2005年版《中国药典》三部中的部分病毒类制品标准与国外标准的比较

《中国药典》三部是我国生物制品生产、质控和监管必须依照的法定标准。世界卫生组织（WHO）生物制品规程通常为世界各国药品管理当局制定本国相关生物制品标准的重要依据。《欧洲药典》是欧盟各国必须遵守的药品质量标准。     

2005年版《中国药典》三部附录修订主要内容

源于《中国生物制品规程》的《中国药典》三部已于2005年7月1日正式执行。附录部分是2005年版药典三部编纂工作的重点之～。在广泛开展科研工作的基础上，参考世界卫生组织生物制品相关规程、《中国药典》二部及欧美等国药典，对2005年版药典三部附录内容进行了增修和规范。该版药典三部共收载附录140个，其中新增62个，修订78个，删除1个。     

GMP大事记

11982年5月,卫生部颁布《关于加强生物制品和血液制品管理的规定（试行）》,同年6月发布《开展整顿生物制品和血液制品的实施办法》,并颁布生物制品规程。这是我国药品GMP的最早雏形。     

实施《中国药典》2010年版三部完善生物制品质量控制

目的促进《中国药典》2010年版三部的贯彻实施。方法通过解析《中国药典》2010年版三部增修订概况,探讨生物制品国家标准的进一步完善和提高。结果与结论 新版药典三部对生物制品生产规范、质量控制提出了新的要求。     

《中国生物制品规程》的沿革及现状

《中国生物制品规程》的沿革及现状李桂萱（中国药品生物制品检定所１０００５０）生物制品属于药品，它多数以微生物作为材料制备而成，所以又称生命制品。如果制品质量不好，就可能产生不良后果，从这个意义上讲，生物制品的质量就是生命。《中国药典》是药品的质量标准...     

新生物制品审批办法补充规定

根据《药品管理法》和《新生物制品审批办法》实施的经验,现作如下补充规定:第一条、新生物制品与新药品难以区分者按以下办法处理.原则上按其用途,用作免疫预防者属生物制品;用作临床治疗者属药品;但该产品的生产工艺,质量控制标准及其检测方法接近生物制品者,虽属治疗用品仍按新生物制品有批程序申报,申报时需参考《新药审批办法》中有关技术要求.在申请临床研究时所报资料除符合《新生物制品审批办法》要求外,尚需根据不同制品增加必要的新药申请临床研究的资料,并需在卫生部指定的临床基地或卫生部认可的单位进行临床研究,完成临床研究后需同时请西药分委员会的有关临床专家审评.     

生物制品研究进展

1 我国生物制品发展概况 新中国成立后提出“预防为主”的卫生方针,生物制品事业获得蓬勃发展。卫生部在全国先后建立了北京、上海、武汉、长春、兰州、成都6个生物制品研究所及中国药品生物制品检定所、中国医学科学院昆明医学生物学研究所。培训了生物制品人员,经过40余年的努力,我国生物制品事业逐步走上轨道,不断研制出大量人民急需的生物制品。由于坚持“质量第一”的方针,制品质量不断提高。1988年卫生部颁布了《生物制品 GMP》,进一步加强了全面质量管理,我国生物制品逐步达到WHO标准,充分发挥了生物制品在防病、治病和诊断疾病上的作用。一些严重威胁人民健康的传染病,由于能用疫苗有效预防已多数被控制。     

法国和美国生物制品管理的介绍

20 0 1年 2月 2 8日人大常委会通过的《药品管理法》中明确加强了生物制品的国家管理。随着科学技术日新月异的发展 ,生物技术在医药领域已经占有了相当重要的地位 ,代表着当今医药发展的潮流。新的生物技术医药产品不断问世 ,而我国传统的管理模式已经显现出不适应。无论是实施新的《药品管理法》 ,还是我国加入世界贸易组织以后面对的形势 ,都给生物制品的管理提出了更高的要求。由于生物制品本身的生物变异性和特殊性 ,ＷＨＯ对生物制品的管理也提出了相应的管理要求。为了配合新修订的《药品管理法》的实施和配套法规的制订 ,国家药品监…     

《中国药典》2010年版三部增修订概况

《中国药典》2010年版三部已于2010年10月颁布执行。新版药典三部的实施标志着国家对生物制品生产规范、质量管理的要求迈上了一个新的台阶,生物制品行业将面临新的发展机遇和挑战。为进一步完善生物制品国家标准,规范生产过程及加强国家对生物制品生产质量的监管,     

《国际生物制品学杂志》征稿征订启事

《国际生物制品学杂志》（原名《国外医学》预防、诊断、治疗用生物制品分册）属中华医学会系列杂志，是由中华人民共和国国家卫生和计划生育委员会主管、中华医学会和上海生物制品研究所有限责任公司主办的国家级学术期刊。     

