生物类似药研发相关问题问与答
生物技术制药问答题
1、生物技术制药的特征答：高技术、高投入、长周期、高风险、高收益。
2、质粒不稳定分为那两类?答：基因重组菌的稳定性是高水平发酵生产的基本条件。
工程菌在传代过程中经常出现质粒不稳定的现象，质粒不稳定分为分裂不稳定和结构不稳定。
提高质粒稳定性的方法(1)选择合适的宿主菌:遗传稳定(2)选择合适的载体:高拷贝数;(3)选择压力:如加抗生素提高稳定性;(4)分阶段控制培养:先使菌体生长至一定密度;再诱导外源基因的表达 (5)控制培养条件 (6)固定化3、什么是高密度发酵?影响高密度发酵的因素有哪些?可采取哪些方法实现高密度发酵?答：(1)高密度发酵:一个相对概念，一般指培养基中工程菌的菌体浓度在 50gDCW/L 以上，理论上的最高值可达200gDCW/L。
(2)影响高密度发酵的因素:培养基;溶氧浓度;pH;温度;代谢副产物(3)实现高密度发酵的方法①发酵条件的改进 a.培养基的选择 b.建立流加式培养的方式;c.提高供氧能力②构建出产乙酸能力低的工程化宿主菌 a.阻断乙酸产生的主要途径;b.对碳代谢流进行分流;c.限制进入糖酵解途径的碳代谢流; d.引入血红蛋白基因③构建蛋白水解酶活力低的工程化宿主菌4、动物细胞大规模培养的方法答：1.悬浮培养悬浮培养即让细胞自由地悬浮于培养基内生长增殖。
优点是操作简便，培养条件比较均一，传质和传氧较好，容易扩大培养规模，在培养设备的设计和实际操作中可借鉴许多有关细菌发酵的经验。
不足之处是细胞体积较小，较难采用灌流培养，因此细胞密度一般较低。
(目前在生产中用于悬浮培养的设备主要是通气搅拌罐式生物反应器和气升式生物反应器。
)2.贴壁培养贴壁培养是必须让细胞贴附在某种基质上，细胞才能生长繁殖的培养方法。
优点是使用的细胞种类广（因为生产中所使用的细胞绝大多数是贴壁细胞），较容易采用灌流培养的方式使细胞达到高密度。
不足之处是操作比较麻烦，需要合适的贴附材料和足够的面积，培养条件不易均一，传质和传氧较差，这些不足常常成为扩大培养的“瓶颈”。
生物制药技术实验中的常见问题解决方法
生物制药技术实验中的常见问题解决方法生物制药技术是一门将生命科学和工程技术相结合的交叉学科，它通过利用微生物、细胞等生物体来生产药物。
在生物制药技术实验中，常常会遇到一些问题，如细胞培养的污染、蛋白表达量低、产物结构异常等。
本文将分析和解决这些常见问题。
首先，细胞培养的污染是生物制药实验中常见的问题之一。
细胞培养污染的来源多种多样，包括细菌、真菌、酵母等微生物的污染。
解决这个问题的关键是细胞培养的无菌操作。
首先要保证实验室的工作区域和操作仪器、器皿要经过严格的清洁和消毒。
同时，实验操作者要采取严格的个人防护措施，包括戴手套、口罩和实验室服装。
在培养细胞的过程中，要进行无菌操作，使用无菌技术开启培养皿、吸移液等。
另外，定期对培养物进行形态观察，及时发现异常现象。
其次，蛋白表达量低是生物制药实验中常见的问题之一。
蛋白表达量低可能是由于多种原因引起的，如质粒构建不合理、转染效率低、蛋白稳定性差等。
要解决这个问题，首先要对质粒进行构建优化。
选择合适的启动子和进一步优化转录、翻译信号序列，提高转录和翻译效率。
同时，要优化细胞转染过程，选择适合的转染试剂和条件，有效地提高转染效果。
另外，对表达的蛋白进行稳定性的改善，可以通过选择适当的标签或结构域来增加蛋白的稳定性。
最后，产物结构异常是生物制药实验中常见的问题之一。
产物结构异常可能是由于细胞中酶的修饰不完全、非特异性修饰等原因导致的。
解决这个问题的方法包括优化培养条件和细胞工程技术。
首先，要调整培养基成分，提供适合细胞生长所需要的营养物质，并且加入合适的辅助剂来促进酶修饰的完全性。
其次，可以通过细胞工程技术来改善产物的结构。
例如，利用基因编辑技术来删除可能导致结构异常的基因片段，或者通过融合蛋白工程来加入修饰酶，并实现产物的特异修饰。
除了上述常见问题，生物制药技术实验中还可能遇到其他问题，如实验结果不可重复、产物纯度低、细胞生长速度慢等。
对于这些问题，我们应该注重实验的严谨性，重复实验并检查实验步骤和操作是否正确。
生物类似药产品和制造企业面临的局限性问题
生物类似药产品和制造企业面临的局限性问题欧洲药品管理局(EMA)将生物仿制药描述为“一种与已获准使用的另一种生物药物相似的生物药物”。
这种相似性是针对其他已注册和已上市的产品进行评估和确定的-称为参考药品或者叫做原研药。
就其本质而言，生物制药产品本质上是可变的，因此不能称为“仿制药”——这是一个用于表示彼此“相同”的药品术语。
然而，目前生物仿制药还有其他几个术语，包括后续生物制剂(follow-onbiologics，FOB)、后续蛋白质(follow-on-protein，FOP)和后续生物制剂(subsequent entry biologics，SEB)。
生物制品比由相对简单的化学反应产生的化学药物制剂复杂得多。
与小分子相比，生物产品的复杂性源于许多独特的因素，包括：•分子量（通常为10kDa或更多）•组成（例如，蛋白质、碳水化合物、脂质、核酸、细胞碎片）•高级结构（呈现生物功能）•复杂的制造操作、工艺流程和过程控制•制剂，包括佐剂的使用。
鉴于生物产品的复杂性和批次间的可变性，制造企业和监管机构都意识并接受这个观点：生物制品的制造过程、工艺控制、过程限制和规格剂型等多种因素会因所涉及制造过程的可变性而有所不同——两者都相应地设定了对生物制品质量和制造的期望，或者叫监督目的和要求。
生物仿制药的背景在80年代末和90年代，开发并成功注册了一系列基于生长激素和单克隆抗体(mAb)的生物产品。
鉴于它们新颖、特异性且通常较为复杂的制造工艺和应用，其中许多产品的知识产权(intellectual property，IP)受到各种专利的保护。
在同一时期，监管环境的变化包括美国为充分表征（后来更名为良好指定）的生物制剂制定指南，在欧盟制定了可比性协议和等效性协议。
虽然监管要求的这些变化主要是为了支持和促进生物制剂制造过程的变化，但它们引发了生化“桥”概念的演变，由此综合分析（生化和生物物理）比较测试程序可以用作证明的一部分用于证明等效性或相似性。
FDA生物类似物问答201202
Guidance for Industry Biosimilars: Questions and AnswersRegarding Implementation of theBiologics Price Competition andInnovation Act of 2009DRAFT GUIDANCEThis guidance document is being distributed for comment purposes only. Comments and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register.For questions regarding this draft document contact (CDER) Sandra Benton at 301-796-2500 or (CBER) Office of Communication, Outreach and Development at 1-800-835-4709 or 301-827-1800.U.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)Center for Biologics Evaluation and Research (CBER)February 2012BiosimilarityGuidance for Industry Biosimilars: Questions and Answers Regarding Implementation of theBiologics Price Competition andInnovation Act of 2009Additional copies are available from:Office of Training and CommunicationDivision of Drug Information, HFD-240Center for Drug Evaluation and ResearchFood and Drug Administration5600 Fishers LaneRockville, MD 20857(Tel) 301-827-4573/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htmand/orOffice of Communication, Outreach and Development, HFM-40Center for Biologics Evaluation and ResearchFood and Drug Administration1401 Rockville Pike, Rockville, MD 20852-1448/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/default.htm(Tel) 800-835-4709 or 301-827-1800U.