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MEDICATED TAMPONS

          Medicated tampons are solid, single-dose preparations intended to be inserted into the body cavities for a limited period of time. They consist of a suitable material such as cellulose, collagen or silicone impregnated with one or more active ingredients.

          Production In manufacturing, packaging, storage and distribution of medicated tampons, suitable means are taken to ensure their microbial quality.

          Microbial limit Comply with the “Limits for Microbial Contamination” (Appendix 10.5).

NASAL PREPARATIONS

          Nasal preparations are liquid, semi-solid or solid preparations containing one or more active ingredients. They are intended for administration to the nasal cavities (nostrils) for local or systemic effects. Nasal preparations should as far as possible be non-irritating and should not adversely affect the functions of the nasal mucosa and its cilia. Aqueous Nasal preparations are usually isotonic. Nasal preparations are supplied in multiple-unit or single-unit containers provided, if necessary, with a suitable administration device.

          Unless otherwise justified and authorized, aqueous nasal preparations supplied in multiple-unit containers contain a suitable antimicrobial preservative in appropriate concentration, except when the preparation itself has adequate antimicrobial properties.

          Five categories of nasal preparations may be distinguished: (1) nasal drops; (2) liquid nasal sprays; (3) nasal powders; (4) semi-solid nasal preparations; (5) nasal washes.

          Minimum fill Nasal preparations comply with the test described in the “Minimum Fill” (Appendix 4.26).

          Labelling The label of nasal preparations states the instructions for use.

Nasal Drops

          Nasal drops are solutions, emulsions or suspensions intended for instillation into the nostrils. Emulsions should not show evidence of phase separation; they have a uniform appearance after shaking. Suspensions may show a sediment which is readily redispersible on shaking to give a suspension which remains sufficiently stable to enable the correct dose to be delivered.

          Production Single doses of nasal drops intended for systemic absorption of active ingredients through the nasal mucosa are tested for uniformity of volume, content or weight.

          Containers Nasal drops are usually supplied in glass or plastic containers provided with a suitable applicator.

          Uniformity of weight Nasal drops that are solutions comply with the following test: weigh individually the contents of ten containers emptied as completely as possible, and determine the average mass. Not more than two of the individual masses deviate by more than 10 per cent from the average mass and none deviates by more than 20 per cent.

          Uniformity of content Nasal drops that are suspensions comply with the “Content Uniformity” (Appendix 4.28).

Liquid Nasal Sprays

          (Note Where liquid nasal sprays are supplied in aerosol containers, these comply with the appropriate requirements for Aerosols.)

          Liquid nasal sprays are solutions, emulsions or suspensions intended for spraying into the nostrils. See also under Nasal Drops.

          Production For liquid nasal sprays that are suspensions, the size of the dispersed particles of the spray should be such as to localize their deposition in the nostril.

          Single doses of liquid nasal sprays intended for systemic absorption of active ingredients through the nasal mucosa are tested for uniformity of volume, content or weight.

          Packaging and storage Liquid nasal sprays are supplied in glass or plastic containers with atomizing devices or in aerosol containers fitted with a suitable adapter and with or without a metering dose valve. They may also be administered by means of suitable inhalers. Aerosol preparations shall be stored at a temperature not exceeding 50º and protected from frost.

          Uniformity of weight Metered dose nasal sprays that are solutions comply with the following test: discharge once to waste. Wait for not less than 5 seconds and discharge again to waste. Repeat this procedure for a further three actuations. Weigh the mass of the container, discharge once to waste and weigh the remaining mass of the container. Calculate the difference between the two masses. Repeat the procedure for a further nine containers. They comply with the test if not more than two of the individual values deviate by more than 25 per cent from the average value and none deviates by more than 35 per cent.

          Uniformity of delivered dose Metered dose nasal sprays that are suspensions or emulsions comply with the following test: use an apparatus capable of quantitatively retaining the dose leaving the actuator of the atomising device.

          Shake a container for 5 seconds and discharge once to waste. Wait for not less than 5 seconds, shake for 5 seconds and discharge again to waste. Repeat this procedure for a further three actuations. After 2 seconds, fire one dose of the metered dose nasal spray into the collecting vessel by actuating the atomizing device.

          Collect the contents of the collecting vessel by successive rinses. Determine the content of active ingredient in the combined rinses.

