Resolutions to Comments on AAMI/CDV-1 RD61, Concentrates for hemodialysis

Transcription

1 1. Richard 2. Richard 3. Richard 4. Richard 5. Richard s to on AAMI/CDV-1 RD61, Concentrates for hemodialysis Contents Line 107 Comment/Objection: eliminate extra space between endotoxin and levels in Contents Line 113 Comment/Objection: Insert space between 5 and Tests in 5. Contents Line 129 Comment/Objection: Delete Compliance in 5.3. Foreword Paragraph 2, line 203 Foreword Paragraphs 2 and 3, line Comment/Objection: Change first letter of hemodialysis to lower case. Comment/Objection: dit last sentence of the first paragraph, and the second paragraph, to reflect that this is no longer the first edition of RD61. Rewrite the last sentence of the first paragraph as: ANSI/AAMI RD61:2000 was one of three documents that, collectively, superceded ANSI/AAMI RD5:1992. RDN161rev To be corrected in final editing To be done in final editing 1

2 6. Larry 7. Danilo Concepcion, SJHRC 8. Richard Foreword 2.2; 4.1.3; ; 5.1.3; o); A.1; A.4.1.3; A Rewrite the second paragraph as: During its 2004 periodic review, the committee decided to revise ANSI/AAMI RD61:2000 to more closely follow the ISO format. This revision was possible since the development of ANSI/AAMI RD52:2004, Dialysate for hemodialysis, had eliminated the need for RD61 to include user requirements for concentrate. Comment/Objection: ANSI/AAMI RD62:200X, Water treatment equipment for hemodialysis applications Where applicable, replace all references to RD62 with RD52 to incorporate new endotoxin requirement for dialysate. Also, RD52 is geared toward the user therefore it is more appropriate reference. 1.2 Inclusions G Comment/Objection: There are now solutions available (NxStage) that are used for HD application and not CRRT or PD. Should these types of solutions be included in RD61 or later discussion for inclusion in RD52? 1.3 Line Comment/Objection: Many of the exclusions listed in the section have nothing to do with concentrate. The section can be shortened accordingly. Rewrite section as: Although references to dialysate appear herein, this standard Reject RD-61 is a manufacturer standard addressed to the manufacturer RD-62 is a manufacturers standard and RD-52 is a user recommended practice. The amount of water in concentrate is minimal. Reject The production of sterile solutions such as those used with the NxStage system and PD are beyond the scope of this document 2

3 9. Fei Law, 10. Dilip Shah, Aksys, Ltd. 11. Richard 12. Richard does not address dialysate. Also excluded from the scope of this standard are requirements for monitoring the purity of water used for mixing concentrate at a dialysis facility. The recommendations of this committee for monitoring water quality are contained in ANSI/AAMI RD52:2004, Dialysate for hemodialysis. 2.4, 3.21 Comment/Objection: USP 26 NF 21 no longer valid USP 28 NF 23 is most recent revision Replace with USP 28 NF 23 or current USP T Comment/Objection: This statement describes use of bicarbonate concentrate only for proportioning systems. Bicarbonate concentrate dry, is also used for making a batch of dialysate solution. Add Dry bicarbonate may also be used directly to produce a batch of final dialysate solution. 3.8 Line 310 Comment/Objection: liminate the definition of a cation. This is a general definition and is not specific to understanding this document Line Comment/Objection: liminate the definition of electrolyte. This is a general definition and is not However, it is not known what could be added in the future so it is not appropriate to add the sentence or current USP Add the note: Note, in some machines dry powder is used to produce a batch of final dialysate 3

