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.
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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
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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
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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,
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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
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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
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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
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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
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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
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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
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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,
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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