          Repeat the procedure for a further nine containers. Unless otherwise justified and authorized, the preparation complies with the test if not more than one of the individual contents is outside the limits of 75 per cent to 125 per cent and none is outside the limits of 65 per cent and 135 per cent of the average content. If two or three individual contents are outside the limits of 75 per cent to 125 per cent but within the limits of 65 per cent to 135 per cent, repeat the test for twenty more containers. The preparation complies with the test if not more than three individual contents of the thirty individual contents are outside the limits of 75 per cent to 125 per cent and none is outside the limits of 65 per cent to 135 per cent of the average content.

Nasal Powders

          (Note Nasal powders comply with the appropriate requirements for Powders.)

          Nasal powders are powders intended for insufflation into the nostrils by means of a suitable device.

          Production The size of the particles should be such as to localize their deposition in the nostril. Particle size should be verified by adequate methods of particle-size determination.

          Containers See under Nasal Drops.

Semi-solid Nasal Preparations

(Note Semi-solid nasal preparations comply with the appropriate requirements for Topical Semi-solid Preparations.)

          Semi-solid nasal preparations are semi-solid dosage forms such as creams, gels, or ointments, etc. intended for application into the nostrils. Containers The containers for semi-solid nasal preparations should be adapted to deliver the product to the site for application.

Nasal Washes

          Nasal washes are generally aqueous solutions intended for irrigation of the nostrils. Nasal washes intended for application to injured parts or prior to a surgical operation are sterile.

          Sterility Where the nasal washes are labelled as sterile, unless otherwise directed in the individual monograph, they comply with the “Sterility Test” (Method I, Appendix 10.1).

          Containers See under Nasal Drops.

          Labelling The label of nasal washes shall state, where applicable, a statement that the preparations are sterile.

ORAL LIQUIDS

          Oral liquids usually consist of solutions, suspensions or emulsions of one or more active ingredients in a suitable vehicle; some oral liquids may consist of liquid active ingredients as such. They are intended to be swallowed either undiluted or after dilution. Oral liquids may contain suitable antimicrobial preservatives, antioxidants and other auxiliary substances such as dispersing, suspending, thickening, emulsifying, buffering, wetting, solubilizing, stabilizing, flavouring, sweetening agents, and authorized colouring agents. The vehicle for any particular oral liquids should be chosen having regard to the nature of the active ingredient(s) and providing organoleptic characteristics appropriate to the intended use of the preparation.

          Oral liquids other than oral emulsions may be supplied as liquids or prepared just before issue for use by diluting concentrated liquid preparations or dissolving or dispersing granules or powder in the liquid stated on the label.

          Suspensions may show a sediment that is readily dispersible on shaking. Emulsions may show evidence of phase separation but are easily reformed on shaking. The preparation remains sufficiently stable to enable a homogeneous dose to be withdrawn.

          Several categories of oral liquids may be distinguished: (1) elixirs; (2) linctuses; (3) mixtures; (4) oral drops; (5) oral emulsions; (6) oral solutions; (7) oral suspensions; (8) preparations for oral liquids; (9) syrups.

          Deliverable volume Oral liquids comply with the test described in the “Deliverable Volume” (Appendix 4.21).

          Uniformity of dosage units Oral liquids that are suspensions or solids in single-unit containers comply with the “Uniformity of Dosage Units” (Appendix 4.28).

          Packaging and storage Oral liquids should be kept in well-closed containers. They are supplied in multiple-unit or single-unit containers. They are administered either in volumes such as 5 ml, or multiples of 5 ml, or in small volumes (drops). Each dose of a multiple-unit preparation is administered by means of a device suitable for measuring the prescribed volume.

          Oral liquids are supplied in containers that comply with the appropriate requirements given in “Containers” (Appendix 11).

          Labelling The label of oral liquids states for Oral Emulsions, Oral Suspensions and, where appropriate, for Mixtures, that the bottle should be shaken before use.

Elixirs

          Elixirs are clear, flavoured oral liquids containing one or more active ingredients dissolved in a vehicle that usually contains a high proportion of Sucrose or a suitable polyhydric alcohol or alcohols and may also contain Ethanol (95 Per Cent) or Dilute Ethanols.

Linctuses

           Linctuses are viscous oral liquids that may contain one or more active ingredients in solution. The vehicle usually contains a high proportion of Sucrose, other sugars or a suitable polyhydric alcohol or alcohols. Linctuses are intended for use in the treatment or relief of cough, and are sipped and swallowed slowly without the addition of water.

Mixtures

           Mixtures are oral liquids containing one or more active ingredients dissolved, suspended or dispersed in a suitable vehicle. Suspended solids may separate slowly on standing but are easily redispersed on shaking.

