considered undruggable, posing a significant challenge for targeted cancer therapies. However, the development of sotorasib has provided a promising solution to this long-standing problem.Sotorasib's mechanism of action involves covalently binding to the KRAS G12C mutant protein, effectively locking it in an inactiveconformation. This inhibition of the mutant KRAS protein disrupts the downstream signaling cascades that drive uncontrolled cell growth and proliferation, ultimately leading to tumor cell death. The selectivity of sotorasib for the G12C mutation is a key advantage, as it minimizes the impact on wild-type KRAS and potentially reduces the risk of off-target effects.Clinical Trials and Regulatory ApprovalThe efficacy and safety of sotorasib have been extensively evaluated in various clinical trials. The landmark CodeBreaK 100 study, a phase II clinical trial, enrolled patients with KRAS G12C-mutated advanced NSCLC who had received prior systemic therapy. The results of this study were highly promising, with an overall response rate of 37.1% and a median progression-free survival of 6.8 months. These findings led to the accelerated approval of sotorasib by the U.S. Food and Drug Administration (FDA) in May 2021 for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic NSCLC who have received at least one prior systemic therapy.Beyond NSCLC, sotorasib is also being investigated for its potential in other KRAS G12C-driven malignancies. The CodeBreaK 101 study is currently evaluating the efficacy and safety of sotorasib in patients with KRAS G12C-mutated colorectal cancer, pancreatic cancer, and other solid tumors. Preliminary data from this study have shown encouraging results, suggesting that sotorasib may have broaderclinical applications beyond NSCLC.Practical Considerations in the Use of SotorasibThe integration of sotorasib into clinical practice requires careful consideration of several key factors. Firstly, the identification of the KRAS G12C mutation is essential for patient selection. This is typically done through molecular testing, such as next-generation sequencing or real-time PCR, which should be performed on tumor tissue or liquid biopsy samples. Clinicians must ensure that the appropriate testing is conducted and the results are available before initiating sotorasib treatment.Dosing and administration of sotorasib also warrant attention. The recommended dosage is 960 mg taken orally once daily, with or without food. Patients should be advised to take the medication at the same time each day to maintain consistent drug levels. Monitoring for potential adverse events, such as diarrhea, fatigue, and liver function abnormalities, is crucial, and appropriate management strategies should be implemented as needed.Another important consideration is the management of patients with comorbidities or concomitant medications. Sotorasib is primarily metabolized by the CYP3A4 enzyme, and its interaction with other drugs that are substrates, inducers, or inhibitors of this enzyme should be carefully evaluated. Dose adjustments or alternativetreatment options may be necessary in such cases to ensure optimal therapeutic outcomes and minimize the risk of drug interactions.Lastly, the integration of sotorasib into the broader treatment landscape is crucial. Clinicians should consider the patient's overall disease status, prior therapies, and the potential for combination approaches. The role of sotorasib within the comprehensive management plan, including its sequencing with other targeted therapies, chemotherapy, or immunotherapy, should be carefully evaluated to optimize patient outcomes.ConclusionThe introduction of sotorasib represents a significant advancement in the treatment of KRAS G12C-mutated cancers. Its selective and irreversible inhibition of the KRAS G12C mutation has demonstrated promising clinical efficacy, particularly in the management of NSCLC. As clinicians navigate the integration of sotorasib into their practice, careful patient selection, appropriate dosing and administration, vigilant monitoring, and the consideration of comorbidities and drug interactions are essential. By leveraging the potential of this targeted therapy, healthcare providers can offer improved outcomes and enhanced quality of life for patients with KRAS G12C-driven malignancies.。
《细胞治疗产品生产质量管理指南》解读