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)Center for Biologics Evaluation and Research (CBER)February 2012BiosimilarityTABLE OF CONTENTSINTRODUCTION (1)BACKGROUND (2)QUESTIONS AND ANSWERS (4)INTERCHANGEABILITY...........................................................4ORI. B IOSIMILARITYII. PROVISIONS RELATED TO REQUIREMENT TO SUBMIT A BLA FOR A “BIOLOGICAL PRODUCT” (12)III. EXCLUSIVITY (15)Guidance1Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009This draft guidance, when finalized, will represent the Food and Drug Administration’s (FDA’s) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance.INTRODUCTIONThis guidance provides answers to common questions from sponsors interested in developing proposed biosimilar products, biologics license application (BLA) holders, and other interested parties regarding FDA’s interpretation of the Biologics Price Competition and Innovation Act of 2009 (BPCI Act). The questions and answers (Q&As) are grouped below in the following categories:∙Biosimilarity or Interchangeability∙Provisions Related to Requirement to Submit a BLA for a “Biological Product”∙ExclusivityThe BPCI Act amends the Public Health Service Act (PHS Act) and other statutes to create an abbreviated licensure pathway in section 351(k) of the PHS Act for biological products shown to be biosimilar to, or interchangeable with, an FDA-licensed biological reference product (see sections 7001 through 7003 of the Patient Protection and Affordable Care Act (Pub. L. 111–148) (Affordable Care Act)). On November 2 and 3, 2010, FDA held a public hearing and established a public docket to obtain input on specific issues and challenges associated with the implementation of the BPCI Act (see Docket No. FDA-2010-N-0477). This guidance describes FDA’s current interpretation of certain statutory requirements added by the BPCI Act and reflects consideration of the comments concerning those requirements that were submitted to the public docket.1 This guidance has been prepared by the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) at the Food and Drug Administration (FDA or the Agency).Guidance documents are available on the CDER guidance page at/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. We update guidances periodically. To make sure you have the most recent version of a guidance, check the CDER guidance page.This guidance is one in a series of guidances that FDA is developing to implement the BPCI Act. The guidances address a broad range of issues, including:∙ Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product∙ Scientific Considerations in Demonstrating Biosimilarity to a Reference Product∙ Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009When applicable, references to information in these guidances are included in this Q&A guidance.The Q&A format is intended to promote transparency and facilitate development programs for proposed biosimilar products by addressing questions that may arise in the early stages of development. In addition, these Q&As respond to questions the Agency has received from prospective BLA and new drug application (NDA) applicants regarding the appropriate statutory authority under which certain products will be regulated. FDA intends to update this guidance to include additional Q&As as appropriate.2FDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’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 Agency guidances means that something is suggested or recommended, but not required.BACKGROUNDThe BPCI Act was enacted as part of the Affordable Care Act on March 23, 2010. The BPCI Act creates an abbreviated licensure pathway for biological products shown to be biosimilar to, or interchangeable with, an FDA-licensed biological reference product. The objectives of the BPCI Act are conceptually similar to those of the Drug Price Competition and Patent Term Restoration Act of 1984 (Pub. L. 98–417) (commonly referred to as the “Hatch-Waxman Act”), which established abbreviated pathways for the approval of drug products under the Federal Food, Drug, and Cosmetic Act (FD&C Act).3 The implementation of an abbreviated licensure pathway for biological products can present challenges given the scientific and technical complexities that may be associated with the larger and typically more complex structure of biological products, as well as the processes by which such products are manufactured. Most biological products are produced in a living system such as a microorganism, or plant or animal cells, whereas small molecule drugs are typically manufactured through chemical synthesis.2 The process by which FDA is requesting public comment on proposed Q&As and issuing new Q&As is described in the accompanying FEDERAL REGISTER notice.3 See section 505(b)(2) and 505(j) of