Oral Drops

           Oral drops are oral liquids that are intended to be administered in small volumes with the aid of a suitable measuring device (Appendix 1.15).

Oral Emulsions

           Oral emulsions are oral liquids containing one or more active ingredients. They are stabilized oil-in-water dispersions, either or both phases of which may contain dissolved solids. Solids may also be suspended in oral emulsions.

           Containers When issued for use, oral emulsions should be supplied in wide-mouthed bottles.

Oral Solutions

           Oral solutions are oral liquids containing one or more active ingredients dissolved in a suitable vehicle.

Oral Suspensions

           Oral suspensions are oral liquids containing one or more active ingredients suspended in a suitable vehicle. Suspended solids may slowly separate on standing but are easily redispersed.

Preparations for Oral Liquids

           Preparations for oral liquids are solids or mixtures of solids intended for the preparations of solutions or suspensions by dissolving or dispersing them in a suitable vehicle. They may contain auxiliary substances in particular to facilitate dispersion or dissolution and to prevent caking. They are designated “for Oral Solution” or “for Oral Suspension” (e.g., Ampicillin for Oral Suspension).

           Packaging and storage Preparations for oral liquids shall be kept in tightly closed containers.

           Labelling The label of preparations for oral liquids states (1) the directions for preparing the oral liquids including the nature and quantity of liquid to be used; (2) the storage condition; (3) the conditions and the duration of storage after constitution.

Syrups

           Syrups are concentrated aqueous solutions of sucrose, other sugars or sweetening agents, to which small quantities of suitable polyhydric alcohols may be added to retard crystallization or to increase the solubility of the other ingredients. Syrups usually contain aromatic or other flavouring materials and may also contain active ingredient(s). They should be recently prepared unless they contain suitable antimicrobial preservatives.

           Packaging and storage Syrups should be kept in well-closed containers and stored at temperatures not exceeding 30º.

OROMUCOSAL PREPARATIONS

           Oromucosal preparations are solid, semi-solid or liquid preparations, containing one or more active substances intended for administration to the oral cavity and/or the throat to obtain a local or systemic effect. Preparations intended for a local effect may be designed for application to a specific site within the oral cavity such as the gums (gingival preparations) or the throat (oropharyngeal preparations). Preparations intended for a systemic effect are designed to be absorbed primarily at one or more sites on the oral mucosa (e.g., sublingual preparations). Mucoadhesive preparations are intended to be retained in the oral cavity by adhesion to the mucosal epithelium and may modify systemic drug absorption at the site of application. For many oromucosal preparations, it is likely that some proportion of the active substance(s) will be swallowed and may be absorbed via the gastrointestinal tract.

           Oromucosal preparations may contain suitable antimicrobial preservatives and other excipients such as dispersing, suspending, thickening, emulsifying, buffering, wetting, solubilizing, stabilizing, flavouring and sweetening agents. Solid preparations may in addition contain glidants, lubricants and excipients capable of modifying the release of the active substance(s).

           Several categories of preparations for oromucosal use may be distinguished: (1) gargles; (2) mouthwashes; (3) gingival solutions; (4) oromucosal solutions and oromucosal suspensions; (5) semi-solid oromucosal preparations (including for example gingival gel, gingival paste, oromucosal gel, oromucosal paste); (6) oro-mucosal drops, oromucosal sprays and sublingual sprays (including oropharyngeal sprays); (7) lozenges and pastilles; (8) compressed lozenges; (9) sublingual tablets and buccal tablets; (10) oromucosal capsules; (11) mucoadhesive preparations.

           Production During the development of an oromucosal preparation containing an antimicrobial preservative, the effectiveness of the chosen preservative shall be demonstrated to the satisfaction of the competent authority. A suitable test method together with the criteria for judging the preservative properties of the formulation are provided under “Efficacy of Antimicrobial Preservation” (Appendix 10.6).

           In the manufacture, packaging, storage and distribution of oromucosal preparations, suitable means are taken to ensure their microbiological quality; recommendations on this aspect are provided under “Limit for Microbial Contamination” (Appendix 10.5).

           In the manufacture of semi-solid and liquid oromucosal preparations containing dispersed particles,measures are taken to ensure a suitable and controlled particle size with regard to the intended use.

           Uniformity of dosage units Single-unit oromucosal preparations comply with the “Uniformity of dosage units” (Appendix 4.28).

