Safety aspects in the quality control of recombinant products from mammalian cell culture

The recent approval of the recombinant DNA-derived biological, human tissue-type plasminogen activator (rt-PA), obtained from large scale mammalian cell culture, addressed a number of issues concerning the safety of recombinant products. The assurance of the safety of such highly complex proteins requires that the following topics be investigated: the characterisation of the recombinant production organism; control of large scale cell culture production conditions; design of the purification process and consistency of manufacture; the purity, safety, and stability testing of the final product; and clinical studies. Each of the topics described above is discussed with respect to those key quality control issues that ensure the safety of the product. The use of analytical techniques such as peptide mapping and multiantigen ELISA assays to guarantee both the genetic stability and the purity of the final product is also discussed.     

Raw materials in the manufacture of biotechnology products: regulatory considerations

The Food and Drug Administration's Pharmaceutical cGMPs for the 21st Century initiative emphasizes science and risk-based approaches in the manufacture of drugs. These approaches are reflected in the International Conference on Harmonization (ICH) guidances ICH Q8, Q9, and Q10 and encourage a comprehensive assessment of the manufacture of a biologic, including all aspects of manufacture that have the potential to affect the finished drug product. Appropriate assessment and management of raw materials are an important part of this initiative. Ideally, a raw materials program should strive to assess and minimize the risk to product quality. With this in mind, risk-assessment concepts and control strategies will be discussed and illustrated by examples, with an emphasis on the impact of raw materials on cell substrates. Finally, the life cycle of the raw material will be considered, including its potential to affect the drug product life cycle. In this framework, the supply chain and the vendor-manufacturer relationship will be explored as important parts of an adequate raw materials control strategy.     

生物制品的国家管理

由于生物制品生产的原材料、生产工艺和检定方法本身固有的生命易变性和复杂性,以及绝大部分生物和于健康的儿童,ＷＴＯ提出了国家药品管理当局对生物制品管理的６项基本职能,并详细规定了执行该６项基本职能的技术技术。国家药品管理当局通过执行上述职能,即可最大限度地确保生物制品的质量、安全和有效。     

Assessment of biotechnology products for therapeutic use

Biotechnology products for therapeutic use include a very diverse range of products, including growth factors, cytokines, hormones, receptors, enzymes, clotting factors, monoclonal antibodies, vaccines, DNA vaccines, gene transfer products, cell therapies and tissue/organ grafts. While some of these products are regulated as medicinal products, the regulatory status of others such as some cell therapies and tissue/organ-based products differs globally and falls within the borderline between the practice of medicine, medical devices and medicinal products. The unclear regulatory status of some products can add to the complexity of the safety assessment of such products. Conventional non-clinical testing paradigms and guidelines for small molecule development are often not relevant for biotechnology products. Guidelines relating to the non-clinical safety evaluation of biotechnology products, gene transfer products and cell therapy products are available and represent a set of general guiding principals to be applied on a case-by-case basis. The quality, safety and efficacy of biotechnology products for therapeutic use are intricately linked, far more so than for conventional medicinal products, leading to the need for increased communication between those responsible for ensuring product quality and those responsible for non-clinical safety testing. Safety issues include microbiological safety (due to the use of biological materials either during the manufacturing process or as an integral part of the products), pharmacological/ biological toxicity (due to excessive primary pharmacology or undesirable secondary pharmacology), immunogenicity and potential tumourigenicity (for example, for growth factors, immunosuppressive monoclonal antibodies and cell therapy products). Genotoxicity and intrinsic chemical toxicity are less of a problem for biotechnology products.     

A systematic approach to the validation of monoclonal antibody manufacturing processes

Significant resources are required for the development and validation of complex processes used in the manufacture of monoclonal antibodies for clinical trials and commercial production. For those companies contemplating process validation, regulatory guidelines provide a good starting point, particularly with regard to product safety. However, these guidelines leave open the methodology required to determine suitable process limits that are essential to the validation of the robustness of the process. Using a generalized antibody manufacturing process as a guide, the authors present an approach that provides a reliable basis for process validation. Some typical pitfalls, and how these may be avoided, will be discussed for each major stage of validation.     

Current methods and research progress in nanomaterials risk assessment

Nanomaterials have unique physicochemical properties compared with those bulk materials of the same composition. Possible undesirable results of these capabilities are harmful interactions with biological systems and the environment, with the potential to generate toxicity. A number of studies on the effects of Nanomaterials in vitro and in vivo systems have been published. However, while the number of nanomaterials types and applications continues to increase, studies to characterize their effects after exposure and to address their potential toxicity are few in comparison, there is still a need for further studies that conclusively establish their safety/toxicity. The establishment of principles and test procedures to ensure safe manufacture and use of nanomaterials in the marketplace is urgently required and achievable. The major goal of this review is to summarize 1) analytical techniques applied for characterization of nanomaterials, 2) current analytical methods to assess nanomaterials toxicity in vitro and in vivo; 3) research progress of polymeric nanomaterials toxicity; 4) outlook.     