the FD&C Act (21 U.S.C. 355(b)(2) and 355(j)).Section 351(k) of the PHS Act (42 U.S.C. 262(k)), added by the BPCI Act, sets forth the requirements for an application for a proposed biosimilar product and an application or a supplement for a proposed interchangeable product. Section 351(i) defines biosimilarity to mean “that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components” and that “there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product” (see section 351(i)(2) of the PHS Act). A 351(k) application must contain, among other things, information demonstrating that the biological product is biosimilar to a reference product based upon data derived from analytical studies, animal studies, and a clinical study or studies, unless FDA determines, in its discretion, that certain studies are unnecessary in a 351(k) application (see section 351(k)(2) of the PHS Act). To meet the higher standard of “interchangeability,” an applicant must provide sufficient information to demonstrate biosimilarity, and also to demonstrate that the biological product can be expected to produce the same clinical result as the reference product in any given patient and, if the biological product is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between the use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch (see section 351(k)(4) of the PHS Act). Interchangeable products may be substituted for the reference product without the intervention of the prescribing healthcare provider (see section 351(i)(3) of the PHS Act).The BPCI Act also includes, among other provisions:∙ A 12-year exclusivity period from the date of first licensure of the reference product, during which approval of a 351(k) application referencing that product may not be made effective (see section 351(k)(7) of the PHS Act);∙ A 4-year exclusivity period from the date of first licensure of the reference product, during which a 351(k) application referencing that product may not be submitted (seesection 351(k)(7) of the PHS Act);∙ An exclusivity period for the first biological product determined to be interchangeable with the reference product for any condition of use, during which a second or subsequent biological product may not be determined interchangeable with that reference product(see section 351(k)(6) of the PHS Act);∙ An exclusivity period for certain biological products for which pediatric studies are conducted in accordance with a written request (see section 351(m) of the PHS Act);∙ A transition provision for biological products that have been or will be approved under section 505 of the FD&C Act (21 U.S.C. 355) before March 23, 2020 (see section7002(e) of the Affordable Care Act); and∙ A provision stating that a 351(k) application for a biosimilar product contains a “new active ingredient” for purposes of the Pediatric Research Equity Act (PREA) (see section 505B(n) of the FD&C Act).The BPCI Act also establishes procedures for identifying and resolving patent disputes involving applications submitted under section 351(k) of the PHS Act.QUESTIONS AND ANSWERSI. BIOSIMILARITY OR INTERCHANGEABILITYQ. I.1. Whom should a sponsor contact with questions about its biosimilardevelopment program?A. I.1. (Proposed Answer): If the reference product for a proposed biosimilar product isregulated by the Center for Drug Evaluation and Research (CDER), contact theBiosimilars Program Staff in CDER’s Office of New Drugs at 301-796-0700.If the reference product for a proposed biosimilar product is regulated by theCenter for Biologics Evaluation and Research (CBER), contact the Office ofCommunication, Outreach and Development (OCOD) at 800-835-4709 or 301-827-1800 or by email to ocod@.For general questions related to FDA’s implementation of the BPCI Act, contactSandra Benton in CDER’s Office of Medical Policy at 301-796-2500.Q. I.2. When should a sponsor request an initial meeting with FDA and what data and information should a sponsor provide to FDA as background for a proposedbiosimilar development program?A. I.2. (Proposed Answer): FDA recommends that sponsors of proposed biosimilarproducts request an initial meeting with FDA at such time as the sponsor canprovide a proposed plan for its biosimilar development program, manufacturingprocess information (including planned methodology and assay validation), andpreliminary comparative analytical