Gargles

           Gargles are aqueous solutions intended for gargling to obtain a local effect. They are not to be swallowed. They are supplied as ready-to-use solutions or concentrated solutions to be diluted. They may also be prepared from powders or tablets to be dissolved in water before use. Gargles may contain excipients to adjust the pH which, as far as possible, is neutral.

Mouthwashes

           See under Topical Preparations.

Gingival Solutions

           Gingival solutions are intended for administration to the gingivae by means of a suitable applicator.

Oromucosal Solutions and Oromucosal Suspensions

           Oromucosal solutions and oromucosal suspensions are liquid preparations intended for administration to the oral cavity by means of a suitable applicator.

           Oromucosal suspensions may show a sediment which is readily dispersible on shaking to give a suspension which remains sufficiently stable to enable the correct dose to be delivered.

Semi-solid Oromucosal Preparations

            Semi-solid oromucosal preparations are hydrophilic gels or pastes intended for administration to the oral cavity or to a specific part of the oral cavity such as the gingivae (gingival gel, gingival paste). They may be provided as single-dose preparations.

           Semi-solid oromucosal preparations comply with the requirements of the monograph for “Topical semisolid Preparations” (Appendix 1.16).

Oromucosal Drops, Oromucosal Sprays and Sublingual Sprays

           Oromucosal drops, oromucosal sprays and sublingual sprays are solutions, emulsions or suspensions intended for local or systemic effect. They are applied by instillation or spraying into the oral cavity or onto a specific part of the oral cavity such as spraying under the tongue (sublingual spray) or into the throat (oropharyngeal spray).

           Emulsions may show evidence of phase separation but are readily redispersed on shaking. Suspensions may show a sediment which is readily dispersed on shaking to give a suspension which remains sufficiently stable to enable the correct dose to be delivered.

            Liquid oromucosal sprays are supplied in containers with atomizing devices or in pressurized containers having a suitable adaptor, with or without a metering dose valve, which comply with the requirements of the monograph for “Aerosols” (Appendix 1.6).

            The size of the droplets of the spray is such as to localize their deposition in the oral cavity or the throat as intended.

            Unless otherwise prescribed or justified and authorized, oromucosal drops supplied in single-dose containers, single doses of metered-dose oromucosal sprays and sublingual sprays, all intended for systemic action, comply with the following requirement.

Oromucosal Drops in Single-dose Containers

            Uniformity of dosage units Oromucosal drops in single-unit containers comply with the “Uniformity of Dosage Units” (Appendix 4.28).

Metered-dose Oromucosal Sprays and Sublingual Sprays

            Uniformity of dosage units Metered-dose oromucosal sprays and sublingual sprays comply with the “Uniformity of Dosage Units” (Appendix 4.28) or, where justified and authorized, with the test for uniformity of weight or the test for uniformity of delivered dose shown below.

IN THE CASE OF METERED-DOSE OROMUCOSAL SPRAYS AND SUBLINGUAL SPRAYS THAT ARE SOLUTIONS, PROCEED AS FOLLOWS Discharge once to waste. Wait for a minimum of 5 seconds, shake for 5 seconds and discharge again to waste. Repeat this procedure for a further 3 actuations. Weigh the container, discharge once to waste and weigh the container again. Calculate the difference between the 2 weights. Repeat the procedure for a further 9 containers. Determine the weight variation (Appendix 4.28).

IN THE CASE OF METERED-DOSE OROMUCOSAL SPRAYS AND SUBLINGUAL SPRAYS THAT ARE SUSPENSIONS OR EMULSIONS PROCEED AS FOLLOWS Use an apparatus capable of quantitatively retaining the dose leaving the actuator of the atomizing device. Shake the container for 5 seconds and discharge once to waste. Wait for a minimum of 5 seconds, shake for 5 seconds and discharge again to waste. Repeat this procedure for a further 3 actuations. After 2 seconds, fire 1 dose of the metered-dose spray into the collecting vessel by actuating the atomising device. Collect the contents of the collecting vessel by successive rinses. Determine the content of active substance in the combined rinses. Repeat the procedure for a further 9 containers. Determine the content uniformity (Appendix 4.28).

            Weight variation Metered-dose oromucosal sprays and sublingual sprays that are solutions comply with the following test. Discharge once to waste. Wait for a minimum of 5 seconds, shake for 5 seconds and discharge again to waste. Repeat this procedure for a further 3 actuations. Weigh the container, discharge once to waste and weigh the container again. Calculate the difference between the 2 weights. Repeat the procedure for a further 9 containers.