英文回答：The Quality Management Guidelines for the Production of Cellular Therapy Products offer aprehensive framework to ensure the quality of cellular therapy products throughout the production process. These guidelines epass a wide array of areas, such as facility design, personnel training, process validation, and product testing. Adherence to these guidelines allows manufacturers to guarantee that their products meet regulatory requirements and are safe and effective for patients.《细胞治疗产品生产质量管理准则》提供了全面框架，以确保细胞治疗产品在整个生产过程中的质量。
这些准则涉及广泛的领域，如设施设计、人员培训、流程验证和产品测试。
遵守这些准则使制造商能够保证其产品符合监管要求，并对病人安全有效。
One of the main things the guidelines emphasize is setting up a system to make sure the stuff we make is top-notch. This meansing up with step-by-step instructions for how to do everything and keeping track of all the details about how our products are made. By doing this, we can cut down on mistakes and make sure our products are super high quality.准则强调的主要内容之一是建立一个系统，以确保我们制作的东西是顶尖的。
cart细胞制备流程
cart细胞制备流程The process of preparing CAR-T cells, also known as chimeric antigen receptor T cells, involves several steps that are crucial for the successful generation of these specialized immune cells. CAR-T cell therapy has emerged as a promising treatment option for various types of cancer, particularly hematological malignancies. This innovative approach harnesses the power of the patient's own immune system to target and destroy cancer cells. The preparation of CAR-T cells involves multiple perspectives, including the isolation of T cells, genetic modification, expansion and activation, and quality control.The first step in the preparation of CAR-T cells is the isolation of T cells from the patient's blood. This is typically done through a process called leukapheresis, where blood is collected and processed to separate the different components. T cells are then isolated using various techniques, such as density gradient centrifugation or magnetic bead separation. This step is crucial as itprovides the starting material for the subsequent steps of CAR-T cell preparation.Once the T cells are isolated, the next step is to genetically modify them to express the chimeric antigen receptor. This involves introducing a gene encoding the CAR into the T cells using viral vectors, such as retroviruses or lentiviruses. The CAR is designed to recognize specific antigens present on the surface of cancer cells. The genetic modification step is essential as it confers the ability of the T cells to specifically target and eliminate cancer cells.After the genetic modification, the CAR-T cells need to be expanded and activated to increase their numbers and enhance their anti-cancer activity. This is typically achieved by culturing the modified T cells in the presence of specific growth factors and cytokines. The cells are often stimulated with artificial antigen-presenting cells or with antibodies that bind to the CAR. This step is critical to generate a sufficient number of CAR-T cells for therapeutic purposes.Quality control is an integral part of the CAR-T cell preparation process. Various tests are performed to assess the viability, purity, and functionality of the CAR-T cells. Viability assays determine the percentage of live cells, while flow cytometry is used to assess the expression ofthe CAR on the cell surface. Functional assays, such as cytotoxicity assays, evaluate the ability of the CAR-Tcells to kill target cancer cells. These quality control measures ensure that the final product meets the required specifications for safe and effective administration to the patient.In addition to the technical aspects, the preparationof CAR-T cells also requires careful consideration ofethical and regulatory issues. Patient consent and privacy must be respected throughout the process, and ethical guidelines for human research must be followed. Regulatory authorities, such as the Food and Drug Administration (FDA) in the United States, play a crucial role in overseeing the development and approval of CAR-T cell therapies. Compliance with regulatory requirements is essential toensure the safety and efficacy of these innovative treatments.Overall, the preparation of CAR-T cells is a complex and multidisciplinary process that involves various perspectives, including scientific, technical, ethical, and regulatory considerations. Each step, from the isolation of T cells to quality control testing, is essential for the successful generation of CAR-T cells for cancer therapy. This innovative approach holds great promise for improving the outcomes of patients with cancer and represents a significant advancement in the field of immunotherapy.。
ISBT128条码(FDA)
Tissue: UK is using ISBT 128 for tissue banking; being evaluated for use with tissues in the US
Copyright ICCBBA, Inc
Cellular Therapy Coding and Labeling Advisory Group