data with the reference product.Comparative analytical data provide the foundation for a biosimilar developmentprogram and can influence decisions about the type and amount of animal andclinical data needed. Such data should be available early in development andallow for a more detailed discussion with the Agency. FDA will best be able toprovide meaningful input on the extent and scope of animal and clinical studiesfor a proposed biosimilar development program once the Agency has consideredthe comparative analytical data.Q. I.3. Can a proposed biosimilar product have a different formulation than the reference product?A. I.3. (Proposed Answer): Yes, differences between the formulation of a proposedproduct and the reference product may be acceptable. A 351(k) application mustcontain information demonstrating that the biological product is highly similar tothe reference product notwithstanding minor differences in clinically inactivecomponents. In addition, an applicant would need to demonstrate that there areno clinically meaningful differences between the biological product and thereference product in terms of safety, purity, and potency. It may be possible, forexample, for a proposed product formulated without human serum albumin todemonstrate biosimilarity to a reference product formulated with human serumalbumin. For more information about FDA’s current thinking on theinterpretation of the statutory standard for biosimilarity, see FDA’s draftguidances for industry on Quality Considerations in Demonstrating Biosimilarityto a Reference Protein Product and Scientific Considerations in DemonstratingBiosimilarity to a Reference Product.Q. I.4. Can a proposed biosimilar product have a delivery device or container closure system that is different from its reference product?A. I.4. (Proposed Answer): Yes, some design differences in the delivery device orcontainer closure system used with the proposed biosimilar product may beacceptable. It may be possible, for example, for an applicant to obtain licensureof a proposed biosimilar product in a pre-filled syringe or in an auto-injectordevice (which are considered the same “injectable” dosage form), even if thereference product is licensed in a vial presentation, provided that the proposedproduct meets the statutory standard for biosimilarity and adequate performancedata for the delivery device or container closure system are provided. For aproposed biosimilar product in a different delivery device or container closuresystem, the presentation must be shown to be compatible for use with the finalformulation of the biological product through appropriate studies, including, forexample, extractable/leachable studies and stability studies. Also, for certaindesign differences in the delivery device or container closure system, performancetesting and a human factors study may be needed.However, a prospective biosimilar applicant will not be able to obtain licensureunder section 351(k) for its product when a design difference in the deliverydevice or container closure system results in:∙ a clinically meaningful difference between the proposed product and the reference product in terms of safety, purity, and potency;∙ a different route of administration or dosage form; or∙ a condition of use for which the reference product has not been previously approved;or otherwise does not meet the standard for biosimilarity.Additional considerations apply for a proposed interchangeable product. Forexample, in reviewing an application for a proposed interchangeable product,FDA may consider whether the differences from the reference productsignificantly alter critical design attributes, product performance, or operatingprinciples, or would require additional instruction to healthcare providers orpatients, for patients to be safely alternated or switched between the referenceproduct and one or more interchangeable products without the intervention of theprescribing healthcare provider. Additional performance data about the deliverydevice may also be necessary.A proposed biosimilar product in a delivery device will be considered acombination product and may, in some instances, require a separate applicationfor the device.Q. I.5. Can an applicant obtain licensure of a proposed biosimilar product for fewer than all routes of administration for which an injectable reference product