             The preparation complies with the test if maximum 2 of the individual values deviate by more than 25 per cent from the average value and none deviates by more than 35 per cent.

             Uniformity of delivered dose Metered-dose oromucosal sprays and sublingual sprays that are suspensions or emulsions comply with the following test. Use an apparatus capable of quantitatively retaining the dose leaving the actuator of the atomizing device. Shake the container for 5 seconds and discharge once to waste. Wait for a minimum of 5 seconds, shake for 5 seconds and discharge again to waste. Repeat this procedure for a further 3 actuations. After 2 seconds, fire 1 dose of the metered-dose spray into the collecting vessel by actuating the atomizing device. Collect the contents of the collecting vessel by successive rinses. Determine the content of active substance in the combined rinses. Repeat the procedure for a further 9 containers.

             Unless otherwise justified and authorized, the preparation complies with the test if maximum 1 of the individual contents is outside the limits of 75 per cent to 125 per cent and none is outside the limits of 65 per cent to 135 per cent of the average content.

             If 2 or maximum 3 individual contents are outside the limits of 75 per cent to 125 per cent but within the limits of 65 per cent to 135 per cent, repeat the test for 20 more containers. The preparation complies with the test if maximum 3 individual contents of the 30 individual contents are outside the limits of 75 per cent to 125 per cent and none is outside the limits of 65 per cent to 135 per cent of the average content.

Lozenges and Pastilles

             Lozenges and pastilles are solid, single-dose preparations intended to be sucked to obtain, usually, a local effect in the oral cavity and the throat. They contain one or more active substances, usually in a flavoured and sweetened base, and are intended to dissolve or disintegrate slowly in the mouth when sucked. Lozenges are hard preparations prepared by moulding. Pastilles are soft, flexible preparations prepared by moulding of mixtures containing natural or synthetic polymers or gums and sweeteners.

Compressed Lozenges

             Compressed lozenges are solid, single-dose preparations intended to be sucked to obtain a local or systemic effect. They are prepared by compression and are often rhomboid in shape. Compressed lozenges conform with the general definition of tablets.

             Production In the manufacture of compressed lozenges, measures are taken to ensure that they possess suitable mechanical strength to resist handling without crumbling or breaking. This may be demonstrated by examining the “Friability of Uncoated Tablet” (Appendix 4.30) and the “Resistance to Crushing of Tablets” (Appendix 4.31).

             Dissolution For compressed lozenges intended for a systemic effect, a suitable test is carried out to demonstrate the appropriate release of the active substance(s).

Sublingual Tablets and Buccal Tablets

             Sublingual tablets and buccal tablets are solid, single-dose preparations to be applied under the tongue or to the buccal cavity, respectively, to obtain a systemic effect. They are prepared by compression of mixtures of powders or granulations into tablets with a shape suited for the intended use. Sublingual tablets and buccal tablets conform to the general definition of tablets.

             Production In the manufacture of sublingual tablets and buccal tablets, measures are taken to ensure that they possess suitable mechanical strength to resist handling without crumbling or breaking. This may be demonstrated by examining the “Friability of Uncoated Tablet” (Appendix 4.30) and the “Resistance to Crushing of Tablets” (Appendix 4.31).

             Dissolution Unless otherwise justified and authorized, a suitable test is carried out to demonstrate the appropriate release of the active substance(s).

Oromucosal Capsules

             Oromucosal capsules are soft capsules to be chewed or sucked.

Mucoadhesive Preparations

             Mucoadhesive preparations contain one or more active substances intended for systemic absorption through the buccal mucosa over a prolonged period of time. They may be supplied as mucoadhesive buccal tablets or as other mucoadhesive solid or semi-solid preparations.

             Mucoadhesive buccal tablets are prepared by compression of mono- or multi-layered tablets. They usually contain hydrophilic polymers, which on wetting with the saliva produce a flexible hydrogel that adheres to the buccal mucosa.

             Production In the manufacture of mucoadhesive buccal tablets, measures are taken to ensure that they possess suitable mechanical strength to resist handling without crumbling or breaking. This may be demonstrated by examining the “Friability of Uncoated Tablet” (Appendix 4.30) and the “Resistance to Crushing of Tablets” (Appendix 4.31).

             Dissolution Unless otherwise justified and authorized, a suitable test is carried out to demonstrate the appropriate release of the active substance(s).