Biosimilares: balance de eficacia,seguridad y coste

A biosimilar medicinal product is a successor to a biological medicinal product for which patent protection no longer applies. Manufactured by recombinant DNA technology (insertion of gene into the host cell to produce the protein). Comparable with the selected comparator, reference product, in terms of quality, safety and efficacy. The biosimilar product is usually approved for the same indications as the comparator reference product given that they share the same mode of actions.     

A primer of drug safety surveillance: an industry perspective. Part II: Product labeling and product knowledge.

OBJECTIVE: To place the fundamentals of clinical drug safety surveillance in a conceptual framework that will facilitate understanding and application of adverse drug event data to protect the health of the public and support a market for pharmaceutical manufacturers' products. Part II of this series discusses specific issues regarding product labeling, such as developing the labeling, changing the labeling, and the legal as well as commercial ramifications of the contents of the labeling. An adverse event report scenario is further analyzed and suggestions are offered for maintaining the product labeling as an accurate reflection of the drug safety surveillance data. This article also emphasizes the necessity of product knowledge in adverse event database management. Both scientific and proprietary knowledge are required. Acquiring product knowledge is a part of the day-to-day activities of drug safety surveillance. A knowledge of the history of the product may forestall adverse publicity, as shown in the illustration. DATA SOURCES: This review uses primary sources from the federal laws (regulations), commentaries, and summaries. Very complex topics are briefly summarized in the text. Secondary sources, ranging from newspaper articles to judicial summaries, illustrate the interpretation of adverse drug events and opportunities for drug safety surveillance intervention. STUDY SELECTION: The reference materials used were articles theoretically or practically applicable in the day-to-day practice of drug safety surveillance. DATA SYNTHESIS: The role of clinical drug safety surveillance in product monitoring and drug development is described. The process of drug safety surveillance is defined by the Food and Drug Administration regulations, product labeling, product knowledge, and database management. Database management is subdivided into the functions of receipt, retention, retrieval, and review of adverse event reports. Emphasis is placed on the dynamic interaction of the components of the process. Suggestions are offered to facilitate communication of a review of adverse event data for various audiences. CONCLUSIONS: Careful drug safety surveillance is beneficial to the health of the public and the commercial well-being of the manufacturer. Attention to the basic principles is essential and, as illustrated, may be sufficient to resolve some problems.     

Pharmacologic considerations in the design of toxicology experiments

Final assessment of product acceptance must be based on value judgments that include (a) social, (b) economic, and (c) environmental factors as well as risk factors, and not on simple safety statements about the end product. The goal of toxicologic experiments should be to provide sufficient data to allow benefit-to-risk judgments about products. Benefit-to-risk judgments need to be made on a broad data base which includes: manufacturing, distribution, and use factors. Safety assessments begin with concerns associated with initial manufacture of raw materials and end with concerns related to disposal of the end products of use. Current experimental design needs to include biopharmaceutic considerations of the dose form, pharmacokinetic aspects, and pharmacodynamic factors as well as pathologic concerns. These factors stress the point that toxicology is a quantitative science because toxicity resides in the dose and dose form and not in the chemical entity.     

Selection of plastic containers for pharmaceuticals

With the awareness of the possibility of drug-plastic interaction, before substitution of a plastic container for glass, steps should be taken to ensure safety. This process is fraught with difficulties because of the complexity of plastic materials and even wider range of drug substances offered for sale in a variety of dosage forms. The selection of an appropriate container for pharmaceutical should be preceded by adequate testing to recognize the properties of the packaging material, and the stability, safety, and compatibility of the preparation packed in it. The same care and control used in the manufacture of a drug product should be used for the plastic packaging system.     

Cell-Based Therapies Formulations: Unintended components

Cell-based therapy is the fastest growing segment of regenerative medicine, a field that promises to cure diseases not treated by other small molecules or biological drugs. The use of living cells as the active medicinal ingredient present great opportunities to deliver treatment that can trigger the body’s own capacity to regenerate damaged or diseased tissue. Some of the challenges in controlling the quality of the finished cell-therapy product relate to the use of a variety of raw materials including excipients, process aids, and growth promotion factors. The quality of these materials is critical for ensuring the safety and quality of the finished therapeutic products. This review will discuss some of the challenges and opportunities associated with the qualification of excipients as well as that of the ancillary materials used in manufacturing.     

Risk Management in the Pharmaceutical Product Development Process

“The manufacture and use of a drug product, including its components, necessarily entail some degree of risk.”—International Conference for Harmonization (ICH) Q9. This paper examines the role of risk management in pharmaceutical product development in the context of patient safety and drug efficacy. Its objective is to contribute to building a common understanding of this quality risk management among the various functional groups involved in developing, testing, manufacturing, and approving of drug products within pharmaceutical companies and regulatory agencies. Selected aspects of drug substance and drug product development are used to demonstrate principles of risk management in action and presented as case studies.     

