This guideline serves as the general requirements in submission of documents for registration of disposable dialyzer products, so that the quality of documents and efficiency of technical evaluation will be improved. The applicant or manufacturer shall detail the required data and information and determine whether the requirements are applicable for the specific product. If not, reasons and corresponding scientific basis shall be elaborated.
This guideline serves as only guidance document for the applicants, manufacturers and evaluators, and does not include administrative issues involved in the registration procedures. As this guideline is not mandatory, any other methods that meet the related regulations can also be adopted; however, detailed research data and evidences shall be provided. This guideline shall be followed under the precondition of related laws and regulations.
This guideline is formulated based on the existing laws and regulations, as well as the current experiences. With the perfection of laws and regulations, and the development of scientific technology, related content of the guideline will be updated accordingly.
This guideline provides general requirements for registration of products in this category. Submitted documents can place extra emphasis to some requirements depending on its characteristics.
 
Two Scope of Application
This guideline applies to dialyzer products totally or partially complying with the Cardiovascular implants and Artificial Organs Hemodialysis, Hemodiafiltration Device, Hemofiltration and Hemoconcentrators (YY0053-2008), including traditional dialyzer and high-flux dialyzer (ultra-filtration coefficient over 20ml/mmHg.h).
 
Three Basic Requirements
1. Technical report of product
The technical report of the product should elaborate systematically the research, design and development processes, as well as other technical data, including its application, technical features, product design, process program, and the formulation and basis of validation proof, safety evaluation and standard.
 (1) Raw materials
1) Material Composition
Materials of all parts of the product, including dialysis membrane, shell, sealing compound, adhesive, end cap, seal ring, etc. should be specified with chemical name, molecular weight and type (or grade), etc. The manufacturer should try to select those raw materials that have been adopted in the medical industry, and accompany with professional certificates of the raw materials suppliers.
2) Material characteristics
Material characteristics comprise the physical, chemical characteristics, quality standard, biological assessment data and research report. As the raw material characteristics affect the quality of the final product significantly, it’s advised of providing the complete formula of the raw material, including plasticizer, additive, and colorant, etc.
 (2) Biological assessment of product
Geological assessment of the product should be conducted in accordance with the GB/T 16886 series (accumulative action time to be considered), and include the following items:
l  Cytotoxicity;
l  Sensitization;
l  Stimulation or intradermal reaction;
l  Acute toxicity of whole body;
l  Genotoxicity;
l  Blood compatibility;
l  Subchronic toxicity;
l  Implantation;
l  Chemical analysis of filterable substances;
l  Additional test: chronic toxicity, carcinogenicity.
 (3) Structural composition of product
The documents submitted should provide the structural diagram of the product, and specify each structure and the differences between various types. Among them, the structure of dialysis membrane is the critical technical index that determines the product performance and clinical application results, as follows:
l  Area of membrane;
l  Number of fiber;
l  Inner diameter of fiber;
l  Wall thickness of fiber;
l  Aperture range, void content, etc.
Furthermore, if the dialysis membrane has other features, like specificity action on some protein factor, they should also be elaborated. Corresponding data and electron microscope photos should be provided to support the above indexes.
 (4) Performance test
Description and test of the dialyzer should include:
l  Adaptation;
l  Interface type;
l  Clearance rate;
l  Ultra-filtration rate;
l  Pressure drop;
l  Pre-hyperemia volume, etc.
Clearance rate and ultra-filtration rate are the two primary functional parameters of the dialyzer and the critical indexes for assessment of the quality. The clearance rate of urea, creatinine, phosphate, vitamin B12 is taken as the index of filtration performance for normal dialyzers, while the additional performance test or clinical assessment data for the clearance rate of β2 microglobulin should also be provided for the high-flux dialyzer. Ultra-filtration rate is the index of assessing the capability of the dialyzer to filtrate the water. Be noted that the test conditions for the above indexes should be stated. For the clearance rate test, velocity range of blood flow and dizlyzate regulated by the manufacturer should be covered, and for the ultra-filtration test, trans-membrane pressure and velocity range of blood flow regulated by the manufacturer should be covered.
Product for test can represent the products applied for registration in terms of safety and validity. Regarding products with the same membrane material and structure in the same registration unit, products with different membrane area (<1.4m²,1.4m²-2.0m²,>2.0m²) should take physical test. Description of typical product should expound from the perspectives of materials, processes, structure and application scope, instead of the product with the largest output.
The solute clearance rate and ultra-filtration rate of the standard YY 0053-2008 should be stated in the international universal way, different with the 1991 version. The above indexes should be determined by corresponding test methods, or standard test methods. Test conditions should simulate the clinical application to the greatest extent.
 (5) Sterilization
Sterilization methods and processes should refer to Sterilization of health care products--Requirements for validation and routine control--Industrial moist heat sterilization GB 18278, Medical devices--Validation and routine control of ethylene oxide sterilization GB 18279, and Sterilization of health care products—Requirement for validation and routine control—Radiation sterilization GB 18280. Sterile devices normally should meet the 10^-6 sterile assurance level (SAL). The submitted documents should include:
l  Sterilization method;
l  Verification method and sterile assurance level;
l  Description of assurance method;
l  Irradiation dose;
l  Ethylene oxide and 2-chlorohydrin residue quantity in the product;
l  Related information of pyrogen.
During the selection of sterilization methods, influences or possible harm of the method having on the material performance should be fully considered. Sterilization method should fit the packing materials. Different methods have different requirements for packing materials. For example, regarding ethylene oxide sterilization, the packing material should be both blocking bacteria and ventilating; and in γ ray sterilization, irradiation tolerance should be considered.
Sterilization condition is also important to the effect. The manufacturer should provide the sterilization method and detailed sterilization condition and procedures.
(6) Determination of validity period
Period of validity is determined by the test data acquired in the actual storage condition or accelerated test condition, including:
l  Application performance test;
l  Biocompatibility test;
l  Packing completeness checking.
 