4 specific to understanding this document. Comment/Objection: The current Reference Standard ndotoxin Lot is C-6-2 and is identical to USP Reference Standard ndotoxin Lot-G, sublot G- 2. Only LAL manufacturers have access to C-6-2, which LAL manufacturers receive from the FDA (CBR), for the purpose of calibrating the Control Standard ndotoxins sold to LAL users. LAL users who require the Reference Standard ndotoxin would need to purchase vials of the current Lot G sub-lot, from the USP. For the purposes of section 3.13, a reference to the current USP Reference Standard ndoxin, rather than C-6-2, might be more appropriate. In fact, the FDA is not currently re-labeling Sub-Lot G-2 as C-6-2 for the vials that they forward to LAL manufacturers. The designation as C-6-2 only appears on their Product Information Circulars. 13. Malcolm Finkelman, Associates of Cape Cod 3.13 Note 1 T All reference to the specific lot have been removed See above. Alternative text: Replace C-6-2 with the current USP Reference Standard ndotoxin 14. Fei Law, Lines , T Comment/Objection: (when measured as properly diluted dialysate) implies that the testing actually occurs at the final use dilution. Measurements can be done at any dilution, as long as the intent is that the requirements are met at the final use dialysate concentration. replace with (expressed as dialysate concentration). Replace (when measured as properly diluted dialysate) with (expressed as dialysate concentrations) 4

5 15. Larry 16. Richard 17. Larry Comment/Objection: Concentrate containing bicarbonate supplied as a liquid must be provided in a sealed container and must contain less than 200 CFU/mL and less than 2 U/mL of endotoxin at the end of the manufacturer s recommended shelf life. Change must to shall Concentrate containing bicarbonate supplied as a liquid shall be provided in a sealed container and shall contain less than 200 CFU/mL and less than 2 U/mL of endotoxin at the end of the manufacturer s recommended shelf life Line T Comment/Objection: Rewrite to indicate labeled volume or weight. This clause deals with both liquids and powders; powders have a labeled weight, not a labeled volume. Rewrite as: The fill volume of liquid or weight of powder for containers used with single-use batch systems shall be within 2% of the labeled volume or weight. For non-batch use, the average fill volume or weight shall be 100% of the stated volume or weight T Comment/Objection: section does not specify the filtration requirement for bicarbonate. ISO states Bicarbonate concentrates shall be filtered through a similar 0.45 micron filter. Specifying a filtration requirement for bicarbonate may be practical if AAMI plans to incorporate RD61 into an ISO standard. Reject ISO is being revised. The bacterial requirements for bicarbonate are specified in section

6 18. Larry 19. Fei Law, T Add Bicarbonate concentrates shall be filtered through a nominal 0.45-micron or finer particulate filter. If adopt the new requirement, need to update also. Comment/Objection: If the LAL assay is used, maximum endotoxin level shall be less than 2 U/ml. When testing powder, the endotoxin level shall be less than 2 U/ml when properly mixed with water. This section is talking about the concentrate solution (not dialysate). Does this apply to acid and bicarbonate solutions? RD52, section 6.5 states that it is not necessary to perform bacteria and endotoxin testing on acid systems. specify that this requirement only applies to bicarbonate solutions or change RD d) T Comment/Objection: delete The labeling shall clearly indicate the machines for which the concentrate generator is intended to be used This requirement implies providing a listing of machines that will accept the generator. As machines are updated or new machines come on the market, sometimes from various companies, many of them are now being designed to accept concentrate generators. Listing the machine on the disposable creates the likelihood that there is a disconnect between the labeling and the latest available machines, thus causing both unnecessary administrative burden and possibilities of claims that the clinic is using the product off label if the list hasn t been updated with the latest machines Reject RD52 is a user document. It is not reqired to test the concentrates at the usrer level because the manufacturer tests the concentrate during the manufacturing of the concentrate. with modification: The following Note shall be added Note: It is possible that a manufacturer will modify there machine to accept another manufacturers concentrate generator. In this case the machine manufacturer has the responsibility to label the machine with the correct concentrator Generator model and manufacturer 6

7 available. The risk of the concentrate generator being used on the wrong machine is low, since there are specific connections to allow for installation and priming, and ultimately the concentrate has to meet the conductivity requirements. Additionally, if a machine is adapted to accept concentrate generators, the instructions on how to install, prime, and use the disposable are on the machine, not on the disposable. Therefore, the requirement to indicate the machines is not appropriate for the disposable labeling. Delete sentence. Alternatively, this can be discussed in the committee meeting. 20. Fei Law, e) T Comment/Objection: in addition to amount of time, add other options for determining yield of the concentrate generator It appears that the intent of the indication for amount of time is to give the user guidance on the expected yield from the concentrate generator. This can be measured in more than time, for example, volume of concentrate. the amount of solution that the container can reasonably be expected to provide, e.g. the amount of time based on dialysate flow rate (6 hours at a flow rate of 500 ml/min), or volume of solution (in ml, L), etc. with modification. Add to (e) the following statement; Alternately the capacity of the concentrate generator can be expressed as the volume of concentrate produced 21. Richard 22. Larry Line 447 Comment/Objection: Delete of the concentrates from the end of the first sentence. The words are redundant Comment/Objection: When the manufacturer. 7

