Working document QAS/13.539/Rev.1 January 2014 RESTRICTED

1 2 3 4

IMPLEMENTATION OF THE REVISED GENERAL MONOGRAPH ON PARENTERAL PREPARATIONS IN THE INTERNATIONAL PHARMACOPOEIA: LIMITS FOR THE TEST FOR BACTERIAL ENDOTOXINS (3.4)

5 6

REVISED DRAFT FOR COMMENT

7 8 9 10 11 12 13 14

Should you have any comments on this draft,COMMENTS please send these to Dr Herbert Schmidt, DRAFT FOR Medicines Quality Assurance, Technologies, Standards and Norms, World Health Organization, 1211 Geneva 27, Switzerland; fax: (+41 22) 791 4730 or email: [email protected] by 21 March 2014.

15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45

© World Health Organization 2014 All rights reserved. This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. The draft may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole, in any form or by any means outside these individuals and organizations (including the organizations' concerned staff and member organizations) without the permission of the World Health Organization. The draft should not be displayed on any web site. Please send any request for permission to: Dr Sabine Kopp, Group Lead, Medicines Quality Assurance, Technologies, Standards and Norms, Regulation of Medicines and other Health Technologies, Department of Essential Medicines and Health Products, World Health Organization, CH-1211 Geneva 27, Switzerland. Fax: (41-22) 791 4730; email: [email protected]. The designations employed and the presentation of the material in this draft do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by the World Health Organization to verify the information contained in this draft. However, the printed material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use. This draft does not necessarily represent the decisions or the stated policy of the World Health Organization.

Working document QAS/13.539/Rev.1 page 2 46 47 48 49 50 51

SCHEDULE FOR THE ADOPTION PROCESS OF DOCUMENT QAS/13.539: IMPLEMENTATION OF THE REVISED GENERAL MONOGRAPH ON PARENTERAL PREPARATIONS IN THE INTERNATIONAL PHARMACOPOEIA: LIMITS FOR THE TEST FOR BACTERIAL ENDOTOXINS (3.4)

Date Preparation of the document Discussion at informal consultation to discuss new medicines, quality control and laboratory standards Revision of draft proposal

12–14 June 2013 July 2013

Mailing of draft proposal for comments

July 2013

Collation of comments

September 2013

Presentation to 48th meeting of the WHO Expert Committee on Specifications for Pharmaceutical Preparations for discussion Preparation of revision 1 of the document

October 2013 December 2013

Mailing of revision 1 for comments

January–March 2013

Collation of comments

March 2013

Discussion of revision one at informal consultation to discuss new medicines, quality control and laboratory standards Presentation of revision one to 49th meeting of the WHO Expert Committee on Specifications for Pharmaceutical Preparations for discussion Further follow-up action as required

52 53 54

April 2013

2–4 April 2014

October 2014

Working document QAS/13.539/Rev.1 page 3 IMPLEMENTATION OF THE REVISED GENERAL MONOGRAPH ON PARENTERAL PREPARATIONS IN THE INTERNATIONAL PHARMACOPOEIA: LIMITS FOR THE TEST FOR BACTERIAL ENDOTOXINS (3.4)

55 56 57 58 59

Limits for bacterial endotoxins in monographs on parenteral preparations

60 61 62

During the forty-seventh meeting of the Expert Committee on Specifications for Pharmaceutical Preparations in October 2012 a revision of the general monograph on parenteral preparations was adopted.

63 64 65 66 67 68

One of the major changes to the monograph on parenteral preparations was the required compliance of all parenteral preparations with the test for bacterial endotoxins (or, where justified, pyrogens). As a consequence individual monographs on injectable dosage forms in The International Pharmacopoeia (Ph.Int.) were investigated with a view to add a limit for bacterial endotoxins to each monograph that currently does not include such a requirement. The following endotoxin limits are proposed for inclusion in The International Pharmacopoeia:

1

Ph.Int. monographs on parenteral preparations currently lacking limits for the bacterial endotoxins test Artemether injection

2

Artemotil injection

3

Ephedrine sulfate injection

4 5

Ergometrine hydrogen maleate injection Melarsoprol injection

6

Magnesium sulfate injection

7

Oxytocin injection

8

Pentamidine isetionate powder for injections2 Prednisolone sodium phosphate injection3