PARENTERAL PREPARATIONS

             Parenteral preparations are sterile preparations intended for administration by injection, infusion or implantation into the body. There are five main forms of these preparations defined as follows: (1) medicaments or solutions or emulsions thereof suitable for injection, bearing titles of the form, ____ Injection; (2) dry solids or liquid concentrates containing active ingredient(s) with or without buffer(s), diluent(s) or other added substances, and which, upon the addition of suitable solvents, yield solutions conforming in all respects to the requirements for Injections, and which are distinguished by titles of the form, ____ for Injection; (3) solids which are suspended in a suitable fluid medium and which are not to be injected intravenously or into the spinal canal, distinguished by titles of the form, Sterile ____ Suspension; (4) dry solids which, upon the addition of suitable vehicles, yield preparations conforming in all respects to the requirements for sterile suspensions; and which are distinguished by titles of the form, Sterile ____ for Suspension; and (5) sterile solid preparations, of which size and shape are suitable for implantation into body tissues, distinguished by titles of the form, ____ Implant. The term “Injections” may be used for preparations (1) to (4).

             Where used in this Pharmacopoeia, the designation Large-volume intravenous solution applies to a single-dose injection that is intended for intravenous use and is packaged in containers labelled as containing more than 100 ml. The designation Small-volume Injection applies to an injection that is packaged in containers labelled as containing 100 ml or less.

             Production Parenteral preparations are prepared by methods designed to ensure their sterility and to avoid the introduction of contaminants, the presence of pyrogens and the growth of micro-organisms.

             Water used in the manufacture of injections complies with the requirements for Water for Injections in bulk.

             Aqueous vehicles The vehicles for aqueous parenteral preparations comply with the “Pyrogen Test” (Appendix 8.2) or the “Test for Bacterial Endotoxins” (Appendix 8.5), whichever is specified. Water for Injection generally is used as the vehicle, unless otherwise specified in the individual monograph. Sodium Chloride may be added in amounts sufficient to render the resulting solution isotonic; Sodium Chloride Injection, or Ringer’s Injection, may be used in whole or in part instead of Water for Injection unless otherwise specified in the individual monograph. For conditions applying to other adjuvants, see Added substances, in this appendix.

             Other vehicles Fixed oils used as vehicles for nonaqueous injections are of vegetable origin, are odourless or nearly so, and have no odour or taste suggesting rancidity. They comply with the test for solid paraffin under Liquid Paraffin, the cooling bath being maintained at 10º, have a saponification value of between 185 and 200 (Appendix 5.7), have an iodine value of between 79 and 128 (Iodine Bromide Method, Appendix 5.6), and comply with the requirements of the following tests.

             UNSAPONIFIABLE MATTER Reflux on a water-bath 10 ml of the oil with 15 ml of a 16.7 per cent w/v solution of sodium hydroxide and 30 ml of ethanol, with occasional shaking until the mixture becomes clear. Transfer the solution to a shallow dish, evaporate the ethanol on a water-bath, and mix the residue with 100 ml of water: a clear solution results.

             ACID VALUE Not more than 0.22 (Appendix 5.4); using 0.020 M potassium hydroxide as titrant.

             Synthetic mono- or diglycerides of fatty acids may be used as vehicles, provided they are liquid and remain clear when cooled to 10º and have an iodine value of not more than 140 (Iodine Bromide Method, Appendix 5.6).

             These and other nonaqueous vehicles may be used, provided they are safe in the volume of parenteral preparations administered, and also provided they do not interfere with the therapeutic efficacy of the preparation or with its response to prescribed assays and tests.

             Added substances Suitable substances may be added to parenteral preparations to increase stability or usefulness, unless prescribed in the individual monograph, provided they are harmless in the amounts administered and do not interfere with the therapeutic efficacy or with the responses to the specified assays and tests. No colouring agent may be added, solely for the purpose of colouring the finished preparation, to a solution intended for parenteral administration [see also Added Substances, under General Notices, p. 6, and “Efficacy of Antimicrobial Preservation” (Appendix 10.6)].

             Observe special care in the choice and use of added substances in injections that are administered in a volume exceeding 5 ml. The following maximum limits prevail unless otherwise directed: for agents containing mercury and the cationic, surface-active compounds, 0.01 per cent; for those of the types of chlorobutanol, cresol, and phenol, 0.5 per cent; and for sulfur dioxide, or an equivalent amount of the sulfite, bisulfite, or metabisulfite of potassium or sodium, 0.2 per cent.