8 23. Richard 24. Danilo Concepcion, SJHRC 25. Fei Law, recommends chemical disinfectants (see (11)) (11) does not exist. I believe this should reference k Line 451 Comment/Objection: The reference in parentheses should be to (k) Sentence 2 T Comment/Objection: Should acid and bicarb storage tank be differentiated as far as the requirement for a 0.2-micron filter? Sodium bicarbonate storage tanks used for central feed delivery should T Comment/Objection: the requirement for conical or bowl-shaped bases and for 0.2 vent filters is not applicable to acid concentrates. The reason for these requirements was for hygienic purposes to prevent stagnation and related growth of bicarbonate concentrates. This is not applicable to acid. Many clinics currently have storage tanks for acid which are flat bottom, and do not have vent filters. The requirements should not be any different for ready made acid concentrates vs acid concentrates that have to be mixed. The requirements should be limited to bicarbonate storage systems. When used for bicarbonate See below comment 25 with modification. Restate as follows When used for bicarbonate concentrate, storage tanks should have a conical or bowl-shaped base and should drain from the lowest point of the base. Bicarbonate storage tanks should have a tight fitting lid and be vented through a hydrophobic 0.2-micron air filter. 8

9 concentrate, storage tanks. Acid concentrate storage tanks may have a flat bottom. Acid storage tanks should be vented in a way to prevent dirt contamination of the concentrate. All storage tanks should not use clear sight tubes, which will grow algae and fungi. When necessary, means shall be provided to effectively disinfect any storage tank installed in a concentrate distribution system. 26. Richard 27. Larry Line 470 Comment/Objection: Change site to sight Comment/Objection: When necessary, means shall be provided to effectively disinfect any storage tank installed in a concentrate distribution system. In RD52, this requirement is a should Recommend keeping RD61 as a shall and update RD52 at next revision. Use "shall" for bicarb only. see Lee. To be discussed with comment 25 above. 9

10 28. Larry 29. Larry 30. Larry 31. Richard 32. Richard Comment/Objection: When concentrate storage and distribution systems are provided with UV light, the following shall be complied shall misspelled Comment/Objection: recommend frequency of lamp replacement, etc. Remove etc T Comment/Objection: section does not address the need for an endotoxin retaining filter after the UV endotoxin retaining filter is required by RD52 Add It is recommended that UV irradiators be followed by an endotoxin retaining filter Line Comment/Objection: Reformat the requirements into a list [a), b), c), d)]. Correct spelling of shall in the first line. Make 2 of cm2 a superscript. If there are additional requirements, list them instead of using etc. Otherwise, eliminate etc. Make the clause easier to read Line 480 Comment/Objection: Delete chemicals (such as Reject in part This is the manufacturers guideline not the person who is to maintain the system. however, the manufacturer should recommend the frequency of maintenance. This will be added to (n) in the instructions for use use "shall" The following will be added to 4.3.5: Where UV filters are employed it is recommended that tey be followed by a endotoxin retentive filter 10

11 33. Richard 34. Larry 35. Larry aluminum, copper, lead, and zinc) from the first sentence. This requirement is already covered in Clause Line 484 Comment/Objection: Renumber the clause on electrical safety requirements as is used for the clause on piping systems T Comment/Objection: NOT A continuous recirculation loop is one way of accomplishing this. Most bicarb loops do not flow fast enough to minimize bacterial proliferation and biofilm. If the bicarb loop did flow fast enough, it probably would lead to degassing when the bicarb re-enters the storage tank. Delete note or change note to mention frequent disinfection as a means to minimize bacterial proliferation and biofilm b G Comment/Objection: where it is certain that there is not a sustainable electrical path to the patient UL laboratory Standards for electrical leakage currents shall be followed. (see 2.6); Does this mean that current leakage testing is required? How do you determine if there is a possibility of a sustainable electrical pathway to the patient? How do you determine this from inspections as is indicated by b? Change to frequent disinfection UL Reject This is not a design standard and as such will not give guidance on how to avoid electrical pathways. However if someone who is knowledgeable in the subject wishes to write something it could be put into 11