2. Risk management data of product
In accordance with the Medical devices -- Application of risk management to medical devices YY/T 0316-2003, the manufacturer should analyze the energy harm, biology harm, environmental harm, application harm, and harm due to function failure, bad maintenance and aging, and give the prevention measures and residual risk assessment, etc. Risk assessment report should be complete, at least including ① risk management process; ② management system and personnel qualification; ③ analysis of risks: product design and development, selection and usage of materials, manufacturing process, storage and transportation, application; ④ assessment of risks: risk grade, acceptability, etc.
 (1) Risk analysis of the product should include related data and research documents of process, like evaluation of the toxicity and residue during using toxic substances, e.g. adhesive, solvent and aperture making agent, etc.
 (2) Sterilization method and residue safety of the dialyzer are also important assessment items. For example, initial use syndrome is closely related to the residue of ethylene oxide. As different materials need different sterilization methods and residues are also different. Biological assessment is a must. Residue content control of ethylene oxide can follow the standard YY 0053-2008.
 (3) Pyrogen action has severe impact on the dialyzer. Pyrogen cannot be eliminated by sterilization. Apart from the endotoxin, other chemical substances that can cause pyrogen action exist. It’s necessary to control and prevent the pyrogen substances intruding the products during the production process. Rabbit method should be used to test the pyrogen, instead of testing the endotoxin only.
3. Standard of product
According to the quality control characteristics of the safety and validity of the product, industrial standard YY0053 can be totally or partially adopted. The standard of product should not be less strict than the industrial standard. As to inapplicable items, they should be explained in the formulation description. Technical requirements and test methods in the standard of product should have been verified.
 