islicensed?A. I.5. (Proposed Answer): Yes, an applicant may obtain licensure of a proposedbiosimilar product for fewer than all routes of administration for which aninjectable reference product is licensed. An applicant must demonstrate that thereare no clinically meaningful differences between the proposed biosimilar productand the reference product in terms of safety, purity, and potency. This mayinclude providing information from one or more studies using a route ofadministration for which licensure is not requested (e.g., a study usingsubcutaneous administration may provide a more sensitive comparativeassessment of immunogenicity of the reference product and a proposed biosimilarproduct, even though licensure of the proposed biosimilar product is requestedonly for the intravenous route of administration).Q. I.6. Can an applicant obtain licensure of a proposed biosimilar product for fewer than all presentations (e.g., strengths or delivery device or container closuresystems) for which a reference product is licensed?A. I.6. (Proposed Answer): Yes, an applicant is not required to obtain licensure for allpresentations for which the reference product is licensed. However, if anapplicant seeks licensure for a particular indication or other condition of use forwhich the reference product is licensed and that indication or condition of usecorresponds to a certain presentation of the reference product, the applicant mayneed to seek licensure for that particular presentation (see also responses to Q. I.4and Q. I.5).Q. I.7. Can an applicant obtain licensure of a proposed biosimilar product for fewer than all conditions of use for which the reference product is licensed?A. I.7. (Proposed Answer): Yes, a biosimilar applicant generally may obtain licensurefor fewer than all conditions of use for which the reference product is licensed.The 351(k) application must include information demonstrating that the conditionor conditions of use prescribed, recommended, or suggested in the proposedlabeling submitted for the proposed biosimilar product have been previouslyapproved for the reference product (see section 351(k)(2)(A)(i)(III) of the PHSAct).Q. I.8. Can a sponsor use comparative animal or clinical data with a non-U.S.-licensed product to support a demonstration that the proposed product is biosimilar tothe reference product?A. I.8. (Proposed Answer): Yes, a sponsor may use a non-U.S.-licensed comparatorproduct in certain studies to support a demonstration that the proposed biologicalproduct is biosimilar to the U.S.-licensed reference product. However, as ascientific matter, analytical studies and at least one clinical pharmacokinetic (PK)study and, if appropriate, at least one pharmacodynamic (PD) study, intended tosupport a demonstration of biosimilarity must include an adequate comparison ofthe proposed biosimilar product directly with the U.S.-licensed reference product.We note, however, that for certain complex biological products, a modifiedapproach may be needed.If a sponsor seeks to use data from an animal study or a clinical study comparingits proposed biosimilar product to a non-U.S.-licensed product to address, in part,the requirements under section 351(k)(2)(A) of the PHS Act, the sponsor shouldprovide adequate data or information to scientifically justify the relevance ofthese comparative data to an assessment of biosimilarity and to establish anacceptable bridge to the U.S.-licensed reference product. The type of bridgingdata needed likely would include a clinical PK and/or PD study conducted withthe U.S.-licensed reference product.Issues that a sponsor may need to address to use a non-U.S.-licensed comparatorproduct in a biosimilar development program include, but are not limited to, thefollowing:∙ the relevance of the design of the clinical program to support a demonstration of biosimilarity to the U.S.-licensed reference product for the condition(s) ofuse and patient population(s) for which licensure is sought;∙ the relationship between the license holder for the non-U.S.-licensed product and BLA holder for the U.S.-licensed reference product, including whetherthe non-U.S.-licensed product, and/or any components thereof, aremanufactured in the same facility(ies) as the U.S.-licensed reference productduring the relevant time period;∙ whether the non-U.S.