Formed in 2005 to broaden the use of ISBT 128 in the area of cellular therapy
Formerly International Council for Commonality in Blood Bank Automation
Not-for-profit US-based organization Develops and manages ISBT 128 Standard Works with advisory groups of experts in the fields
Copyright ICCBBA, Inc
ISBT 128 Product Codes
Define the product in terms of its cellular content, anticoagulant, storage temperature and other attributes
All facilities in the world are assigned a unique Facility ID code by ICCBBA
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Separate process environment for each product
Automated processing devices
Regulations and Standards for Cell Therapy Products
FDA-CBER OCTGT, CDRH
1 Minimally manipulated (not activated, encapsulated, expanded ex vivo ,or genetically modified) AND 2 Intended for homologous use AND 3 Not combined with a drug or device
Cytotherapy 2003 5:289 298 Cell & Gene Therapy 2004 1:16-22
Unique Challenges of Cell Therapy
Biotechnology
Product Raw Material Variability, Heterogeneity Product Definition Process, Testing Process Scale
Foundation for the
Accreditation of Cellular Therapy (FACT)
Clinical Laboratory Improvement
Amendments (CLIA)
Cytotherapy 2003 5:289 298
FDA Requirements - GCPs, GTPs, GMPs
Cell Therapy
Living cells are product Unique, primary tissue Substantial
>99% CDX+ cells
?% CDY+ cells ?% CDY- cells
Cytotherapy 2003 5:289 298 Cell & Gene Therapy 2004 1:16-22
Unique Challenges of Cell Therapy
Biotechnology
Product Definition Process, Testing
Well-defined, definable products Established early
Cell Therapy
– Regulated using IND/IDE framework, clinical trial pathway – GMPs, GTPs, GCPs required
THEN…
– IND or IDE NOT required – GTPs ARE required
Cytotherapy 2003 5:289 298
Product defined through trials
Full definition likely unattainable
Evolve through trials
INDs Cell Therapy Gene Therapy 903 372
IND Amendments 13,527 8,090
Unique Challenges of Cell Therapy
Biotechnology
Product Raw Material Variability, Heterogeneity
Cultured cells generate product Seed cell lines Limited
Good Manufacturing Ensure consistent manufacture of safe, pure, potent products Practices (GMPs)
Prevent infectious disease transmission
Donor screening and testing
BioProcessing 2003 2:1-4 Cell & Gene Therapy 2004 1:16-22
Making Coffee One Cup at a Time:
Automated, Functionally-Closed Systems
Individualized, cup-specific brewing of a variety of coffees, teas, cocoa, even mochaccino with extra foam.
Application of FDA Regulatory Requirements
Minimally Manipulated
IF a cell therapy product meets criteria 1 and 2 and 3, and (4a or 4b or 4c).
Nearly any interesting cell therapy meets criteria for the more-than-minimally manipulated category
FDA Regulatory Requirements Increase With Product Development
Full definition likely unattainable
Evolve through trials Patient-specific products common
Cytotherapy 2003 5:289 298 Cell & Gene Therapy 2004 1:16-22
Cell Therapy Product Manufacturing Strategies
• Manufacturing process must protect product, patient
– Focus on product characterization, process control – Controlled, consistent processes → controlled, consistent products
Automated, Functionally-Closed Systems
Preloaded, disposable, individualized raw material sets
BioProcessing 2003 2:1-4 Cell & Gene Therapy 2004 1:16-22
Cultured cells generate product Seed cell lines Limited Well-defined, definable products Established early Bulk processes predominate
Cell Therapy
Living cells are product Unique, primary tissue Substantial Product defined through trials
Preloaded, disposable, individualized raw material sets
Separate process environment for each product
Automated processing device
High Throughput Cell Therapy Product Manufacturing:
AND
4a. Does not have a systemic effect, AND Primary function does not depend on metabolic activity of viable cells OR 4b. Has a systemic effect and is intended for autologous, related- allogeneic, or reproductive use OR 4c. Primary function depends on metabolic activity of viable cells) and is intended for autologous, related- allogeneic, or reproductive use
Good Tissue Practices (GTPs) Good Manufacturing Practices
(GMPs)
American Association of Blood
Banks (AABB)
American Association of Tissue
Banking (AATB)
Good Tissue Practices Prevent cross-contamination, mixups (GTPs)
Product recovery, processing, storage, labeling, distribution
Ethical, scientific quality standards
Good Clinical Practices
(GCPs)
United States Pharmacopeia
(USP)
Institutional Review Board,
Biosafety Committee
College of American Pathologists
(CAP)
• High throughput, parallel processing to achieve scale