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This standard is drafted in accordance with the rules given in GB/T 1.1-2009.
This standard replaces YY 0598-2006 Concentrates for Haemodialysis and Related Therapies; in addition to editorial changes, the main technical differences made with respect to YY 0598-2006 are listed in Annex A.
This standard is modified in relation to ISO 13958:2009 Concentrates for Haemodialysis and Related Therapies. The technical differences between this standard and ISO 13958:2009 are listed in Annex B.
Attention is drawn to the possibility that some of the elements of this document may be the subject of patent rights. The issuing body of this document shall not be held responsible for identifying any or all such patent rights.
This standard was proposed by the China Food and Drug Administration.
This standard is under the jurisdiction of National Technical Committee on Extracorporeal Circuit Equipment of Standardization Administration of China (SAC/TC 158).
This standard was issued in 2006 for the first time and was revised in 2015 for the first time.
Concentrates for Haemodialysis and Related Therapies
1 Scope
This standard specifies the chemical composition, purity, microbial contamination, handling, measuring, labelling, requirements for container and various tests required for quality inspection of the concentrates.
This standard is applicable to the concentrates for haemodialysis and related therapies.
This standard is not applicable to the mixing process in which concentrate and dialysis water are formulated to a final working concentration during therapy.
This standard is not applicable to the regeneration system of dialysis fluid.
2 Normative References
The following documents for the application of this document are essential. For dated references, only the edition cited applies. For undated reference, the latest edition (including all the amendments) applies.
GB/T 13074-2009 Terms of Blood Purification
YY 0572 Water for Haemodialysis and Related Therapies (YY 0572-2015, ISO 13959:2009, MOD)
ISO 11663:2009 Quality of Dialysis Fluid for Haemodialysis and Related Therapies (MOD)
WS-10001-(HD-0476)-2002 Magnesium Chloride
Pharmacopoeia of the People’s Republic of China (2015 Edition)
3 Terms and Definitions
For the purposes of this document, the terms and definitions established in GB/T 13074-2009 and the following ones apply.
3.1
acetate concentrate
mixture of salts containing acetate, which when diluted with dialysis water, yields bicarbonate-free dialysis fluid for use in dialysis
Note 1: Acetate concentrate might contain glucose.
Note 2: Sodium acetate is used to provide a buffer in place of sodium bicarbonate.
Note 3: Acetate concentrate is generally used as a single concentrate.
3.2
acid concentrate
A-concentrate
acidified concentrated mixture of salts that, when diluted with dialysis water and bicarbonate concentrate, yields dialysis fluid for use in dialysis
Note 1: The term “acid” refers to the small amount of acid (usually acetic acid) that is included in the concentrate.
Note 2: Acid concentrate might contain glucose.
Note 3: Acid concentrate can be in the form of a liquid, a dry powder or a combination of the two.
3.3
batch system
apparatus in which the dialysis fluid is prepared in bulk before each dialysis session
3.4
bicarbonate concentrate
B-concentrate
concentrated preparation of sodium bicarbonate that, when diluted with dialysis water and acid concentrate, makes dialysis fluid used for dialysis
Note 1: Some bicarbonate concentrates also contain sodium chloride.
Note 2: Bicarbonate concentrate can be in the form of a liquid or a dry powder.
Note 3: Dry sodium bicarbonate, without added sodium chloride, is also used in concentrate generators to produce a saturated solution of sodium bicarbonate used by the dialysis machine to make dialysis fluid.
3.5
bulk delivery
delivery of large volume containers of liquid concentrate to a dialysis facility
Note: Bulk delivery includes containers such as drums, which can be pumped into a storage tank maintained at the dialysis facility. Alternatively the drums can be left at the facility and used to fill transfer containers to transfer the liquid concentrate to the dialysis machines. Bulk delivery can also include large containers for direct connection to a central concentrate supply system.
3.6
bulk storage tank
tank at the dialysis facility for storage of dialysis water or liquid concentrate from bulk deliveries, or for liquid concentrate prepared in bulk at the dialysis facility from powder and dialysis water
3.7
central concentrate system
system that prepares and/or stores liquid concentrate at a central point for subsequent distribution to its points of use
3.8
concentrate generator
system where the concentrate is delivered to the user as a powder in a container, suitable for attachment to the dialysis machine with which it is intended to be used, and then converted into a liquid concentrate by the dialysis machine
Note: The solution produced by the concentrate generator is used by the dialysis machine to make the final dialysis fluid delivered to the dialyser.