-licensed product was manufactured in a facility(ies) licensed and inspected by a regulatory authority that has similar scientific andregulatory standards as FDA (e.g., International Conference on Harmonisation(ICH) countries);∙ whether the non-U.S.-licensed product was licensed by a regulatory authority that has similar scientific and regulatory standards as FDA (e.g., ICHcountries) and the duration and extent to which the product has beenmarketed; and∙ the scientific bridge between the non-U.S.-licensed product and the U.S.-licensed reference product, including comparative physico-chemicalcharacterization, bioassays/functional assays, and comparative clinical and/ornonclinical PK and/or PD data, as appropriate, and data to address anydifferences in formulation or primary packaging.A sponsor also should address any other factors that may affect the relevance ofcomparative data with the non-U.S.-licensed product to an assessment ofbiosimilarity with the U.S.-licensed reference product.A sponsor may submit publicly available information regarding the non-U.S.-licensed product to justify the extent of comparative data needed to establish abridge to the U.S.-licensed reference product. Sponsors are encouraged to discusswith FDA during the development program the adequacy of the scientificjustification and bridge to the U.S.-licensed reference product. A final decisionabout the adequacy of this scientific justification and bridge will be made by FDAduring review of the 351(k) application.At this time, as a scientific matter, it is unlikely that clinical comparisons with anon-U.S.-licensed product would be an adequate basis to support the additionalcriteria required for a determination of interchangeability with the U.S.-licensedreference product.Q. I.9. Is a clinical study to assess the potential of the biological product to delay cardiac repolarization (a QT/QTc study) or a drug-drug interaction studygenerally needed for licensure of a proposed biosimilar product?A. I.9. (Proposed Answer): No. In general, a proposed biosimilar product may relyupon the reference product’s clinical evaluation of QT/QTc interval prolongationand proarrhythmic potential and drug-drug interactions.Q. I.10. How long should sponsors retain reserve samples of the biological products used in comparative clinical PK and/or PD studies intended to support a 351(k)application?A. I.10. (Proposed Answer): The requirements in 21 CFR 320.38 and 320.63 for retentionof reserve samples of the products used in bioavailability and bioequivalencestudies apply to applications submitted under section 505 of the FD&C Act.However, FDA recommends that the sponsor of a proposed biosimilar productretain reserve samples in the same manner and for the same time period (at least 5years) as described in 21 CFR 320.38 and 320.63 following a comparative clinicalPK or PD study of the reference product and the proposed biosimilar product (orother clinical study in which PK or PD samples are collected) that is intended tosupport a submission under section 351(k) of the PHS Act. Retention of samplesused in a comparative clinical PK or PD study or other clinical study in which PKor PD samples are collected would serve the same purpose described in the FinalRule for the cited regulations (58 FR 25918, April 28, 1993). Specifically,reserve samples establish the identity of the products tested in the actual study,allow for confirmation of the validity and reliability of the results of the study,and facilitate investigation of further follow-up questions that arise after thestudies are completed.Q. I.11. Can an applicant extrapolate clinical data intended to support a demonstration of biosimilarity in one condition of use to support licensure of the proposedbiosimilar product in one or more additional conditions of use for which thereference product is licensed?A. I.11. (Proposed Answer): Yes. If the proposed product meets the statutoryrequirements for licensure as a biosimilar product under section 351(k) of thePHS Act based on, among other things, data derived from a clinical studysufficient to demonstrate safety, purity, and potency in an appropriate condition ofuse, the potential exists for the biosimilar product to be licensed for one or moreadditional conditions of use for which the reference product is licensed.However, the applicant would need to provide sufficient scientific justification forextrapolating clinical data