Technical Review Guideline For Calcuim Phosphrous Silicone Filling Materials
2021-06-22
Appendix 1 Technical Review Guideline for Registration of Calcium Phosphate/Silicone Bone Filling Materials This guideline aims not only to provide the applicant with the technical guidance for the registration of calcium phosphate /silicon bone filling materials, but also to offer technical reference for the food and drug supervision and administration department to review the registration materials. This guideline is the general requirements for the registration materials of calcium phosphate/silicon bone filling materials, and the applicant shall enrich and refine the registration materials according to the specific characteristics of the product, and determine whether the specific content is applicable or not according to the features of specific product. This guideline is a guiding document for the applicant and the reviewer, but not including the administrative matters involved in the registration and approval, nor enforced as a regulation compulsorily. —2—— If there are other methods that can meet the requirements of relevant laws and regulations, they can also be adopted, but detailed research and verification materials need to be provided. This guideline shall be used in accordance with the relevant regulations and standards. This guideline is in formulated under current laws, regulations and standard system as well as current cognitive level. With the constant improvement of laws, regulations and standards as well as the continuous development of science and technology, related content of this guideline will also be timely adjusted. I. Applicable scope In this guideline, calcium phosphate/silicon bone filling materials include synthetic calcium phosphate bioceramics, calcium silicon bioactive glass and calcium phosphate bone cement, suitable for the filling of bone defect caused by orthopaedic trauma and surgery without affecting the stability of bone structure, i.e., unstructured graft of arms, legs and spine. In this guideline, calcium phosphate/silicon bone filling materials cover two cases. One case is the calcium phosphate/silicon bone filling materials with part degradation after implantation and long-term in situ retention of implant materials, and the other case is the calcium phosphate/silicon —3—— bone repair materials with complete degradation after implant and defect parts able to autologous bone repair. This guideline does not cover all the submission requirements of calcium phosphate/silicon bone filling materials with growth factors (such as bone morphogenetic protein), collagen compound, nanoscale materials and/or nano-technology, composite degradable high-polymer materials (such as poly lactic acid), the new type of calcium phosphate/silicon bone filling materials and so on. II. Division principles of registration units The products with different main composition materials, preparation principles and key performance indicators (such as the contents of main components, liquid/solid phase ratio, degree of crystallinity, pore size distribution, porosity and grain size degree) shall be divided into different registered units. III. Registration material requirements (i) Summary material
Regulatory category, classification coding and normative naming According to the Classification Rules of Medical Device, Common Naming Rules of Medical Device and other relevant —4—— documents as well as the design characteristics and applicable scope of to-be-registered product, the regulatory category, classification coding and normative naming are determined with the discussion of its determination basis.
Product description The design principle (such as bone conduction principle, function principle of each component and the hydration reaction principle of calcium phosphate bone cement), manufacture principle (such as synthetic principle and pore-forming principle) and degradation principle and performance (if applicable) of to-beregistered product shall be described to clarify that compared with the marketed calcium phosphate/silicon bone filling materials in China, the to-be-registered product belongs to imitated, modified or newly designed product. The components, contents, primary packaging forms and materials of to-be-registered product shall be described. The general names of all raw materials, material brand number (if any), molecular formula and the compliant relevant standards (including national, industrial and international standards) of the to-be-registered product shall be clarified. For raw materials without corresponding standards, —5—— the quality control standard and acceptance report shall be provided to clarify the raw material supplier and supplier brand number. It is recommended that the above information shall be provided in the form of a list, and the raw material quality control standards and acceptance reports are provided in the form of attachments. The appearance and structure features of different types of products shall be described in the form of photos, structural drawings and text to define and mark key dimensions. For porous-structure product or the cured porous-structure product, the geometric characteristics of porous structure inside the product shall be described, including total porosity, open porosity and/or pore connection rate, average pore diameter, pore size distribution and so on. For the products with certain shapes, such as block and column, the basic mechanical properties are described, such as compressive strength and anisotropy.
Specifications In the same registration unit, it is suggested to divide the products with different outline structures, sterilization methods and packaging materials into different types, while divide the products with the same outline structure, sterilization method and packing —6—— material but different sizes and loading quantities into different specifications. In the case of multiple models and specifications of the to-be-registered products, all characteristic differentiation information of the products with each specification is described in the form of a list.
Packaging specification The packaging information of the to-be-registered product is clearly shown in the form of package structure analysis diagram, and the information of all packaging contents and packaging materials are shown in the form of a list. For multi-component products, such as the solid and liquid parts of calcium phosphate bone cement, the packaging information of each componentshall be clearly shown. The quality control standards for primary packaging (sterile barrier) materials suitable for sterilization method shall be provided.