9

Proposed limits for the bacterial endotoxins test1 Less than 1.56 IU of endotoxin per mg Artemether Less than 1.04 IU of endotoxin per mg Artemotil Less than 1.7 IU of endotoxin per mg Ephedrine sulfate Less than 700 IU of endotoxin per mg of Ergometrine hydrogen maleate Less than 1.39 IU of endotoxin per mg Melarsoprol Less than 0.18 IU of endotoxin per mg Magnesium sulfate heptahydrate Less than 0.5 IU of endotoxin per IU of oxytocin Less than 1.25 IU of endotoxin per mg Pentamidine isetionate Less than 4.09 IU of endotoxin per mg Prednisolone

1

The complete phrase to be used in The International Pharmacopoeia should be: “Bacterial Endotoxins. Carry out the test as described under 3.4 Test for bacterial endotoxins; contains … (phrase of the table to be added).” 2 Title of the monograph to be changed to: Pentamidine isetionate for injection. 3 Title of the monograph to be changed to: Prednisolone phosphate injection.

3

Working document QAS/13.539/Rev.1 page 4 10

Quinine dihydrochloride injection

11

Zidovudine intravenous infusion

Less than 1.0 IU of endotoxin per mg Quinine dihydrochloride Less than 1.0 IU of endotoxin per mg Zidovudine

69 70 71

Table 1. Proposed limits for bacterial endotoxins in Ph.Int. monographs on parenteral preparations lacking such specification

72 73

The limits are determined following the approaches listed in Annex 1.

74 75 76

Further changes to The International Pharmacopoeia following the implementation of the revised general monograph on parenteral preparations

77

The following additional changes to The International Pharmacopoeia are proposed:

78

In the new general monograph on Parenteral preparations the statement is made that:

79 80 81

“For powders and concentrates for injections and intravenous infusions, the amount of the preparation to be tested and the nature and volume of the liquid in which it is to be dissolved, suspended or diluted is specified in the individual monograph.”

82 83 84 85

It is proposed to delete this sentence since the preparation of the sample solution is described in Chapter 3.4 Test for bacterial endotoxins. The text requires that samples should be dissolved or diluted in aqueous solutions so that the final solutions do not exceed the maximum valid dilution (MVD).

86 87

In the monograph on Metronidazole injection the following provision for the test for bacterial endotoxins is made:

88 89 90 91

“Carry out the test as described under 3.4 Test for bacterial endotoxins. Dilute the injection, if necessary, with water LAL to give a solution containing 5 mg per ml (solution A). Solution A contains not more than 3.5 IU of endotoxin per ml. Carry out the test using the maximum valid dilution of solution A calculated from the declared sensitivity of the lysate used in the test.”

92 93

Again, details of the sample solution preparation should be deleted and the sentence should be changed to read:

94 95

“Carry out the test as described under 3.4 Test for bacterial endotoxins; contains not more than 3.5 IU of endotoxin per ml.”

96

In general, two phrases are used to specify endotoxin limits in The International Pharmacopoeia:

Working document QAS/13.539/Rev.1 page 5 97 98 99 100 101 102

• •

“… not more that x IU of endotoxin per mg/ml …” ; and “… not more that x IU of endotoxin RS per mg/ml …”.

All expressions using “IU of endotoxin RS” should be changed to “IU of endotoxin”. Chapter 3.4 Test for bacterial endotoxins already requires the use of the WHO International Standard for endotoxin when performing the test (or an endotoxin reference standard that has been calibrated against this standard; see section Preparation of standard endotoxin stock solution).

103 104 105

5

Working document QAS/13.539/Rev.1 page 6 106

Annex 1

107

Calculation of bacterial endotoxin limits

108 109

The endotoxin limits proposed in Table 1 are calculated using the following approaches:

110 111 112

•

113 114 115

•

116 117 118 119 120 121

•

For the monograph on Ergometrine hydrogen maleate injection, the limit given in The International Pharmacopoeia for the active pharmaceutical ingredient (for parenteral use) was applied. For the monographs on Ephedrine sulfate injection, Magnesium sulfate injection, Oxytocin injection, Prednisolone sodium phosphate injection and Zidovudine intravenous infusion, limits given in monographs of other pharmacopoeias were taken over. For the monographs on Artemether injection, Artemotil injection, Melarsoprol injection, Pentamidine isetionate powder for injections and Quinine dihydrochloride injection, the endotoxin limits were calculated using recommendations given in Chapter 3.4 Test for bacterial endotoxins: The endotoxin limit for parenteral preparations, defined on the basis of dose, is equal to:
   =



122 123 124 125

K = threshold pyrogenic dose of endotoxin per kilogram of body mass (i.e. 5.0 IU per kg body weight for any route of administration other than intrathecal; 2.5 IU per kg body weight for intravenous route of radiopharmaceuticals; 0.2 IU per kg body weight for intrathecal route).