鼻用生物制品的进展与挑战

生物制品发展迅猛,在应对多类疾病的治疗时展现出其独特的优势与潜力。然而目前常用的口服、注射等给药方式中,生物制品常存在稳定性差、体内半衰期短、中枢神经系统利用度差等问题,限制了生物制品的应用范围与发展。通过鼻腔对生物制剂进行给药的鼻用生物制品,充分利用鼻腔中天然存在的鼻脑通路、黏膜免疫淋巴组织等功能组分递送药物分子,具有高效递送、提高药物利用度的潜力,成为一种很有前景的策略。本文通过已发表文献、临床试验数据库、相关产品信息等公开资料,从作用机制、应用现状、发展前景等方面对鼻用大分子治疗药物、鼻用疫苗及鼻用细胞疗法等鼻用生物制品主要类别的研究现状进行总结,进一步对鼻用生物制品的发展提出建议。     

The development and assessment of biological treatments for children

The development of biological agents with specific immunological targets has revolutionized the treatment of a wide variety of paediatric diseases where traditional immunosuppressive agents have been partly ineffective or intolerable. The increasing requirement for pharmaceutical companies to undertake paediatric studies has provided impetus for studies of biologics in children. The assessment of biological agents in children to date has largely relied upon randomized controlled trials using a withdrawal design, rather than a parallel study design. This approach has been largely used due to ethical concerns, including use of placebo treatments in children with active chronic disease, and justified on the basis that treatments have usually already undergone robust assessment in related adult conditions. However, this study design limits the reliability of the data and can confuse the interpretation of safety results. Careful ongoing monitoring of safety and efficacy in real-world practice through national and international biologics registries and robust reporting systems is crucial. The most commonly used biological agents in children target tumour necrosis factor-α, interleukin-1, interleukin-6 and cytotoxic lymphocyte-associated antigen-4. These agents are most frequently used in paediatric rheumatic diseases. This review discusses the development and assessment of biologics within paediatric rheumatology with reference to the lessons learned from use in other subspecialties.     

Application of Mechanistic Models for Process Design and Development of Biologic Drug Products

Modeling approaches play a valuable role at various stages of development and life-cycle management of biopharmaceutical products. In Quality-by-Design (QbD) paradigm, quality needs to be designed into the product rather than merely confirming it through end product testing; this requires in-depth understanding of the product quality and impact of manufacturing process on product quality (Group IEW 2005, 2008, 2009). Modeling strategies in support of QbD paradigm for biologics are particularly important because of the costs involved in the development of biologic products (Group CBW 2009; Fissore and Antonello (Qual Des Biopharm Drug Prod Dev 18:565–93, 2015)). This mini-review focuses on the application of mechanistic models in the development of biologic drug products as ready-to-use solutions or lyophilized drug products. The choice of the modeling approach is dependent on the specific processes involved in the unit operation as well as intent of application of modeling. The application of models to unit operations in biologics drug product processing such as mixing (compounding), membrane transfer (ultrafiltration/diafiltration), freeze-thaw, and lyophilization, to characterize the quality risks, define the design space, provide input to control strategy, and build robustness in the process will be discussed.     

Injectable in-situ gel depot system for targeted delivery of biologics to the retina

Abstract

In current clinical settings, frequent intravitreal (IVT) injections of anti-vascular endothelial growth factors are used due to their short in-vivo half-life and rapid clearance from the back of the eye. The IVT injections are associated with pain, risk of infection, retinal detachment, and financial burden. Biologics molecules can undergo physical, chemical, and enzymatic degradation during formulation development and in the biological environment. Moreover, the complex ocular structures also act as a rate-limiting barrier for these biologics. Thus, delivering stable and clinically relevant biologics concentration to the back of the eye is still a challenge. Compare to other drug delivery platforms, injectable in-situ gelling depot systems (IISGDs) have emerged as an effective system for biologics delivery. In this review, we have discussed various biologics used in ocular therapeutics and their associated challenges. Different routes of delivery and associated tissue barriers are also discussed. Different types of IISGDs developed to date for biologics delivery to the back of the eye were also covered. To conclude, various critical parameters related to the formulation development process and injectable depot systems that need careful consideration and further investigations were highlighted.     

Early development of therapeutic biologics--pharmacokinetics

Modern biologics are biotechnology-derived pharmaceuticals. They are mostly used for diagnosis, prevention and treatment of serious and chronic diseases. Today, therapeutic biologics range from traditional biologics like blood and blood components, fractionated blood products, and antitoxins to modern biologics such as monoclonal antibodies, cytokines (e.g. interferon, interleukine), tissue growth factors, vaccines directed against non-infectious disease targets, and gene transfer products. Chemical as well as pre-clinical development are major challenges for biologics due to their different physicochemical properties (mostly protein structure) compared to small molecules. They demonstrate much more complex pharmacokinetic behaviour, which strongly influences their pre-clinical testing strategy. Biologics are often highly species-specific in action and immunogenic in test animal species and humans. Immunogenicity of therapeutic biologics may influence their pharmacokinetic behaviour as well as pharmacodynamics and toxicity. Biologics are frequently regulated by different procedures compared to small molecules. New guidances are evolving which reflect the rapid development of new technologies in this field. Bioanalytical method development and validation is a prerequisite not exclusively for pharmacokinetic studies but for the whole pre-clinical and clinical development. Due to their unique properties, different kinds of bioanalytical assays (mass assays, activity assays, immunogenicity assays) are necessary in early development of biologics.     