12 36. Richard 37. Richard 38. Richard 39. Richard This section should give guidance as to how to avoid the possibility of a sustainable electrical pathway to the patient such as using magnetic drive pumps, heaters used for disinfection should not be turned on while patients are being dialyzed, etc b) Line 494 Comment/Objection: Change first letter of standards to lower case Paragraph 1, line Paragraph 2, line Paragraph 3, line 525 Comment/Objection: Insert (see 2.1) and (see 2.3) after the respective references. Consistency with the rest of the document. Comment/Objection: Reword the paragraph. Improve readability Rewrite as: Compliance with the requirements of for new or non-traditional concentrate constituents can be determined by inspection of the product label and by comparison of the manufacturing records and final product analysis with the manufacturer s specification. Comment/Objection: Change contaminate to contaminant. the Annex It is further noted that designers of these systems will normally be familiar with the electrical safety standards. 12

13 40. Fei Law, c T Comment/Objection: add determination of dextrose by liquid chromatography Possible to determine through HPLC 41. Richard Dextrose: polarimetry, enzymatic, liquid chromatography, or chemical methods Line Comment/Objection: Insert see before 2.1 and 2.4. Consistency with the rest of the document. 42. Larry Comment/Objection: The total viable count should be less than 200 CFU/mL. In RD52 section 4.1.2, this requirement is a shall. Change to The total viable count shall be less than 200 CFU/mL. 13

14 43. Fei Law, 44. Fei Law, T Comment/Objection: add option to incubate at 30 35C for 72 hours the trend for bacteriology testing has been to go to lower temperatures for longer periods of time. The USP method for Microbial Limits <61> defines incubation to be hold the contatiner in air that is thermostatically controlled at a temperature between 30 and 35. The subsection for the plate method gives instructions to incubate for hours. USP <1231> also lists testing conditions for drinking water, purified water, and water for injection to be between 30 and 35C, and hours. In order to not contradict RD62, the suggestion is to add this as an additional option rather than a replacement. Add in line 560: Alternatively, incubate at C and count colonies after 72 hours T Comment/Objection: Refer to comment on d. This section may be affected based on committee decision on that item relates to Dependent on committee decision re: d. The last sentence from A4.1.4 has been moved to as a note as follows Note: Other methods which have been shown by test results to give at least substantially equivalent results may be used in place of the reference test described in Because of the change to section a note will also be added to this section as follows Note: it is recognized by the committee that the dialysis machine manufacture may modify his equipment to use another manufacturers concentrate generator. When this occurs it becomes the machines manufacturers responsibility to ensure that 14

15 45. Richard 46. Larry 47. Dilip Shah, Aksys Ltd. (affirmative 48. Fei Law, Line Comment/Objection: Add - National Formulary after United States Pharmacopoeia and italicize a G Comment/Objection: Compliance can be determined by the tests for non-isolated patient connection found in IC :2004 (see 2.7) or UL laboratory standards Is AAMI going to provide these documents on the dialysis CD? Where can clinics get these documents? Would it be possible to include the testing requirements from these documents in RD61? b) 648 T Comment/Objection: Do not need manufacturing date if expiry date is provided. Products C marked requires expiration date, thus eliminating a need to provide manufacturing date if the product is also sold in US. date of manufacture, if no expiry date is used; b) and c) T Comment/Objection: Label expiration date. Use manufacturing date if there is no expiration date. If there is an expiration date, the manufacturing date is less relevant. the concentrate generator is compatible with the dialysis machine. Reject AAMI does not provide these only the requirements to do the testing. many times the testing is done by an outside laboratory that specializes in electrical safety testing. The initial testing should be done by the manufacturer Add b to comply with b) See comment 48 below as modified. A note was added stating that the expire date in normally used 15