Validation of biotechnological production processes

Due to the biological synthesis of biotechnologically produced pharmaceuticals the product quality and safety of the drug is influenced by various factors. The correct nucleotide sequence and stability of the host cell/vector system provide the corresponding amino acid sequence of the protein. The posttranslational processing of the protein requires a well characterized production cell line. Suitable equipment for fermentation allowing a sterile production of the producing monoculture and consistent conditions are the basic requirements for the validation of the fermentation process. A constant specific productivity is one of the major criteria for the reproducibility of the production. For the validation of recovery and purification it is necessary to examine yield after each process step, product quality before and after each single process step and purification factors for removal of contaminating proteins, nucleic acids and potential viruses. In addition to the validation of the entire production process, reproducibility of quality of the formulated product has to be determined by a number of protein analytical, immunological and biochemical test methods concerning the identity, purity, safety and potency of the drug.     

刍议美国生物类似药行动计划

生物类似药是指在质量、安全性和有效性方面与已获准上市的参比制剂具有相似性的治疗性生物制品。结合美国、欧盟、日本和世界卫生组织对生物类似药研发及监管思路,重点介绍了2018年度美国食品药品监督管理局发布的《生物类似药行动计划——简介和概述：创新与竞争间的平衡》,以期对我国生物类似药监管政策的制定提供借鉴。     

骨架片在缓释给药系统中应用

本文研究的主要内容是骨架片作为一种有效的缓释给药系统的基本信息。骨架片是用来调节药物释放最常用的方法。骨架片受到广泛的欢迎，而且是治疗的首选，因为它能提高患者的顺应性，减少药物剂量和副作用，还能增加安全性。不同的聚合物材料能够被用来设计出适宜的释放曲线，并提供一个可行的和一致性的生产模式。     

Clinical safety of biosimilar recombinant human erythropoietins

Introduction: A "biosimilar" or "similar biological medicinal product" is a biological agent that is similar in terms of quality, safety, and efficacy to an authorized reference biological medicine. Since the expiration of the epoetin alfa patent in Europe, three agents have received marketing authorization from the European Medicines Agency: Binocrit (epoetin alfa; aka Abseamed and Epoetin Alfa Hexal), Retacrit (epoetin zeta; aka Silapo), and Eporatio (epoetin theta; aka Biopoin and Ratioepo). Areas covered: Using the EMA dossiers and journal publications, this article reviews clinical safety data for these products, with emphasis on serious/severe adverse events and a special consideration of immunogenicity, venous thromboembolism, and mortality. Expert opinion: A review of the available safety evidence shows that all three agents discussed have similar safety profiles. None were statistically higher on safety parameters to what is known about ESA as a class, when stratified by population. As with ESAs in general, immunogenicity, venous thromboembolism, and mortality are all concerns. What is known about ESAs regarding safety can be extended to biosimilar erythropoietins. Since biosimilars are unique, complex biological molecules, safety profiles may evolve from common to differentiated, once long-term product-specific safety data are available. Large-sample, long-term, observational studies of real-world practice will provide the heterogeneity and statistical power to demonstrate product-specific effectiveness and safety profiles. Statistically, out of the commercially available formulations of the three products reviewed, no single product is less or more safe.     

Biosimilars of biological drug therapies: regulatory, clinical and commercial considerations

Biologicals are distinct from small molecule drugs in that they are larger, more structurally complex agents. While the overall risk is modest, the active protein structure characteristic of biologicals makes them more prone to induce an acute and/or chronic immune response. Biosimilars are a new class of drugs intended to offer comparable safety and efficacy to the reference, off-patent biological. They are not generic alternatives per se and are generally not interchangeable. Given their structural complexity, multifaceted manufacturing process and risk for immunogenicity, unique regulatory pathways are required for biosimilars. In this article, we review the clinical, safety and submission requirements for biosimilars in several major markets. We also highlight issues of ongoing debate amongst key stakeholders and examine some of the commercial challenges faced by developers of biosimilars. As the leader of biosimilars drug approval and product uptake, the EU is highlighted.     

Approaches to the analysis of cell signaling networks and their application in drug discovery

The ability to predict the safety and efficacy of novel drugs prior to clinical testing is a key goal in pharmaceutical drug discovery. Gaining a mechanistic understanding of the complex cell signaling networks (CSNs) underlying disease processes promises to help reduce the number of clinical failures by identifying points of intervention as well as redundancies and feedback mechanisms that contribute to toxicities, lack of efficacy and unexpected biological activities. Experimental and computational approaches to analyzing and modeling CSNs are currently being validated using simple organisms and cell lines. In vitro cell systems of sufficient complexity to resemble human disease physiology, but which are also amenable to chemical and genetic perturbations on a large scale, are now required for deciphering the signaling networks operating in human disease. In this review, experimental and computational methods for modeling complex CSNs and the applications of these approaches to pharmaceutical drug discovery are discussed.     

生物制品GMP管理中生物安全问题浅析

目的为药品监督管理部门加强生物安全管理提供参考意见。方法采用文献法和调研法,着重对国外和我国生物制品生产与质量控制中的生物安全相关问题进行全面分析。结果与结论保证生物制品安全和生产安全问题,应引起生物制品行业的高度重视。