Working document QAS/14.

571
February 2014
DRAFT FOR COMMENT

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4 REVISION OF GENERAL MONOGRAPH: SUPPOSITORIES
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6 (February 2014)
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8 DRAFT FOR COMMENT
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12 Should you have any comments on thisFOR
DRAFT draft,COMMENTS
please send these to Dr Herbert Schmidt,
13 Medicines Quality Assurance , Technologies, Standards and Norms, World Health
14 Organization, 1211 Geneva 27, Switzerland; fax: (+41 22) 791 4730 or email:
15 schmidth@who.int by 26 April 2014.
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19 © World Health Organization 2014

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21 All rights reserved.
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23 This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. The draft may
24 not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole, in any form or by
25 any means outside these individuals and organizations (including the organizations' concerned staff and member organizations)
26 without the permission of the World Health Organization. The draft should not be displayed on any web site.
27
28 Please send any request for permission to:
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30 Dr Sabine Kopp, Group Lead, Medicines Quality Assurance, Technologies, Standards and Norms, Department of Essential
31 Medicines and Health Products, World Health Organization, CH-1211 Geneva 27, Switzerland. Fax: (41-22) 791 4730; email:
32 kopps@who.int.
33
34 The designations employed and the presentation of the material in this draft do not imply the expression of any opinion whatsoever
35 on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or
36 concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there
37 may not yet be full agreement.
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39 The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by
40 the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the
41 names of proprietary products are distinguished by initial capital letters.
42
43 All reasonable precautions have been taken by the World Health Organization to verify the information contained in this draft.
44 However, the printed material is being distributed without warranty of any kind, either expressed or implied. The responsibility for
45 the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages
46 arising from its use.
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48 This draft does not necessarily represent the decisions or the stated policy of the World Health Organization.
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50 SCHEDULE FOR THE ADOPTION PROCESS OF DOCUMENT QAS/14.571

51 REVISION OF GENERAL MONOGRAPH: SUPPOSITORIES

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53
Date 54
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Draft monograph received from a WHO February 2014 57
Expert 58

Draft monograph mailed out for comments February – April 2014

Discussion at informal consultation on 3–4 April 2014

specifications for The International
Pharmacopoeia

Collation of comments April 2014

Presentation to forty-ninth WHO Expert October 2014

Committee on Specifications for
Pharmaceutical Preparations for discussion

Further follow-up action as required

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59 REVISION OF GENERAL MONOGRAPH: SUPPOSITORIES

60

61 [Note from the Secretariat.

62 The proposed general monograph is part of the review of general monographs endorsed by the
63 Expert Committee at its 42nd meeting. It is proposed to replace the current general monograph on
64 suppositories with a general monograph including solid, liquid and semi-solid dosage forms
65 intended for rectal application.]

66

67 RECTAL PREPARATIONS

68 Definition

69 Rectal preparations are liquid, semi-solid or solid preparations that may contain one or more active
70 ingredients. They are intended for rectal application in order to obtain a systemic or local effect.

71 Rectal preparations may require the use of excipients of various types. Any excipient must be
72 proven through product development studies not to adversely affect the stability of the final
73 product, nor the availability of the active ingredient(s) at the site of action; incompatibility between
74 any of the components of the dosage form should be avoided.

75 The different categories of rectal preparations include:

76 – suppositories;
77 – rectal capsules;
78 – rectal solutions, emulsions and suspensions;
79 – powders and tablets for rectal solutions and suspensions;
80 – semi-solid rectal preparations.

81 Manufacture

82 The following information is intended to provide broad guidelines concerning main steps to be
83 followed during production.

84 Manufacturing and filling processes for rectal preparations should meet the requirements of good
85 manufacturing practices (GMP).

86 During development, the effectiveness of any antimicrobial preservative present in the preparation
87 shall be demonstrated to the satisfaction of the relevant regulatory authority.

88 During development it must be demonstrated that the nominal contents can be withdrawn from the
89 container of liquid and semi-solid rectal preparations presented in single-dose containers.
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90 In the manufacture, packaging, storage and distribution of rectal preparations, suitable measures are
91 taken to ensure their microbial quality; recommendations on this aspect are provided in the chapter
92 Microbial examination of non-sterile products: acceptance criteria for pharmaceutical
93 preparations, published in the Supplementary information section.

94 In the manufacture of rectal preparations containing dispersed particles, measures are taken to
95 ensure a suitable and controlled particle size.