16 49. Dilip Shah, Aksys, Ltd 50. Fei Law, 51. Dilip Shah, Aksys, Ltd b) expiration date, if applicable. c) manufacturing date, if expiration date is not applicable g) T Comment/Objection: The final formulation statement on acid bottle is appropriate for systems which use only one bicarbonate concentrate formulation. For multiple bicarbonate formulations the list can be long and confusing. For home use, there are 4 different bicarbonate concentrates for Aksys system. There are also 16 acid formulations on a 400 ml bottle. The final formulations are provided in other documents. There is no need to print them on each acid bottle for home use. Add if appropriate at the end of the sentence g) Comment/Objection: Delete in the final diluted solution editorial. Reference to dialysate already previously present in the same sentence. delete Delete in the final diluted solution from line h) 664 T Comment/Objection: Weight measure for dry concentrate is missing and quantity of water statement is not required for automatic systems. Dry bicarbonate concentrate with net weight is appropriate measure and should be included. Also, batch system can have automatic mixing where machine can determine how much in part Add a note 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. in principal A note will be added to 6.1 to clarify that special situations exist for special purpose machines. A rational will also be added to 16

17 52. Dilip Shah, Aksys, Ltd 53. Fei Law, 54. Dilip Shah, Aksys, Ltd water is needed. Adding a measure of how much water to be added on the label can be confusing to the home user who is not involved in mixing or dilution. for batch systems, the volume or weight of the dialysis concentrate; and water that shall be mixed unless mixing is automatic and user is not involved in dilution process; j) 668 T Comment/Objection: Trade name does not exist Product name is used in place of Trade name trade name or description of the product; l) T Comment/Objection: Delete example Refer to comment on d. Concentrate generators are not that specific to the dialysis delivery system. It s the dialysis delivery system that is designed to accept the concentrate generators. nd sentence after the word product in line o) T Comment/Objection: Statement applies only when manual dilution is involved or different manufacturers products are used to make dialysis solution Aksys batch system does not require any manual or external dilution and the concentrates are not used with any other system. A statement to such an effect is on the bottles, so there is no need to write A6.1 to clarify this note. Add if Appropriate See comment 51 17

18 55. Dilip Shah, Aksys, Ltd 56. Larry 57. Dilip Shah, Aksys, Ltd 58. Dilip Shah, Aksys, Ltd that AAMI RD62 quality water should be use. Add if appropriate to the statement p) 684 T Comment/Objection: Statement is required only if bicarbonate concentrate is mixed externally. Aksys PHD system mixes bicarbonate concentrate without exposure to air, in a closed system. It will be confusing to the user if such a statement is printed where a home user does not have to be involved. Add if applicable to the sentence ; Comment/Objection: Note: If color coding is used, red should be used for acid and blue for bicarbonate. This requirement is a shall in the current RD61. Did you mean to change to should? RD52 is a should e) T Comment/Objection: A statement of conductivity on the bottle is not useful when the user is a home patient. Aksys PHD system alarms when the final conductivity is not correct long before the start of the dialysis. The user is required to contact service person and start a new batch cycle. Add if applicable to the sentence c) 742 T Comment/Objection: A statement for the amount of water required for reconstitution is not appropriate when the machine determines automatically the See comment 51 Reject It is stated are agreed there are so many exceptions to the rules that it is difficult to define. The end result is that it is up to the user to use the correct concentrate See comment 51 See comment 51 18

19 water required. A statement to reconstitute bicarbonate with water can mislead the user for automatic systems. 59. Fei Law, Add if appropriate to the sentence c) Comment/Objection: Delete Redundant requirement. The mixing instructions are already required in 6.1.1b, line 740. Additionally, some concentrates are designed to be mixed to a total volume of xx liters or gallons. Amount of water will not be defined perse. 60. Richard 61. Richard Delete c) Line 742 Comment/Objection: Delete powder concentrates Redundant; the entire clause deals with powder concentrates f) Line 750 Comment/Objection: Delete for powder concentrates Redundant; the entire clause deals with powder concentrates. See comment 59 above 62. Fei Law, f) Comment/Objection: Delete for powder concentrates in line 750 This entire section applies to powder concentrates. Redundant verbiage. See comment 51 above Start sentence with The water 19