126 127 128

M = maximum recommended bolus dose of product per kilogram of body mass. (When the product is to be injected at frequent intervals or infused continuously, M is the maximum total dose administered in a single hour period.)

129 130 131 132 133

Table 2 lists data used in the calculation of the proposed bacterial endotoxin limits.

Working document QAS/13.539/Rev.1 page 7 Ph.Int. monographs lacking endotoxin limit

Endotoxin limits in pharmacopoeias

Artemether injection

Artemotil injection

Ephedrine sulfate injection

Ephedrine sulfate injection (USP 36): NMT 1.7 USP Endotoxin Unit per mg of ephedrine sulfate

Ergometrine hydrogen maleate injection

Ergometrine hydrogen maleate (Ph.Int. 4.3): NMT 700.0 IU of endotoxin RS per mg substance for parenteral use.

Melarsoprol injection

Magnesium sulfate injection Oxytocin injection

Information on dosage and route of application

K

M

“Intramuscular injection for adults, artesunate 2.4 mg/kg BW IV or IM given on admission (time = 0), then at 12 h and 24 h, then once a day is the recommended treatment. Artemether, or quinine, is an acceptable alternative if parenteral artesunate is not available: artemether 3.2 mg/kg BW IM given on admission then 1.6 mg/kg BW per day.”4 “Artecef® 150 must only be applied via the intramuscular route. Medical treatment consists of a 3-day course. The initial dose consists of an injection of 4.8 mg artemotil per kg body weight evenly divided over both anterior thighs. The follow-up doses consist of 1.6 mg per kg body weight after 6, 24, 48 and 72 hours in alternating thighs.”5

5 IU/kg

3.2 mg/kg

5 IU/kg

4.8 mg/kg

“Treatment of T. brucei rhodesiense and T. brucei gambiense with meningoencephalitic involvement [ ], by slow intravenous injection, ADULT and CHILD, dose gradually increased from 1.2 mg/kg to maximum of 3.6 mg/kg daily in courses of 3–4 days with intervals of 7–10 days between courses; [ ].”6 (page 209)

5 IU/kg

3.6 mg/kg

Magnesium sulfate injection (USP 36): NMT 0.09 USP Endotoxin Unit per mg of magnesium sulfate Oxytocin Injection (USP 36): NMT 35.7 Endotoxin Units per USP Oxytocin Unit Oxytocin (EP 7.8): less than 300 IU per mg Oxytocin, corresponding to less than 0.5 IU per IU of Oxytocin

4

Guidelines for the treatment of malaria, 2nd edition, page 41, World Health Organization, Geneva, 2010. Product Information Leaflet, Artecef BV 150 mg/ml injection, see WHO Prequalification website, dossier assessment, MA027 and MA028. 6 Information taken from the WHO Model Formulary, based on the 15th Model List of Essential Medicines 2007, World Health Organization, Geneva, 2009. 5

7

Working document QAS/13.539/Rev.1 page 8 Pentamidine isetionate powder for injections Prednisolone sodium phosphate injection

5 IU/kg

4 mg/kg

“Treatment of multidrug-resistant P. falciparum malaria (in patients unable to take quinine by mouth), by slow intravenous infusion (over 4 hours), ADULT, initially 20 mg/kg (quinine dihydrochloride), followed by 10 mg/kg (quinine dihydrochloride) every 8 hours; CHILD, initially 20 mg/kg (quinine dihydrochloride), followed by 10 mg/kg (quinine dihydrochloride) every 12 hours; initial dose should be halved in patients who have received quinine, quinidine or mefloquine during the previous 12–24 hours.”6 (page 198)

5 IU/kg

5 mg/kg

Prednisolone sodium phosphate injection (USP 36): NMT 5.0 USP Endotoxin Units per mg of prednisolone phosphate

Quinine dihydrochloride injection

Zidovudine intravenous infusion

“Visceral leishmaniasis (unresponsive to, or intolerant of, antimonial compounds), by deep intramuscular injection or by intravenous infusion, ADULT and CHILD, 4 mg/kg 3 times a week for 5–25 weeks or longer, until 2 consecutive splenic aspirates taken 14 days apart are negative.”6 (page 186)

Zidovudine injection (USP 36): NMT 1.0 USP Endotoxin Unit per mg of zidovudine

Table 2. Data used in the calculation of bacterial endotoxin limits ***