3.9
concentrate mixer
mixer for preparation of dialysis concentrate or dialysis fluid at a dialysis facility
3.10
dialysis fluid delivery system
device that:
1) Prepares dialysis fluid on line from dialysis water and liquid concentrate or that stores and distributes premixed dialysis fluid;
2) Circulates the dialysis fluid through the dialyser;
3) Monitors the dialysis fluid for temperature, conductivity (or equivalent), pressure, flow and blood leaks;
4) Prevents dialysis during disinfection or cleaning modes
Note 1: The term includes reservoirs, conduits, proportioning devices for the dialysis fluid, and monitors and associated alarms and controls assembled as a system for the purposes listed above.
Note 2: The dialysis fluid delivery system can be an integral part of a single-patient dialysis machine or a centralized preparation system which feeds multiple bedside monitoring systems.
Note 3: Dialysis fluid delivery systems are also known as proportioning systems and dialysis fluid supply systems.
3.11
dialysis water
water that has been treated to meet the requirements of YY 0572 and which is suitable for use in haemodialysis applications, including the preparation of dialysis fluid, reprocessing of dialysers, preparation of concentrates and preparation of substitution fluid for online convective therapies
3.12
manufacturer
entity that designs, manufactures, fabricates, assembles, formulates or processes a finished device
Note: Manufacturers include, but are not limited to, those who perform the functions of contract sterilization, installation, relabelling, remanufacturing, repacking, or specification development, and initial distributors of foreign entities performing these functions. The term does not cover preparation of liquid concentrates from prepackaged dry chemicals at a dialysis machine or the handling of bulk concentrates at a dialysis machine after responsibility for the concentrate is transferred from the manufacturer to the user.
3.13
user
physician, nurse or relevant engineering technician responsible for the actual production and handling of dialysis fluid in medical institution
Note: This standard is mainly directed to device manufacturers, and in that context the “user” is as noted above.
4 Materials
4.1 Containers
The contents of the containers (including the closures) shall not affect the concentration limits and other technical requirements specified in 5.2 during handling, storage and shipment. The volume of each container shall not be less than the labelled volume of the volume or mass of the concentrate contained. Containers and closures shall be capable of maintaining the microbiological conditions.
4.2 Chemical raw materials
All chemical raw materials shall meet the requirements of the following standards, and shall be inspected batch by batch when being delivered to the factory.
4.2.1 Sodium chloride (NaCl)
It shall comply with the relevant provisions on sodium chloride in the Pharmacopoeia of the People’s Republic of China (2015 Edition).
4.2.2 Calcium chloride (CaCl2·2H2O)
It shall comply with the relevant provisions on calcium chloride in the Pharmacopoeia of the People’s Republic of China (2015 Edition).
4.2.3 Potassium chloride (KCl)
It shall comply with the relevant provisions on potassium chloride in the Pharmacopoeia of the People’s Republic of China (2015 Edition).
4.2.4 Magnesium chloride (MgCl2·6H2O)
It shall comply with the relevant provisions on magnesium chloride in WS-10001-(HD-0476)-2002.
4.2.5 Sodium acetate (CH3 COONa·3H2O)
It shall comply with the relevant provisions on sodium acetate in the Pharmacopoeia of the People’s Republic of China (2015 Edition).
4.2.6 Anhydrous glucose (C6H12O6)
It shall comply with the relevant provisions on anhydrous glucose in the Pharmacopoeia of the People’s Republic of China (2015 Edition).
4.2.7 Glucose (C6H12O6·H2O)
It shall comply with the relevant provisions on glucose in the Pharmacopoeia of the People’s Republic of China (2015 Edition).
4.2.8 Sodium bicarbonate (NaHCO3)
It shall comply with the relevant provisions on sodium bicarbonate (for haemodialysis) in the Pharmacopoeia of the People’s Republic of China (2015 Edition).
4.2.9 Glacial acetic acid (C2H4O2)
It shall comply with the relevant provisions on glacial acetic acid in the Pharmacopoeia of the People’s Republic of China (2015 Edition).