Beyond humanization and de-immunization: tolerization as a method for reducing the immunogenicity of biologics

Immune responses to some monoclonal antibodies (mAbs) and biologic proteins interfere with their efficacy due to the development of anti-drug antibodies (ADA). In the case of mAbs, most ADA target ‘foreign’ sequences present in the complementarity determining regions (CDRs). Humanization of the mAb sequence is one approach that has been used to render biologics less foreign to the human immune system. However, fully human mAbs can also drive immunogenicity. De-immunization (removing epitopes) has been used to reduce biologic protein immunogenicity. Here, we discuss a third approach to reducing the immunogenicity of biologics: introduction of Treg epitopes that stimulate Treg function and induce tolerance to the biologic protein. Supplementing humanization (replacing xeno-sequences with human) and de-immunization (reducing T effector epitopes) with tolerization (introducing Treg epitopes) where feasible, as a means of improving biologics ‘quality by design’, may lead to the development of ever more clinically effective, but less immunogenic, biologics.     

Comparability and biosimilarity: considerations for the healthcare provider

Abstract

Background:

Healthcare providers use recombinant biologics such as monoclonal antibodies to treat a variety of serious illnesses. Manufacturing of approved biotechnology products is complex, and the quality of the resulting biologic is dependent on careful control of process inputs and operating conditions. Biosimilars, which are similar but not identical to innovator biologics, are entering regulatory evaluation, approval, and marketing in regions with biosimilar approval pathways.     

Comparability and biosimilarity: considerations for the healthcare provider

BACKGROUND: Healthcare providers use recombinant biologics such as monoclonal antibodies to treat a variety of serious illnesses. Manufacturing of approved biotechnology products is complex, and the quality of the resulting biologic is dependent on careful control of process inputs and operating conditions. Biosimilars, which are similar but not identical to innovator biologics, are entering regulatory evaluation, approval, and marketing in regions with biosimilar approval pathways. SCOPE AND FINDINGS: This article describes the evaluation and potential impact of manufacturing process changes and biosimilar product development, and explores the similarities and distinctions between the two. Regulatory agencies generally require a comparability exercise following a manufacturing process change. This comparability is focused primarily on analytical characterization of the approved product before and after the manufacturing process change, with non-clinical and clinical confirmation required when determined necessary. When developing a biosimilar, the manufacturer does not have access to key information including the innovator manufacturer's cell line, cell culture conditions, purification procedures, and fill and finish processes. Further, the biosimilar manufacturer does not have access to information about the innovator manufacturer's product development history, including knowledge about the quality attributes of lots used in non-clinical and clinical development. We define the biosimilar manufacturer's lack of information as the knowledge gap. As a result, a biosimilarity exercise to compare a biosimilar to an approved innovator biologic requires a rigorous evaluation to ensure the safety and efficacy of the biosimilar. CONCLUSION: Given the knowledge gap under which biosimilars are developed, data to establish biosimilarity should go beyond a simple comparability exercise.     

Biosimilarity for Follow-on Biologics

With dramatic increased spending on biologics and approaching patent expirations for existing biological products, there is a need to consolidate thinking on the regulatory approval pathway of biosimilars. However, biologics have much greater complexity by nature. The traditional paradigm currently used for generic chemical drugs, where bioequivalence is the focus, cannot be extrapolated to biologics. In the biosimilars scenario, the comparability of pharmacokinetic and pharmacodynamic parameters, and the comparability of efficacy and safety from clinical trials are the keys for the success of follow-on biologics. Developing sensitive bioanalytical methods to detect small, meaningful differences is critical. This article proposes a novel reference-scaled method to evaluate the comparability of pharmacokinetics parameters, and illustrates the method using a study comparing a test drug to a reference drug in a cancer study.     

《中国药典》2015年版四部增修订概况

《中国药典》2015年版一个重要变化是将原药典中药、化学药、生物制品三部分别收载的附录,包括制剂通则、检验方法和指导原则进行整合,与药用辅料一并单列成卷,作为药典第四部。新版《中国药典》四部作为药典标准的共性要求,是药典标准的重要组成部分。新版《中国药典》四部在制剂通则的规范、检验方法的完善、先进检测技术的应用、全面质量控制的建立、药用辅料标准的完善和品种收载均取得很大进步,对提升药典标准整体水平、加强药品质量控制、提高药品质量发挥重要作用。