Application scope and contraindication Calcium phosphate/silicon bone filling materials are applicable to the filling of bone defects caused by orthopaedic trauma and surgery without affecting the stability of bone structure. The applicant shall further explain the specific applicable population, using sites, maximum filling defect size, internal and/or external fixation devices —7—— for coordinated use, whether used with bone marrow, blood and etc., using precautions and other information according to the design characteristics of to-be-registered product. Product contraindications shall be described, including absolute contraindications and relative contraindications, such as inappropriate use population, diseases and other situations.
Reference similar products or previous products The applicant shall provide the information on similar products (both domestic and foreign marketed products) or previous products (if any), and explain the R&D background and purpose of the to-beregistered products. For similar products, the reasons for selecting them as research and development references shall be explained. Meanwhile, the similarities and differences between to-beregistered product and reference product (similar product or previous product) in the working principle, structure, manufacturing materials, performance index, function mode, applicable scope and other aspects.
Other content to be explained The approval number and the copy of approval document shall be provided for the approved parts or combined-use accessories. If the to-be-registered product is expected to be used in combination with —8—— other medical devices, it shall be explained. (ii) Research materials
Product performance study (1) Calcium phosphate bioceramics Calcium phosphate bioceramics mainly include hydroxyapatite, β-tricalcium phosphate and biphasic calcium phosphate ceramics as the component. Such products are generally made of calcium phosphate powder and binder mixed to form slurry, generated by different pore-forming methods (such as pore-forming agent method, gas pore-forming method and chemical foaming method) for producing porous structure and high temperature burning after molding. The research materials to be submitted by the applicant include but are not limited to the followings: ① Because the properties of powders (such as calcium/phosphorus ratio and crystallinity) and particle size distribution have great influences on the properties of bioceramics, it is necessary to submit research materials on powder preparation and quality control; ② The clearly selected pore-forming agent and its selection —9—— basis are required to provide the quality control standard and dosage of pore-forming agent, describe the principle and process of poreforming agent removing, submit pore-forming agents and their reaction products (such as carbide) residue control and validation data; ③ The research data of porous structure (such as porosity, opening porosity and/or pore connectivity, average pore diameter and pore size distribution), phase composition and crystallinity of bioceramics are provided; ④ Electron micrograph of bioceramic microstructure is provided to characterize its morphology. ⑤ For expected degradable products, the research materials on degradation performance are provided, referring to GB/T 16886.14- 2003 Section 14 of Medical Device Biological Evaluation: Quality and Quantity of Ceramic Degradation Product (note: the latest version is applicable to the standard of this guideline, hereinafter the same) for in vitro research on degradation performance; ⑥ The research materials on mechanical properties (such as compressive strength and anisotropy) of the products with certain shapes such as block and column are provided; ⑦ For biphasic calcium phosphate ceramics, the research —10—— materials of biphasic proportion optimization are provided (the determination basis of proportion); ⑧ The performance indicators included in the technical requirements of products and the determination basis for acceptance criteria and test methods shall be provided. (2) Calcium silicate bioactive glass Common bioactive glass is Na2O-CaO-SiO2-P2O5 quaternary system, including network former SiO2, glass network outer body Na2O, CaO and phosphorus oxygen tetrahedron, such as 45S5 series, which is made from high temperature melting to be the amorphous solid material with irregular random network structure, generally as powder or granular shape. The inside surface is exchanged with fluid ion to deposit as carbonated hydroxyapatite layer with low crystallinity. The research materials to be submitted by the applicant include but are not limited to the followings: ① The proportion of each raw material and provide the preferred research materials (the determination basis of the proportion) is clearly shown; ②Research materials on the content of each component in the —11—— final product are provided; ③ An electron micrograph of the microstructure of bioactive glass is presented to characterize its morphology; ④ The research materials showing that it is in the glass state are provided; ⑤The research materials on product granularity and distribution are provided; ⑥ For the expected degradable products, the research materials of degradation performance are provided, referring to GB/T 16886.14 for in vitro study of degradation performance; ⑦ The performance indicators included in the technical requirements of products and the determination basis of acceptance criteria and test methods are provided. (3) Calcium phosphate bone cement Calcium phosphate bone cement is generally composed of solid components, liquid components and additives, of which solid components are commonly mixed by two or more powder calcium phosphate (acidic and alkaline calcium phosphate); liquid components can be normal saline, dilute phosphoric acid and etc.; additives are added to promote solidification, enhance strength, —12—— improve anti-collapse performance and adjust degradation performance. After solid phase and liquid phase are mixed evenly in accordance with relevant specified proportion, the shapeable paste can be obtained. Through a series of hydration reactions, weakcrystallization hydroxyapatite crystals are generated and gradually solidified in the in vivo environment. The acid-base reaction between the byproducts of hydration ensures the continuous hydration reaction. The conventional calcium phosphate bone cement solidifies only to form micro-pores, and the absorption process is carried out layer by layer from the surface to the inside