4.2.10 Acetic acid (C2H4O2)
It shall comply with the relevant provisions on acetic acid in the Pharmacopoeia of the People’s Republic of China (2015 Edition).
4.2.11 Other materials
They shall comply with the current technical requirements of the Pharmacopoeia of the People’s Republic of China (2015 Edition) and national drug standards, including all applicable provisions as well as the applicable test methods in the annex of Pharmacopoeia of the People’s Republic of China (2015 Edition) and those in national drug standards.
4.3 Water
The quality of water used in the preparation of the liquid concentrate shall be in accordance with YY 0572.
5 Requirements
5.1 State
Liquid concentrate or that prepared from dry powder shall be free of visible foreign matter and shall not be darker than No.1 yellow (or yellow-green) colorimetric solution.
5.2 Solute concentrations
During the shelf life, the concentration of sodium ions shall be 97.5% to 102.5% of the labelled amount, and the concentration of other solutes shall be 95.0% to 105.0% of the labeled amount.
5.3 Microbial limits
For the liquid concentrate (or that prepared from dry powder in use proportion) containing bicarbonate, the total count of bacteria in it shall be no more than 100 CFU/mL and that of fungi shall be no more than 10 CFU/mL, while Escherichia coli shall not be detected.
Note: There is no literature reporting that acid concentrate supports bacterial growth, and this clause is not applicable to acid concentrate.
5.4 Endotoxin limits
The concentrate shall be formulated and packaged using a process validated to produce dialysis fluid with endotoxin limit no more than 0.5 EU/mL from bacterial endotoxin and water.
5.5 Fill volume
The fill volume of liquid concentrate shall be no less than the labelled volume. The fill volume of dry powder shall be 98.0% to 102.0% of the labelled volume.
5.6 Particulate contamination
Insoluble particulates after dilution of concentrate into dialysis fluid: particulates of ≥10 μm shall be no more than 25 pcs/mL, and particulates of ≥25 μm shall be no more than 3 pcs/mL.
Note: The liquid concentrate shall be filtered through a nominal 1 μm or finer particulate filter. The particulate filter used shall have a non-fibre-releasing membrane that does not contain material of known potential for human injury.
6 Test Methods
6.1 State
6.1.1 General
The state of liquid concentrate or that prepared from dry powder shall be tested according to the methods given in 6.1.2 and 6.1.3, and all the observation results shall meet the requirements of 5.1.
6.1.2 Visible foreign matters
Take five parts of the sample, with each into a 10mL Nessler tube, and test the samples according the visible foreign matter inspection method (light inspection method) stated in Annex IXH to the Pharmacopoeia of the People’s Republic of China (2015 Edition); no visible foreign matters such as metal chips, glass chips, and cilia and lumps with length or maximum grain size larger than 2mm shall be detected, and no smoke-like particulate columns shall be detected when rotating.
6.1.3 Colour of solution
The colour test shall be carried out according to the method specified in Annex IXA - “Solution Color Inspection Method (Method I)” of the Pharmacopoeia of the People’s Republic of China (2015 Edition).
6.2 Solute concentrations
6.2.1 Preparation and determination of test solution
Precisely measure out the liquid concentrate (in case of dry powder, prepare the liquid concentrate according to the instructions for use). The sampling amount of any kind of liquid concentrate shall be no less than 10mL, and two samples shall be taken in parallel. Prepare the samples into dialysis fluids with the concentration (labelled amount) indicated in 7.2 with water according to the mixing ratio required by the instructions for use and take them as the test solutions (if necessary, prepare the samples into the test solutions with the concentration range required by the test method), and immediately carry out determination by taking the dialysis water as the blank test solution. The result shall be the arithmetic mean of the measured values of the two samples.
Note 1: The test method involved in 6.2 is applicable to the test of solute concentration of acetate dialysis fluid and bicarbonate dialysis fluid and is only reference for the test for other types of dialysis fluids.
Note 2: For the test of other solute concentrations, the method given in the Pharmacopoeia of the People’s Republic of China shall be used first. If the Pharmacopoeia does not provide a test method or the test method is not applicable, the method used shall be stated in the report. Any analytical method can be used as long as the analysis reliability is proven. "Analysis reliability" means the analytical method selected demonstrates sufficient accuracy, precision, selectivity, linearity and sensitivity and is applicable to the concentrates for haemodialysis and related therapies.