96 Throughout manufacturing, certain procedures should be validated and monitored by carrying out
97 appropriate in-process controls. These should be designed to guarantee the effectiveness of each
98 stage of production.

99 Labelling

100 Every rectal preparation must comply with the labelling requirements established under GMP.

101 The label should include:

102 1) name of the pharmaceutical product;

103 2) name(s) of the active ingredient(s); International Nonproprietary Names (INN) should be
104 used whenever possible;
105 3) amount of active ingredient(s) in a dose unit and the number of dose units in the container or
106 the amount of active ingredient(s) in suitable dose volume and the volume of the container;
107 4) where applicable, the name of any added antimicrobial agent;
108 5) batch (lot) number assigned by the manufacturer;
109 6) expiry date and, when required, the date of manufacture;
110 7) any special storage conditions or handling precautions that may be necessary;
111 8) directions for use, warnings and precautions that may be necessary;
112 9) name and address of the manufacturer or the person responsible for placing the product on
113 the market.

114 Requirements for specific types of rectal preparations

115 Suppositories

116 Definition

117 Suppositories are solid single-dose preparations intended for rectal application. They are prepared
118 by moulding or compression. The shape, volume and consistency of suppositories are suitable for
119 rectal application.

120 Suppositories contain one or more active ingredients dispersed or dissolved in a suitable basis that
121 may be soluble or dispersible in water or may melt at body temperature. When prepared by
122 moulding, suppository bases such as magrogols, gelatinous mixtures consisting of, for example,
123 gelatin, water and glycerol, hydrogenated vegetable oils, hard fat or cocoa butter are usually
124 employed.
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125 Excipients such as diluents, adsorbents, surface-active agents preferably of nonionic type,
126 lubricants, antimicrobial preservatives and colouring matter authorized by the appropriate national
127 or regional authority, may be added when necessary.

128 Manufacture

129 It is common to use a suppository base in which the active ingredient(s) does not dissolve in order
130 to avoid problems associated with partition between the molten or softened base and the rectal
131 liquid. The release of the active ingredient(s) may in case of a suspension be dependent on
132 sedimentation of the solid particles in the molten or softened base to the interface of the rectal
133 liquid. The particle size of the active ingredient(s) should therefore be optimized to take both
134 sedimentation and dissolution in the rectal liquid into account.

135 In the manufacture of suppositories containing dispersed active ingredient(s), measures are taken to
136 ensure a suitable and controlled particle size.

137 When prepared by moulding, the medicated mass, sufficiently liquefied by heating, is poured into
138 suitable moulds. The suppositories solidify on cooling. In certain cases, it is also possible to cold-
139 mould by compression in a suitable press.

140 The softening time is determined according to the text Softening time determination of lipophilic
141 suppositories, published in the Supplementary information section.

142 A suitable test is carried out to demonstrate the appropriate release of the active ingredient(s) from
143 suppositories.

144 Packaging must be adequate to protect suppositories from light, excessive heat, moisture, and
145 damage due to handling and transportation. It is necessary to ensure that the suppositories can be
146 released from the packaging easily and without damage.

147 Visual inspection

148 Suppositories are elongated, smooth and have a uniform texture and appearance.

149 Evidence of physical and/or chemical instability is demonstrated by noticeable changes in:

150 – surface texture or form, and

151 – colour and odour.

152 Disintegration

153 Suppositories comply with 5.4 Disintegration test for suppositories and rectal capsules unless
154 intended for sustained release. For suppositories with a lipophilic base, examine after 30 minutes,
155 and for suppositories with a water-soluble base, examine after 60 minutes.

156 Uniformity of mass

157 Suppositories comply with 5.2 Uniformity of mass of single-dose preparations.

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158

159 Uniformity of content

160 Suppositories comply with 5.1 Uniformity of content of single-dose preparations when the content
161 of active ingredient is 5 mg or less per suppository or 5% or less of the total mass. If the suppository
162 has more than one active ingredient, the requirement applies only to those active ingredients that
163 fall into the above category. If the test for uniformity of content is prescribed, the test for uniformity
164 of mass is not required.

165 Containers

166 Suppositories should be supplied in a well-closed container. The container material should not
167 adversely affect the quality of the preparation, nor should it allow diffusion into or across the
168 container material or yield foreign substances into the preparation.