4. Clinical data of the products
The clinical test data should be provided in strict accordance with the requirements of “Provision of Medical Device Clinical Trials”. In addition, the following aspects should also be paid attention to:
(1) Testing program
1) Testing subjects should be representative and inclusion and exclusion criteria should be described in details.
① Inclusion criteria: Testing subjects should be representative and should in principle be stable dialysis adult patients with chronic renal failure, whose age, gender, primary disease and special requirements should be indicated.
② Exclusion criteria: Testing subjects are the patients with severe anemia, infection, tumor, active bleeding, severe heart, liver, lung diseases, mental disorders or unstable condition etc, or  other unsuitable for tests situations such as product risk can do harm to patients or affect treatment.
2) If using control group，dialyzer whose dialysis parameters and membrane material are similar should be chosen. Test conditions, method steps, clinical observation and postoperative follow-up time of the testing groups and control groups should be consistent. Both groups should be allocated according to random principles. If using standard comparison, industry-recognized clinical indicators should be chosen;
3) in a multi-center study, each center’s program should be consistent;
4) sufficient sample  quantity，meeting the statistical requirements, statistical analysis based on the unit case，using the classical, recognized statistical method, formula and statistical software;
5) clinical model should choose the dialyzer membrane area less than 1.5m² and more than 1.5m² to carry on clinical trials separately;
6) evaluation indicator
① general indicators：routine blood test;
② biochemical indicators：plasma creatinine, urea nitrogen, kalium, sodium, calcium, chloride, phosphorus, carbon dioxide partial pressure（PCO_2）, albumin, globulin, C-reactive protein and β2-MG（high-flux dialyzer）。
③ main evaluation indicators：dialyzer creatinine, urea nitrogen clearance, β2-MG rate of decline（high-flux dialyzer）。
④ minor evaluation indicators：overall dialysis creatinine, urea nitrogen clearance, urea reduction rate（URR）, ultrafiltration rate, serium inorganic phosphorus, C-reactive protein（CRP）, sap（start of dialysis and 15min） and product compliance;
⑤ biocompatibility test：after the start of dialysis 15min, leukocyte and blood platelet rate of decline。
 7) Evaluation method
① ultrafiltration rate: ultrafiltration rate（ml/h）=total amount of water removed（ml）/treatment time (h)
② dialysis solute clearance rate：
                        
In the formula，and  adopt the same concentration unit. in the formula：
 refers to the concentration of the hemodialysis or hemodiafiltration device blood inlet；
refers to the concentration of the hemodialysis or hemodiafiltration device blood outlet；
 refers to the blood flow rate of product inlet end；
 refers to the filtration flow rate（ultrafiltration rate）.
note：stable dialysis 60min，blood flow rate and dialysate under fixed working condition（usually ultrafiltration rate set  0 or 10ml/min）,at the same time, draw off blood from the end of the dialyzer arteriovenous，detection creatinine, BNU, β2-MG and calculate clearance rate.
③ decline rate of dialysis solute: decline rate of dialysis solute＝1－(blood concentration after dialysis／blood concentration before dialysis)％。
note：when determination of the decline rate，draw off blood at the beginning and end of dialysis，stop ultrafiltration, after the blood flow rate reduced to 100ml/min，then stop pumping and draw off blood from the patient.
8) Clinical trials records should be accurate and detailed, including product name and its ancillary equipment, therapeutic procedures, operation method, used drug or reagent, heparin dosage, treatment parameters（blood flow, dialysate flow, transmembrane pressure, water removed amount and treatment time）, observation indicators, sampling time and method, side effects and treatment plans, records in real time during the test, disposal in the end, and adverse events with measures;
9) Side effects and treatment plans including（expected side effects may occur in the test and how to deal with them )：
① hypotension（treatment plan )；
② allergic reactions（treatment plan）；
③ fever,toxemia,bacteremia,septicemia etc.（treatment plan）；
④ hemolysis（treatment plan）；
⑤ hemorrhage（treatment plan）；
⑥ aeroembolism（treatment plan）；
⑦ rupture louxue（treatment plan）；
⑧ other accidents（treatment plan）。
10) Observational index including:
① vital signs：blood pressure,pulse,body temperature,cardiac rate；
② general state of the patient：self-sensation of the patient,syndromes and signs of change when first use；
③ data changes associated with dialyzers；
④ laboratory parameters associated with dialyzer function.
 
(2) Clinical Trial Report
1) Clinical trial report should be consistent with clinical trial program;
2) Make sure if all patients complete follow-up and finish if all follow-ups are included in the statistics. Those loss follow-up cases should make sure the causes;
3) Original data involved in the process of therapeutic evaluation and safety evaluation should be submitted;
4) Time, cause, consequence and the relationship with test equipments of all adverse events should be reported. Treatment measures taken need to be cleat.
 