             A suitable substance or mixture of substances to prevent the growth of micro-organisms must be added to preparations intended for injection that are packaged in multiple-dose containers, regardless of the method of sterilization employed, unless otherwise specified in the individual monograph, or unless the active ingredients are themselves antimicrobial. Such substances are used in concentrations that will prevent the growth of or kill micro-organisms in the preparations. Such substances also comply with the “Efficacy of Antimicrobial Preservation” (Appendix 10.6) and “Content of Antimicrobial Agents” (Appendix 6.22). Sterilization processes are employed even though such substances are used [see also Added Substances, under General Notices, p. 6, and “Sterilization and Sterility Assurance” (Appendix 12)]. The air in the container may be evacuated or be displaced by a chemically inert gas. If the injection is oxygen-sensitive, that information must appear in the labelling.

              Containers for parenteral preparations Containers, including the closures, for parenteral preparations do not interact physically or chemically with the prepara-tions in any manner to alter the strength, quality, or purity beyond the official requirements under the ordinary or customary conditions of handling shipment, storage, sale, and use. The container is made of material that permits inspection of the contents. Parenteral preparations are supplied in glass ampoules, bottles or vials or in other containers such as plastic bottles or bags and in prefilled syringes the integrity of which is ensured by suitable means. The type of glass preferable for each parenteral preparation is usually stated in the individual monograph.

              For definitions of single-dose and multiple-dose containers, see Containers under General Notices, p. 10. Containers comply with the “Containers” (Appendix 11). Containers are closed by fusion, or by application of suitable closures, in such manner as to prevent contamination or loss of contents. Closures for multipledose containers permit the withdrawal of the contents without removal or destruction of the closure. The closure permits penetration by a needle, and, upon withdrawal of the needle, at once recloses the container against contamination.

              Containers for sterile solids Containers, including the closures, for dry solids intended for parenteral use do not interact physically or chemically with the preparation in any manner to alter the strength, quality, or purity beyond the official requirements under the ordinary or customary conditions of handling, shipment, storage, sale and use.

              A container for a sterile solid permits the addition of a suitable solvent and withdrawal of portions of the resulting solution or suspension in such manner that the sterility of the product is maintained.

              Where the Assay in a monograph provides a procedure for Assay preparation in which the total withdraw able contents are to be withdrawn from a single-dose container with a hypodermic needle and syringe, the contents are to be withdrawn as completely as possible into a dry hypodermic syringe of a rated capacity not exceeding three times the volume to be withdrawn and fitted with a 21-gauge needle not less than 2.5 cm in length, care being taken to expel any air bubbles, and discharged into a container for dilution and assay.

              Volume in containers Each container of an injection is filled with a volume in slight excess of the labelled size or the volume which is to be withdrawn. The excess volumes recommended in the accompanying table are usually sufficient to permit withdrawal and administration of the labelled volumes.

              DETERMINATION OF VOLUME OF INJECTIONS IN CONTAINERS Select one or more containers if the volume is 10 ml or more, three or more if the volume is more than 3 ml and less than 10 ml, or five or more if the volume is 3 ml or less. Take up individually the contents of each container selected into a dry hypodermic syringe of a rated capacity not exceeding three times the volume to be measured, and fitted with a 21-gauge needle not less than 2 cm (1 inch) in length. Expel any air bubbles from the syringe and needle, and then discharge the contents of the syringe, without emptying the needle, into a standardized, dry cylinder (graduated to contain rather than to deliver the designated volumes) of such size that the volume to be measured occupies at least 40 per cent of its rated volume. Alternatively, the contents of the syringe may be discharged into a dry, tared beaker, the volume, in ml, being calculated as the weight, in g, of injections taken divided by its density. The contents of two or three 1-ml or 2-ml containers may be pooled for the measurement, provided that a separate, dry syringe assembly is used for each container. The content of containers holding 10 ml or more may be determined by means of opening them and emptying the contents directly into the graduated cylinder or tared beaker.

              The volume is not less than the labelled volume in the case of containers examined individually or, in the case of 1-ml and 2-ml containers, is not less than the sum of the labelled volumes of the containers taken collectively.

              For injections in multiple-dose containers labelled to yield a specific number of doses of a stated volume, proceed as directed in the foregoing, using the same number of separate syringes as the number of doses specified. The volume is such that each syringe delivers not less than the stated dose.

              For injections containing oil, warm the containers, if necessary, and thoroughly shake them immediately before removing the contents. Cool to 25º before measuring the volume.

              Constituted solutions Sterile dosage forms from which constituted solutions are prepared for injection bearing titles of the form, ____ for Injection comply with the “Constituted Solutions” (Appendix 4.20).