to support a determination of biosimilarity for eachcondition of use for which licensure is sought.Such scientific justification for extrapolation should address, for example, thefollowing issues for the tested and extrapolated conditions of use:∙ the mechanism(s) of action in each condition of use for which licensure is sought; this may include:o the target/receptor(s) for each relevant activity/function of the product;o the binding, dose/concentration response and pattern of molecularsignaling upon engagement of target/receptors;o the relationships between product structure and target/receptorinteractions;o the location and expression of the target/receptor(s);∙ the PK and bio-distribution of the product in different patient populations (relevant PD measures also may provide important information on themechanism of action);∙ differences in expected toxicities in each condition of use and patient population (including whether expected toxicities are related to thepharmacological activity of the product or to “off-target” activities); and ∙ any other factor that may affect the safety or efficacy of the product in each condition of use and patient population for which licensure is sought.Q. I.12. How can an applicant demonstrate that its proposed injectable biosimilar product has the same “strength” as the reference product?A. I.12. (Proposed Answer): Under section 351(k)(2)(A)(i)(IV) of the PHS Act, anapplicant must demonstrate that the “strength” of the proposed biosimilar productis the same as that of the reference product. As a scientific matter, there may be aneed to take into account different factors and approaches in determining the“strength” of different types of biological products.In general, we expect injectable biological products to have both the same totalcontent of drug substance (in mass or units of activity in a container closure) andthe same concentration of drug substance (in mass or units of activity per unitvolume) as the reference product to have the same “strength” under section351(k)(2)(A)(i)(IV) of the PHS Act. We note, however, that for certain complexbiological products, a modified approach may be needed.The total content of drug substance generally should be expressed using the samemeasure as the reference product. For example, if the strength of the referenceproduct is expressed as milligrams (mg) per total volume in a container closure,for example mg/5 milliliters (mL), the proposed biosimilar product generallyshould also describe its strength in mg/5 mL, rather than units per 5 mL. If thetotal content of drug substance is expressed in units of activity (e.g., internationalunits (IU) or units per total volume in a container closure), the units of theproposed biosimilar product should be the same as the reference product.。
关于生物仿制药药学研究问题的思考
关于生物仿制药药学研究问题的思考【摘要】随着人类社会的飞速发展，人类的生命周期逐步延长，越来越多的人把生命健康摆在第一位，世界上很多发达国家都高度重视医药行业。
国家各部门纷纷出台扶植医药产业发展的政策与指导原则，政府从民众的需求出发，提出迫切需要制药企业能够提升研发能力。
但由于全球药品市场增速逐渐放缓的影响下，国内医药市场也不得不受其影响。
国内多数药企把重点工作放在仿制药申报上，针对制药企业在仿制药研发过程中所遇到问题进行了初步的探讨。
【关键词】仿制药；研发；专利随着人类社会的飞速发展，人类的生命周期逐步延长，越来越多的人把生命健康摆在第一位，那么同时对各种人类疾病的治疗用药也成为医患人群所重视的方面，而制药企业作为药品的制造者，责无旁贷的承担起人类生命质量与安全的重要责任。
制药企业一直被人们认为是高科技高附加值的行业，世界上很多发达国家都高度重视医药行业，以美国为例，在美国联邦预算中，对生命科学的研发投入占到了对民用研发总投入的一半，德国教研部支持了21个生物医药科研合作网络的建设。
日本政府则提出要大力研发世界一流的卫生保健技术。
1.国内生物仿制药研发情况分析我国生物仿制药的研究可追溯到上世纪的70年代。
在进入90年代后，我国的生物仿制药研究开始逐步发力，成为医药药学发展的重点研究领域。
同时，生物仿制药的申报注册也呈现出较高的增长趋势。
这一时期的生物仿制药相对成功的有：IFN a、1I=2 、G –CSF、GM –CSF等。
进入新世纪之后，我国的生物仿制药逐步脱离了低级的重复性仿制，开始了跟踪仿制阶段，主要是针对国外已上市的单抗类药物进行跟踪研究。
受我国生物制药研发能力等因素的影响，在漫长的发展中，我国始终未能很好地突破药品研发这一瓶颈。
这也将导致在未来的一段时间内，仿制性的生物药品仍会在市场占据主导地位[2]。
在以主要是以提高产量和质量为目的采用新工艺或新表达体系制备的生物仿制药生产模式中，药物研究的价值开始突显，其不仅能够对药物的可控性进行研究，也可以通过产品与已上市产品的比较来达到对产品质量、安全性等方面的评估，这一评估的结果在一定程度上决定了该药物的临床和非临床指标，可为药物的后续研发提供方向和路径。
CDE解答仿制药研发的15大共性问题
CDE解答仿制药研发的15大共性问题问&答一问题一：我公司现开发一种单剂量口服溶液，原研制剂的处方加入了防腐剂，考虑到防腐剂的加入对人体还是存在一定的危害性的，且此口服液中并未含有蛋白或多糖成分，甜味剂是三氯蔗糖，并不容易染菌。
故我公司研发中去除了产品的防腐剂，同时加强了产品工艺过程的控制。
1、溶液在灌装前进行0.22um的滤膜除菌过滤。
2、对灌装后的溶液进行105℃30分钟的蒸汽灭菌。
多批样品的检测结果，以及6个月的稳定性研究结果中微生物限度检查均合格。
这种情况下，产品中不加防腐剂是否可行？答：从目前口服溶液生产环境的控制要求、口服溶液剂型特点和处方特点考虑，口服溶液在生产和贮藏过程中，发生微生物污染及繁殖的可能性较大。
上述问题中，虽对产品的处方组成与是否易造成微生物污染进行了分析，但尚无充分的文献资料和试验资料的支持，同时也未对原研制剂的处方、以及原研制剂中使用防腐剂的情况进行深入的研究。
对于上述问题中所提及的生产过程中所采取的降低微生物污染的各项措施，其有效性并未通过验证来加以确证。
此外，微生物限度检查同无菌检查一样，由于微生物分布的不均匀性、微生物检验误差较大等原因，即便是样品的微生物限度检查符合要求，也并不能够完全代表样品的微生物符合要求。
综上，对于口服溶液而言，处方中不使用防腐剂，其微生物污染超标的风险将远大于处方中使用防腐剂。
如处方中使用防腐剂，应对防腐剂的种类、用量、质控标准等进行全面的筛选研究。