5. Product Manual, Label and packaging marks
(1). Product marking
Product marking should include at least the following information:
1) name of the production plant；
2) product name；
3) product specifications model or identification code of the manufacturer device；
4) production batch；
5) if applicable，mark of the blood and dialysate flow；
6) maximum transmembrane pressure；
7) effective date；
8) sterilization method；
9) Instruction of disposable.
 
(2). Marks on single package
At least the following information can be seen on or through the single package：
1) name and address of the production plant;
2) product name；
3) product specifications model or identification code of the manufacturer device；
4) production batch；
5) sterile and pyrogen statement, 3 possibilities can be available.
① the entire product package is sterile and pyrogen；
② liquid channel（blood and dialysate）is sterile and pyrogen；
③ only blood channel is sterile and pyrogen.
6) sterilization method;
7) effective date；
8) instruction of disposable;
9) explanatory note for “please read the manual before using” should be included;
10) if applicable，instruction of ultrafiltration control device requirements should be included.
 
(3). Marks on external package
External package should at least include the following information:
1) name and address of the production plant;
2) product name，description of product catalog and quantity is included in external package；
3) product specifications model or identification code of the manufacturer device；
4) production batch；
5) sterile and pyrogen statement；
6) warning and instruction relating to handling and storage；
7) effective date；
8) if applicable, instruction of ultrafiltration control device requirements should be included.
 
(4).Random files
At least the following information should be provided for each external package：
1) name and address of the production plant;
2) product name;
3) instruction
① explanation regarding ancillary equipments among the user guide provided by the production plant；
② connection location of extracorporeal circulation piping（if applicable）and connection location of dialysis tubing；
③ explanation regarding recommended priming, rinsing and termination in the operation steps of hemodialysis and hemodiafiltration；
④ explanation regarding blood flow（if applicable）；
⑤ typical connection diagram；
⑥ explanation regarding anti-coagulation and by the doctor；
⑦ detailed requirements of some ancillary equipments.
4) precautions and warnings:
① pressure limitation；
② dialysate flow limitation recommended by companies（only for hemodialysis and hemodiafiltration device）；
③ blood flow restriction recommended by companies；
④ introduction of recommended rinsing products before using；
⑤ explanation of requiring specialized equipments；
⑥ list for known adverse event；
⑦ list for general or specific contraindications，such as“suggestion of not used for pediatric”，“supplier system of un-degassed dialysate is not allowed to use”；
⑧ When device is used under lower some flow rate or lower some pressure and in a specific direction（horizontal and vertical）,warning and contraindication of functions weakening.
5) product specifications model or identification code of the manufacturer device;
6) sterile and pyrogen statement，sterilization method;
7) instruction of disposable;
8) Performance parameters of the product should be included and indicated. For new products, performance parameters of the dialyzers should include effective membrane area，clearance rate，screening factor、ultrafiltration rate、dialysate and blood side pressure drop and blood chamber capacity. Functional parameters should include or mention：
① if applicable，explain that results measured in vitro are likely to be different from those measured in vivo. Numerical value differences should be estimated；
② if applicable，explain that performances may change with the duration of observation；
③ used for each testing method to ensure performance characteristics.
9) common name of the membrane（if applicable）and product name: Common name of the membrane should include the complete chemical name of membrane material;
10) product universal description: the information should include the specific features of the products, for example, filtration flow rate requires the side effects of the specific specialized controller or the dialysate foam;
11) recommended connector interfaced with dialysate or filtrate;
12) model should be set relating to how to connect blood pipe joints with products;
13) common name of the structural materials of those products direct or indirect contact with blood.
In addition, in order to have a comprehensive and full elaboration for the functional structure characteristics of the dialyzers, symbols in YY 0466 Medical Device Symbols used in label, mark and information of the medical device can also be adopted.
 
Four Term Explanation
(1) Hemodialyses: it is an approach to correct solute imbalance of the patients blood, by leading blood out of the body, mainly through the dispersion effect of the semipermeable membrane dialyzer.
(2) Multi-center clinical trial: it refers to the clinical trial in which many researchers in different institutions participate and simultaneously carry on in the same way according to the same test program requirements.世联翻译公司完成食药监办械英文翻译

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