169

170 Rectal capsules

171 Definition

172 Rectal capsules are solid, single-dose preparations generally similar to soft capsules as defined in
173 the monograph on Capsules, except that they may have a lubricating coating. The contents of rectal
174 capsules are usually solutions or suspensions of the active ingredient(s) in non-aqueous liquids, e.g.
175 vegetable oil, or in semi-solid mixtures of suitable excipients.

176 Manufacture

177 See the manufacturing instructions for soft capsules. Other considerations for soft capsule
178 suppositories include the study of and suitable controls for pH, leakage and pellicle formation.

179 A suitable test is carried out to demonstrate the appropriate release of the active ingredient(s) from
180 rectal capsules.

181 Visual inspection

182 Rectal capsules are of elongated shape, smooth and have a uniform external appearance.

183 Unpack and inspect at least 20 rectal capsules. They should be smooth and undamaged. Evidence of
184 physical instability is demonstrated by gross changes in physical appearance, including hardening
185 or softening, cracking, swelling, mottling or discoloration of the shell.

186 Disintegration

187 Rectal capsules comply with 5.4 Disintegration test for suppositories and rectal capsules unless
188 intended for sustained release. Examine the state of the rectal capsules after 30 minutes unless
189 otherwise prescribed in the individual monograph.
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190

191 Uniformity of mass

192 Rectal capsules comply with the requirements to capsules in 5.2 Uniformity of mass of single-dose
193 preparations.

194 Uniformity of content

195 Rectal capsules comply with 5.1 Uniformity of content of single-dose preparations when the
196 content of active ingredient is 5 mg or less per suppository or 5% or less of the total mass. If the
197 rectal capsule has more than one active ingredient, the requirement applies only to those active
198 ingredients that fall into the above category. If the test for uniformity of content is prescribed, the
199 test for uniformity of mass is not required.

200

201 Rectal solutions, emulsions and suspensions

202 Definition

203 Rectal solutions, emulsions and suspensions (also called enemas) are liquid preparations intended
204 for rectal application to obtain a local or systemic effect, or they may be intended for diagnostic
205 purposes. They contain one or more active ingredients dissolved or dispersed in water, glycerol,
206 macrogols, vegetable oil or mixtures thereof.

207 Rectal emulsions may show evidence of phase separation but are readily redispersed on shaking.
208 Rectal suspensions may show a sediment that is readily dispersible on shaking to give a suspension
209 that remains sufficiently stable to enable the correct dose to be delivered.

210 They may contain excipients, for example to adjust the viscosity of the preparation, to adjust or
211 stabilize pH, to increase the solubility of the active ingredient(s) and to stabilize the preparation.
212 The excipients do not, at the concentrations used, cause undue local irritation.

213 Rectal solutions, emulsions and suspensions are supplied in single-dose containers containing a
214 volume in the range of 2.5 ml to 2000 ml. The container is adapted to deliver the preparation to the
215 rectum or is accompanied by a suitable applicator.

216

217 Powders and tablets for rectal solutions and suspensions

218 Definition

219 Powders and tablets intended for the preparation of rectal solutions or suspensions are single-dose
220 preparations that are dissolved or dispersed in water or other suitable solvents at the time of
221 administration. They may contain excipients to facilitate dissolution or dispersion or to prevent
222 aggregation of the particles.
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223 After dissolution or suspension, the preparation complies with the requirements for rectal solutions
224 or rectal suspensions as appropriate.

225 Disintegration

226 Tablets for rectal solutions or suspensions comply with the following test: Place one tablet in a
227 250 ml beaker containing 200 ml of water R at 15–25 °C. Repeat the operation on five additional
228 tablets. The tablets comply with the test if each of the six tablets used in the test dissolves or
229 disintegrates within 3 minutes, unless otherwise specified in the individual monograph.

230 Labelling

231 The label states:

232 – the method of preparing the rectal solution or suspension;

233 – when necessary, conditions and duration of storage of the final preparation.
234

235 Semi-solid rectal preparations

236 Definition

237 Semi-solid rectal preparations are ointments, creams or gels intended for local treatment in the
238 rectum.

239 They are usually supplied as single-dose preparations in containers adapted to deliver the
240 preparation to the rectum or are accompanied by a suitable applicator.

241 Semi-solid rectal preparations comply with the requirements for Topical semi-solid dosage forms.

242 Manufacture

243 When supplied in multidose containers, the expected reproducibility of the delivery of the intended
244 volume must be ensured.

245

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