Note 3: During the test, the influence of the test object (such as calcium ion) contained in the test water (dialysis water) on the test results shall be deducted.
6.2.2 Ions
Use the recommended methods shown in Table 1 to carry out test and calculate the ion concentration of the test solution. The result after deduction of the blank shall meet the requirements of 5.2.
Table 1 Methods for Testing Ions
No. Ion Method
1 Calcium Ion chromatographya, EDTA titrimetric method and atomic absorption spectrophotometry
2 Magnesium Ion chromatographya, EDTA titrimetric method and atomic absorption spectrophotometry
3 Potassium Ion chromatographya and flame emission spectroscopy
4 Sodium Ion chromatographya and flame emission spectroscopy
5 Chlorine Ion chromatographya, potentiometric titration and silver nitrate titration
6 Acetate Ion chromatographya, liquid chromatography and UV spectrophotometry
7 Bicarbonate Potentiometric titration and hydrochloric acid titrationa
a It is an arbitration method. If the ion content is determined with a non-arbitration method, comparison test shall be carried out with respect with the arbitration method, and the non-arbitration method shall be used according to the test result.
6.2.3 Glucose
Take the test solution and test it according to the method under “Glucose and Sodium Chloride Injection” in the Pharmacopoeia of the People’s Republic of China (2015 Edition). Multiply the arithmetic mean of the results of optical rotation determination of the sample obtained from three tests by 2.0852 and take the product as the mass (g) of glucose hydrate (C6H12O6·H2O) in the test solution, and the calculation result shall meet the requirements of 5.2.
Note: Interference from other optically active substances shall be excluded.
6.3 Microbial limits
6.3.1 Preparation of test solution
In case of liquid concentrate, directly take sample as the test solution;
In case of dry powder, weigh out 20g of sample and prepare it into a liquid concentrate by using sterile sodium chloride-peptone buffer solution (pH7.0) according to the instructions for use, and use the solution as the test solution.
6.3.2 Inspection on the counts of bacteria and fungi
After the test solution is filtered through membrane, it shall be subject to inspection according to the method specified in Annex XIJ - “Inspection Method of Microbial Limits” in the Pharmacopoeia of the People’s Republic of China (2015 Edition) and shall meet the requirements of 5.3.
6.3.3 Inspection on Escherichia coli
The inspection shall be carried out according to the method specified in Annex XIJ - “Inspection Method of Microbial Limits” to the Pharmacopoeia of the People’s Republic of China (2015 Edition) and shall meet the requirements of 5.3.
6.4 Endotoxin limits
Preparation and determination of test solution:
In case of liquid concentrate, directly take sample as the test solution;
In case of dry powder, weigh out 5g of sample and prepare it into a liquid concentrate by using bacterial endotoxin test water according to the instructions for use, and use the solution as the test solution.
Mix the test solution according to proportion given by the instructions for use, dilute it with bacterial endotoxin test water instead of dialysis water, and then carry out inspection according to the Annex XIE to the Pharmacopoeia of the People’s Republic of China (2015 Edition). The calculation result shall meet the requirements of 5.4.
6.5 Fill volume
The test shall be carried out with the applicable method of measuring volume or weight and the results shall meet the requirements of 5.5.
6.6 Particulate contamination
Preparation of the test solution: According to the method of 6.2, take sample of a kind of liquid concentrate (in case of dry powder, mix the dry powder with the water for injection into liquid concentrate according to the instructions for use) and dilute it to the final concentration and take the diluted solution as the test solution of the concentrate and carry out the determination immediately.
The test solution shall be subject to test according to Annex IXC - “Inspection Method (Light Blockage Method) for Insoluble Particulates in Liquid Injection)” to the Pharmacopoeia of the People’s Republic of China (2015 Edition), and calculate the particulate content per unit volume of dialysis fluid with the background particulate number of water for injection deducted (in case of bicarbonate dialysis fluid, solutions A and B shall be subject to determination of particulate content separately, and the particulate content of dialysis fluid shall be calculated in combination), and the result shall meet the requirements of 5.6.