问&答二问题二：我公司现开发一种口服固体制剂，经对原研制剂的处方进行研究分析，确定其处方中使用了一种抗氧剂，但在国内无法购买到有合法来源有药用批准文号的该抗氧剂，请问可以使用食品级标准吗？答：原则上，除了应采用已获准注册的药用辅料外，在研发中更应关注通过全面的供应商审计工作、不同供应商产品的比较研究工作、辅料内控质量标准的制定、制剂的处方工艺研究和质量控制研究工作等，选择并固定合适的供应商，制定严格的辅料内控质量标准，以有效保证产品质量；对所用辅料应提供药用辅料批准证明文件、来源证明、质量标准及检验报告。
生物技术制药问答题
生物技术药物的特性有哪些？○1分子结构复杂○2具有种属特异性○3治疗针对性强○4稳定性差○5基因稳定性○6免疫原性○7体内半衰期短○8受体效应○9多效性和网络性效应○10检验的特殊性原核细胞的分类及各自的特点有哪些？1大肠杆菌○1产品多为胞内产物○2常形成不溶性包含它○3不存在翻译后的修饰作用○4N端常多一个甲硫氨酸残基会引起免疫反应○5会产生内毒素，难以除去2枯草芽孢杆菌○1可以将蛋白质产物直接分泌到培养液中，不形成包含它○2不能使蛋白质产物糖基化○3有很强的胞外蛋白酶，对产物进行不同程度降解3链霉菌○1非致病，使用安全○2分泌能力强○3具有糖基化能力理想的微载体需具备哪些条件？○1微载体表面性质与细胞具有良好的相容性，适于细胞附着、伸展和增殖○2微载体的材料无毒性○3微载体的材料是惰性的不与培养基化学成分发生化学变化，也不会吸收培养基中的营养成分○4微载体的比重为1.030—1.045g/ml，使载体在低速搅拌下就可悬浮，而在静止时又可以很快沉降便于换液和收获○5粒径在60—250um(溶胀后)之间为好，并要尽可能的均一，差异不大于20um ○6具有良好的光学透明性，适于在倒置显微镜下观察细胞在载体上的生长情况○7基质的性质最好是软性的，避免在搅拌中由于载体相互摩擦而损伤细胞○8可耐120℃高温便于采用高压蒸汽灭菌○9经简单的适当处理后，可反复使用○10原料充分，制作简便，价廉固定化酶的特点有哪些？1优点：○1可以在较长时间内多次使用，而且在多数情况下，酶的稳定性提高○2反应后，酶与底物和产物易于分开产物中无残留酶，易于纯化，产品质量高○3反应条件易于控制，可实现转化反应的连续化和自动控制○4酶的利用效率提高，单位酶催化的底物量增加用酶量减少○5比水溶性酶更适合于多酶反应2缺点：○1固定化时，酶的活力有损失○2增加了生产成本，工厂初始投资大○3只能用于可溶性底物，而且较适用于小分子底物对大分子底物不适宜○4胞内酶必须经过酶的分离纯化过程○5与完整菌体相比不适于用于多酶，特别是需要辅助因子的反应修饰酶的特性有哪些？○1热稳定性高○2抗各类失活因子能力提高○3抗原性消除○4体内半衰期延长○5最适PH改变○6酶学性质变化○7对组织分布能力改变基因工程药物的生产流程基因工程药物的生产可以分为上游和下游两个阶段，上游阶段主要是分离目的基因、构建工程菌（细胞）。
关于生物仿制药Biosimilarproducts药学研究问题的思考.doc
关于生物仿制药（Biosimilar products）药学研究问题的思考与小分子的化学药品不同，生物制品的分子量较大且结构复杂，产品质量尤其是生物学活性易受各种因素影响且不太稳定，再加之目前可行的分析方法有限，因此难以通过有限的比较研究来完全确认不同企业产品之间的一致性。
基于生物制品的上述特性，目前国内外药品监管部门均认为，对传统的仿制药品（generic drug）的评价理念和标准并不适用于仿制性的生物制品，不同企业生产的同名的生物制品只能达到相似而非一致，因此对于仿制性的生物制品一般不称为generic drug，而称作Biosimilar products或Follow-on Biologics，而且在进行此类生物制品的研发时需进行非常广泛的比较性研究，包括质量、非临床以及临床试验等，以充分确认其安全性和有效性。
鉴于目前国内对于此类生物制品尚无法定而统一的称谓，因此为简化起见，本文暂称之为生物仿制药。
以下笔者将就此类生物制品药学研究的意义以及国内外相关技术要求等进行简要回顾，并在此基础上提出一些对于生物仿制药药学研究问题的个人观点和看法。
一、关于生物仿制药药学研究的总体考虑药学研究（包括生产和质量研究等）是药物研发的基础性工作。
对于生物仿制药来讲，药学研究不但是为了达到产品质量可控的目的，而且通过对生物仿制药与已上市药物质量的比较，可以对仿制品的安全有效性进行初步的判断，并据此确定后续研发阶段的研究内容，可以说药学研究结果在相当大的程度上决定了对于后续非临床和临床试验研究的技术要求。
因此，任何企业如果进行生物仿制药的研发并期望减少耗资巨大的非临床和临床试验，则应高度重视药学研究工作，并以之作为整体研发工作的重要基础。
二、国内外生物仿制药药学申报资料要求简介就药学方面的技术资料要求来讲，生物仿制药的研究内容与其他生物产品包括创新性产品并无很大不同，只是更加强调与已上市产品的比较性研究。
在这一点上国内外的相关法规和技术指南是基本一致的。
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生物类似药研发相关问题问与答
发布日期：20190731
自2015年2月原国家食品药品监督管理总局发布《生物类似药研发与评价技术指导原则（试行）》以来，截至目前国内已有多个治疗用生物制品按生物类似药申报，并已有产品获准上市。
随着国内生物类似药研发的不断深入，相关研究单位通过沟通交流咨询的生物类似药相关技术问题也显著增多。
经过系统梳理，现就比较集中和普遍的问题以及我们当前的考虑总结如下：
问题一、生物类似药的适用范围？
答：适用于结构和功能明确的治疗用重组蛋白质制品。
候选药物的氨基酸序列原则上应与参照药相同。
建议使用与参照药类似的宿主细胞和表达体系，因为不同的细胞类型会影响翻译后修饰的模式，如糖基化等。
如果使用不同于参照药的表达体系，需进行充分的药学比对研究证明所表达的蛋白具有相同的氨基酸序列、相当的高级结构和翻译后修饰以及生物学活性；如果生物类似药候选药与参照药进行药学比较后，发现二者之间翻译后修饰程度和类型上有差异，还须对安全性和有效性潜在的影响进行论证。
如果候选药采用新的表达系统，通常会增加糖基化模式的差异和新的工艺相关杂质，还应考虑对临床免疫原性的影响问题。
问题二、生物类似药的整体研发策略？
答：类似药研发的总体思路是以比对试验证明其与参照药的相似性为基础，支持其安全、有效和质量可控。
应采用逐步递进的顺序，分阶段开展药学、非临床、临床比对试验。
完成前期药学和非临床比对研究后，建议申办方与中心开展pre-IND沟通交流，明确后续的研究内容和研究设计。
建议临床研究阶段应先进行PK比对研究，在完成PK研究后建议与中心进行沟通交流，经初步评估具有PK等效性后，再开展头对头的疗效和安全性比对研究。
问题三、参照药的选择和来源？
答：参照药应选择在国内上市销售的原研药，研发过程中各阶段所使用的参照药，应尽可能使用相同产地来源的产品。
对不能通过商业途径在国内获得的，可以考虑其他合适的途径，但应增加不同来源参照药的桥接比对研究或提供不同来源
参照药之间可比的证据，同时关注原液的来源。
申请人应尽可能选择已在我国获批进口注册或临床试验的原研药作为生物类似药临床试验用参照药。
为保护受试者安全，对申请人拟选择与在我国获批进口注册或临床试验产地不一致的同一企业的原研药品作为参照药的，在临床试验开始前，应提供不同产地原研药之间可比的证据或按照我国药品监管部门关于生物类似药研究与评价的相关技术指导原则要求，开展不同产地原研药品的比对研究并证明二者可比后，以补充申请方式提交国家药监局药品审评中心。
待国家药监局药品审评中心审评认可后，申请人方可将未获批产地的原研药用于临床试验。
申请人在研发的各个阶段开展相似性比较研究所选择的参照药应为同一产地产品。
问题四、免疫原性比对试验的一般考虑？
答：建议申办方在所有临床研究（包括人体PK或PD研究）中收集全部受试者免疫原性的数据。
根据不同产品的免疫原性特征设定合理的取样时间点和随访期限，需考虑疗程的持续时间、制剂药代动力学特征以及体液免疫反应的发生时间等因素。
建议结合具体品种与CDE进行讨论。
生物类似药和参照药间任何的免疫应答差异都应引起重视，并结合具体情况分析导致差异的原因、对有效性及安全性的影响等。
问题五、如何确定生物类似药临床比对研究的等效性界值？
答：生物类似药临床疗效比较研究中，需要合理选择比值或差值作为主要终点指标的效应量。
等效性界值一般基于原研产品疗效的置信区间进行估算，并结合临床意义进行确定。
原研产品的疗效通常依据于原研产品与标准治疗（或安慰剂）随机对照优效性研究的Meta分析结果。
纳入Meta分析文献的选择、分析结果的利用等需要综合考虑目标适应症国内外临床实践、种族差异、样本量可行性等因素。
问题六、生物类似药适应症的外推需考虑那些方面？
答：参照药已在国内获批多个适应症的，如果候选药通过比对研究证实了与参照药临床相似，可以考虑外推至参照药的其他适应症。
适应症外推需根据品种特点和相似性研究数据的充分性个案化考虑。
外推的适应症，应当是临床相关的病理机制和/或有关受体相同，且作用机理以及靶点相同的；临床比对试验中，选择了合适的适应症，并对外推适应症的安全性和免疫原性进行了充分的评估。
申请人须提供充分的科学证据以支持适应症外推的申请。
问题七、与参照药进口说明书相比，生物类似药说明书撰写的注意事项？
答：生物类似药说明书的撰写应当以不影响临床使用和有利于上市后安全性监测为基本考虑。
目前，建议在说明书首页页眉添加，例如：“类似药商品名（XYZ单抗）是参照药商品名（XYZ单抗）的生物类似药”；首页页脚添加生物类似药的定义：“生物类似药是指支持此生物制品获得上市批准的数据已证明该生物制品与国家药品监督管理局批准的参照药高度相似，并且没有临床意义上的差异。
本品说明书与原研产品说明书保持一致。
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生物类似药说明书中的临床试验数据应体现有效性和安全性，而不是体现相似性。
生物类似药说明书中名称的使用需注意参照药商品名、类似药商品名与通用名的差别。
在引用参照药临床研究数据时，建议使用参照药的通用名而非商品名。