20 63. Fei Law, 64. Fei Law, 65. Fei Law, quality b) T Comment/Objection: in addition to amount of time, add other options for determining yield of the concentrate generator It appears that the intent of the indication for amount of time is to give the user guidance on the expected yield from the concentrate generator. This can be measured in more than time, for example, volume of concentrate. length of time a concentrate generator can be expected to function and provide concentrate to the machine or volume of concentrate that the generator can be expected to provide e) T Comment/Objection: is input water temperature applicable? except for maybe extreme hot water, water temperature should not be a mixer issue. However, extreme hot water is not really a likely occurrence. delete references to water temperature in line e) T Comment/Objection: is input water temperature or quality really an issue for the mixer manufacturer to ed as modified: b) " the length of time that the concentrate generator can reasonably be expected to provide solution, based on dialysate flow rate to the dialyzer (e.g. 6 hours at a flow rate of 500 ml/min.); alternately, the capacity of the concentrate generator can be expressed as the volume of concentrate produced." Time seems to be the most usable indicator to the user. If another method is given the user will be required to compute the length of usability of the generator. The commenter is correct in that there needs to be a flow rate at the specified time. Delete the example of water temperature. Delete reference to water quality 20

21 define? water quality seems more to be an issue for the concentrate mix manufacturer to define as the commenter stated this is an issue for the powder manufacturer 66. Richard 67. Richard 68. Richard A.1 Paragraph 2, line A.1 Paragraph 3, line A.1 Paragraph 4, line delete and input water quality in line 791. Revise sentence to read: operating specifications, such as pressure and flow rate Comment/Objection: liminate this paragraph. The paragraph has nothing to do with concentrates. Comment/Objection: Rewrite the first two sentences to reflect that the decision to split up RD5 is history. Rewrite as: When the AAMI Renal Disease and Detoxification Committee reviewed the original Hemodialysis systems standard in 1996, it decided to separate the document into three separate standards covering water, equipment, and concentrates. Comment/Objection: Rewrite for clarity and to indicate what was done in the present revision. Rewrite as: ANSI/AAMI RD61, Concentrates for hemodialysis, took into consideration developments over the preceding years, including: the addition of a maximum endotoxin concentration; the addition of new methods for preparing concentrate, such as powder 21

22 69. Richard 70. Larry 71. Richard concentrate generators built into a dialysis machine; and, the bulk delivery of concentrate. When this concentrate standard was revised in 2004, further developments, such as the use of mixing systems to prepare concentrates at a dialysis facility, were added. Also, the publication of ANSI/AAMI RD52:2004, Dialysate for hemodialysis eliminated the need for the concentrate standard to include requirements directed at the user. This change allowed the concentrate standard to be reformatted in the style of an ISO standard. A.1 Paragraph 5, Comment/Objection: Move the paragraph back one line position. Delete for the used from the second line and change new standard to recommended practice in the fifth line. Improve the readability of the clause. A.1 5 th paragraph Comment/Objection: Along with the three standards addressed to manufacturers the AAMI committee also determined there was a need to develop a recommended practice for the used to cover the users responsibilities for water and dialysate quality. Change used to user, and change users to user s Along with the three standards addressed to manufacturers the AAMI committee also determined there was a need to develop a recommended practice for the user to cover the user s responsibilities for water and dialysate quality A.2 Paragraph 1, Comment/Objection: Change Concentrate 22

23 72. Richard 73. Richard 74. Larry line 845 A.2 Paragraph 2, line 849 A.2 Paragraph 3, line A th paragraph solutions to Concentrates Dry concentrates are not solutions. Comment/Objection: Insert and, after patient; Comment/Objection: Use recommended practice and not standard when referring to RD52. Rewrite the last two sentences as: To that end, the AAMI Renal Disease and Detoxification Committee developed a new recommended practice, ANSI/AAMI RD52:2004, Dialysate for hemodialysis, that addresses the user s responsibilities. Users should review and follow the recommendations contained in this document to maintain dialysate quality in the dialysis facility. Comment/Objection: Bicarbonate dialysate can increase precipitation and scaling within the dialysate path, including on monitoring electrodes. something is missing here. This was correct changed to help clarify 75. Fei Law, A Line 914 Comment/Objection: is the reference to 2% tolerance still relevant to this version? The tolerance for Sodium has been 2.5% since The tolerance for Sodium has been 2.5% Yes 2% was the level set originally and has since been revised to 2.5% to follow the ISO standard 23