7 Labelling
7.1 General
The label on the concentrate container shall, at a minimum, provide the applicable information contained in 7.2 to 7.4. Symbols may be used where appropriate.
With some machines the mixing of liquid concentrate is automated and not performed by the user. In these cases the instructions for use can be modified to fit the appropriate situation. For example, if the machine takes powder and liquid concentrate and mixes them internally, it would not be necessary to state that the “l(fā)iquid concentrate be mixed well before use.” The design of the machine shall take this into account and mix the concentrate appropriately.
7.2 General labelling requirements for concentrates
General labelling requirements for concentrates shall include the following:
a) Name and address of the manufacturer/distributor;
b) Expiry date, if applicable;
Note: Normally, the expiry date and not the manufacturing date will be on the product;
c) Manufacturing date, only if expiry date is not applicable;
d) Identifying lot number;
e) A list of all ingredients in the final concentrate and the following;
f) Composition;
g) Composition of the dialysis fluid, including the nominal concentration of each electrolyte in millimoles per litre (mmol/L) and the concentration of non-electrolytes in the dialysis fluid in grams per litre (g/L) or mmol/L; the chemical concentration of the final dialysis fluid shall be placed on the acid concentrate label;
Note: Where there is insufficient space on the label to properly present the information required, it is acceptable to provide this information in an alternative format such as a package insert.
h) For batch systems, the volumes or weight of dialysis concentrate(s) and the amount and quality of the water that shall be mixed; if mixing is automated an instruction to follow the manufacturer's instructions for use;
i) For proportioning systems, the ratio of dialysis concentrate and water that shall be mixed;
j) Trade name of the product, if appropriate;
k) A statement regarding storage requirements such as, if appropriate: “Store at or below room temperature”; “Do not freeze”; and/or “Short-term exposure to warm conditions (40℃) will not harm acid concentrate”;
l) Any special requirements that are necessary because of the specificity of the product (i.e., the use of concentrate generators with a specific dialysis fluid delivery system);
m) A warning stating that bacterial growth can occur when using bicarbonate concentrate (bicarbonate concentrate only) and any other precautions that must be taken in the mixing of the concentrate;
n) When appropriate, a statement to test the final dialysis fluid for one of the following parameters: conductivity, pH, osmotic pressure, sodium concentration or chloride concentration;
o) A statement that water meeting the requirements of YY 0572 shall be used to dilute the concentrate to make dialysis fluid;
p) A statement to not overmix bicarbonate concentrate.
7.3 Labelling requirements for liquid concentrate
Labelling for liquid concentrate shall include the following:
a) Instructions for use;
1) The label shall include instructions to mix thoroughly prior to use and instructions not to use damaged containers. When bicarbonate is used, a warning shall be included noting that bacterial growth can occur in concentrated or diluted bicarbonate solutions.
2) The labelling shall state that once opened, the bicarbonate concentrate shall be used within the time limit specified by the manufacturer. The time limit for use (determined by the manufacturer) shall be the period during which the concentrate consistently produces a dialysis fluid that meets the chemical and microbiological recommendations of ISO 11663:2009 when used in a properly maintained system;
3) Liquid concentrate labelling may include geometric symbols (see Table C.1) to differentiate different proportioning ratios. If such symbols are used, the numbers representing the proportioning system shall also be easily visible and located within the boundaries of the geometric symbol. The label shall incorporate a means to differentiate between acid and bicarbonate. If a concentrate contains no potassium or no calcium, that shall be prominently displayed on the label. If colour coding is used, red shall be used for acid, blue for bicarbonate and white for acetate.
b) A statement that the solution is non-pyrogenic, if applicable;
c) Fill volume of the container;
d) Nominal conductivity of the final dialysis fluid when mixed according to the manufacturer's instructions or a statement that such information is available from the manufacturer.
Foreword II
1 Scope
2 Normative References
3 Terms and Definitions
4 Materials
5 Requirements
6 Test Methods
7 Labelling
Annex A (Informative) Main Technical Differences between This Standard and YY 0598-2006 and the Relevant Reasons
Annex B (Informative) Main Technical Differences between This Standard and ISO 13958:2009 and the Relevant Reasons
Annex C (Informative) Equipment and Other Related Requirements
Bibliography