              Particulate matter All large-volume injections for single-dose infusion, and those small-volume injections for which the monographs specify such requirements, are subject to the particulate matter limits set forth in the “Particulate Matter in Injections” (Appendix 4.27). An article packaged as both a large-volume and a smallvolume injection meets the requirements set forth for “Small-volume Injections” where the container is labelled as containing 100 ml or less if the individual monograph includes a test for “Particulate matter”; it meets the requirements set forth for “Large-volume Injections for Single-dose Infusion” where the container is labelled as containing more than 100 ml. Injections packaged and labelled for use as irrigating solutions are exempt from requirements for “Particulate matter”.

              Pyrogen test; Bacterial endotoxins test Parenteral preparations comply with the “Pyrogen Test” (Appendix 8.2) or the “Test for Bacterial Endotoxins” (Appendix 8.5) as specified in the individual monograph.

              Sterility Parenteral preparations comply with the “Sterility Test” (Appendix 10.1). Unless otherwise specified in the individual monograph, carry out the test using Method I.

              Uniformity of dosage units Parenteral preparations that are packaged in single-unit containers comply with the “Uniformity of Dosage Units” (Appendix 4.28). The test for Content Uniformity is required for sterile solids containing a unit weight equal to or less than 40 mg but not required for multivitamin and trace element parenteral preparations.

              Packaging and storage The volume of the parenteral preparations in single-dose containers provides the amount specified for parenteral administration at one time and in no case is more than sufficient to permit the withdrawal and administration of 1 litre.

              Preparations intended for intraspinal, intracisternal, or peridural administration are packaged only in singledose containers.

              Unless otherwise specified in the individual monograph, no multiple-dose container contains a volume of parenteral preparation more than sufficient to permit the withdrawal of 30 ml.

              Injections packaged for use as irrigation solutions or for hemofiltration or dialysis or for parenteral nutrition are exempt from the 1-litre restriction of the foregoing requirements relating to packaging. Containers for injections packaged for use as irrigation solutions or for hemofiltration may be designed to empty rapidly and may contain a volume of more than 1 litre.

              Labelling The label of injection complies with the Labelling, under General Notices, p. 12. The label also states the name of any added substances and the storage conditions.

              The container is so labelled that a sufficient area of the container remains uncovered for its full length or circumference to permit inspection of the contents. In case the area of the container is not sufficient to be labelled as mentioned above, unless otherwise specified in the individual monograph, the label shall state (1) the name of the drug product and (2) the batch or lot number assigned by the manufacturer.

              The label of a single-dose parenteral preparation states that any portion of the contents remaining should be discarded.

              In the case of a dry preparation or other preparation to which a diluent is intended to be added before use, the label includes the following information: the amount of each ingredient, the composition of recommended diluent(s) [the name(s) alone, if the formula is specified in the individual monograph], the amount to be used to attain a specific concentration of active ingredient and the final volume of solution so obtained, a brief description of the physical appearance of the constituted solution, directions for proper storage of the constituted solution, and an expiration date limiting the period during which the constituted solution may be expected to have the required or labelled potency if it has been stored as directed.

POWDERS

              Powders are preparations consisting of solid, loose, dry particles of varying degrees of fineness that contain one or more active ingredients with or without added substances including, where necessary, flavouring agents and authorized colouring matter. Two categories of powders may be distinguished: (1) oral powders; (2) topical powders.

              Minimum fill Powders comply with the test described in the “Minimum Fill” (Appendix 4.26).

              Uniformity of dosage units Powders comply with the “Uniformity of Dosage Units” (Appendix 4.28). The test for Content Uniformity is not required for multivitamin and trace element powders.

              Packaging and storage Powders should be kept in tightly closed containers.

Oral Powders

              Oral powders are generally administered in or with water or another suitable liquid. They may also be swallowed directly.

              Oral powders are presented as single-unit or multiple-unit preparations. For single-unit powders each dose is enclosed in a separate container, for example, a sachet, a paper packet or a vial. Multiple-unit powders require the provision of a measuring device capable of delivering the quantity prescribed.

              Effervescent oral powders are presented as singleunit or multiple-unit powders and generally contain acid substances and either carbonates or bicarbonates that react rapidly in the presence of water to release carbon dioxide. They are intended to be dissolved or dispersed in water before administration.

              Labelling For single-unit containers the label states the name(s) and quantity(ies) of active ingredient(s) per container. For multiple-unit containers the label states the name(s) and quantity(ies) of active ingredient(s) in a suitable amount by weight.