24 76. Richard 77. Richard 78. Larry 79. Richard since Delete first sentence of line 914. A Line 918 Comment/Objection: Change contaminates to contaminants in the clause title. A Line 924 Comment/Objection: Change RD62:2001 to RD62 200x A Comment/Objection: thus there is no requirement for testing or release levels of bacteria in acid concentrate. Is this worded correctly ( or release levels )? A Paragraph 3, line 953 T Comment/Objection: The clause refers to other clauses in the appendix dealing with test methods. These sections do not exist. ither add the sections or delete the reference. Add currently under review to clarify with modification modified text to read: XXX Modified with modification. Use modified text: "Although the importance of controlling the arsenic level in the dialysate is undisputed, the problem was regarding a suitable method for detecting arsenic levels in the concentrate at the 5- ppb level recommended by Keshaviah et al. 24

25 80. Richard 81. Richard 82. Richard 83. Richard A Line 960 T Comment/Objection: The referenced clause does not outline why the committee disagrees with Keshaviah et al. A Paragraph 1, line A Paragraph 2, line A.4.2 Paragraph 2, line Comment/Objection: Rewrite the last sentence for clarity. Rewrite as: Because the connectors could vary, it was considered necessary to state which machines the canisters could be used with. Comment/Objection: Rewrite for clarity. Rewrite as: Concentrate generators cannot be used with some proportioning systems, such as where the sodium bicarbonate is combined with sodium chloride, since there is no way of knowing that the dissolution rates of sodium bicarbonate and sodium chloride will be the same. Comment/Objection: Simplify sentence. Rewrite as: the committee decided that dialysate was better addressed in a (1980).. the committee recommended the 0.05 mg/l level " This will e added back from the 1993 version for your clarity 25

26 84. Richard 85. Richard A Paragraph 1, line 1034 Bibliography Line , , dialysate recommended practice Comment/Objection: Change last word of the first line to support Comment/Objection: Delete the reference to Alfrey and Smythe and the two references to the US PA. These items are not referenced in the document. It may be that they were referenced in a previous section on testing that has been eliminated from this version (see comment on A above). If the section on testing is restored, the references may be needed. Alfrey removed, rest to stay in this bibliography. Keep only cited documents. 86. Nate Levin FOR APPNDIX Clinical experience has made it clear that prescribing physicians may not be fully aware of the amounts of buffer that are added as the result of presence of acetate (in case of liquid concentrate) and acetate and acetic acid (acetic dehydrate) (in the case of dry concentrate). These add 3 or 6 mq/l respectively to whatever bicarbonate concentration is prescribed and may make the final buffer concentration unexpectedly high. with modification: The following will be inserted as a labeling requirement r) a statement reqarding any special buffering concerns, if appropriate. (see A.4.1) The following will be added to the annex clause a.4.1 second paragraph. Bicarbonate buffer equivalents When calculating the total amount of base in the final dialysate, the contribution of acetate (or any other organic anion that may produce bicarbonate as it is metabolized) from the acid concentrate must be considered in addition to the 26

27 bicarbonate contained in the bicarbonate concentrate. Some acid concentrates, for example those formulated with sodium diacetate (a compound comprised of acetic acid and sodium acetate), contain more organic anions than traditional concentrates. When using one of these concentrates, consideration should be given to the significant increase in base derived from the acid concentrate when selecting a dialysate bicarbonate concentration. In dialysis systems that prepare dialysate from water and two concentrates, selecting different dialysate sodium concentrations or performing sodium modeling, changes the total base concentration in the final dialysate. Depending on the treatment parameters selected these variations can be a great as 6%. 27