PRESERVATION,PACKAGING,STORAGE,AND LABELING, chemical structure, molecular formula, Reference Standards

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PRESERVATION,PACKAGING,STORAGE,AND LABELING

Containers— The containeris that which holds the article and is or may be in direct contact with the article.The immediate containeris that which is in direct contact with the article at all times.The closureis a part of the container.

Prior to being filled,the container should be clean.Special precautions and cleaning procedures may be necessary to ensure that each container is clean and that extraneous matter is not introduced into or onto the article.

The container does not interact physically or chemically with the article placed in it so as to alter the strength,quality,or purity of the article beyond the official requirements.

The Pharmacopeial requirements for the use of specified containers apply also to articles as packaged by the pharmacist or other dispenser,unless otherwise indicated in the individual monograph.

Tamper-Evident Packaging — The container or individual carton of a sterile article intended for ophthalmic or otic use,except where extemporaneously compounded for immediate dispensing on prescription,shall be so sealed that the contents cannot be used without obvious destruction of the seal.

Articles intended for sale without prescription are also required to comply with the tamper-evident packaging and labeling requirements of the FDAwhere applicable.

Preferably,the immediate container and/or the outer container or protective packaging used by a manufacturer or distributor for all dosage forms that are not specifically exempt is designed so as to show evidence of any tampering with the contents.

Light-Resistant Container (seeLight Transmission underContainers á661ñ)— Alight-resistant container protects the contents from the effects of light by virtue of the specific properties of the material of which it is composed,including any coating applied to it.Alternatively,a clear and colorless or a translucent container may be made light-resistant by means of an opaque covering,in which case the label of the container bears a statement that the opaque covering is needed until the contents are to be used or administered.Where it is directed to “protect from light”in an individual monograph,preservation in a light-resistant container is intended.

Where an article is required to be packaged in a light-resistant container,and if the container is made light-resistant by means of an opaque covering,a single-use,unit-dose container or mnemonic pack for dispensing may not be removed from the outer opaque covering prior to dispensing.

Well-Closed Container— Awell-closed container protects the contents from extraneous solids and from loss of the article under the ordinary or customary conditions of handling,shipment,storage,and distribution.

Tight Container— Atight container protects the contents from contamination by extraneous liquids,solids,or vapors;from loss of the article;and from efflorescence,deliquescence,or evaporation under the ordinary or customary conditions of handling,shipment,storage,and distribution;and is capable of tight reclosure.Where a tight container is specified,it may be replaced by a hermetic container for a single dose of an article.

Agas cylinder is a metallic container designed to hold a gas under pressure.As a safety measure,for carbon dioxide,cyclopropane,helium,nitrous oxide,and oxygen,the Pin-Index Safety System of matched fittings is recommended for cylinders of Size Eor smaller.

NOTE—Where packaging and storage in a tight containeror a well-closed containeris specified in the individual monograph,the container used for an article when dispensed on prescription meets the requirements under Containers—Permeation á671ñ.

Hermetic Container— Ahermetic container is impervious to air or any other gas under the ordinary or customary conditions of handling,shipment,storage,and distribution.

Single-Unit Container— Asingle-unit container is one that is designed to hold a quantity of drug product intended for administration as a single dose or a single finished device intended for use promptly after the container is opened.Preferably,the immediate container and/or the outer container or protective packaging shall be so designed as to show evidence of any tampering with the contents.Each single-unit container shall be labeled to indicate the identity,quantity and/or strength,name of the manufacturer,lot number,and expiration date of the article.

Single-Dose Container (see alsoContainers for Injections under Injections á1ñ)— Asingle-dose container is a single-unit container for articles intended for parenteral administration only.Asingle-dose container is labeled as such.Examples of single-dose containers include prefilled syringes,cartridges,fusion-sealed containers,and closure-sealed containers when so labeled.

Unit-Dose Container— Aunit-dose container is a single-unit container for articles intended for administration by other than the parenteral route as a single dose,direct from the container.

Unit-of-Use Container— Aunit-of-use container is one that contains a specific quantity of a drug product and that is intended to be dispensed as such without further modification except for the addition of appropriate labeling.Aunit-of-use container is labeled as such.

Multiple-Unit Container— Amultiple-unit container is a container that permits withdrawal of successive portions of the contents without changing the strength,quality,or purity of the remaining portion.

Multiple-Dose Container (see alsoContainers for Injections underInjections á1ñ)— Amultiple-dose container is a multiple-unit container for articles intended for parenteral administration only.

Storage Temperature and Humidity— Specific directions are stated in some monographs with respect to the temperatures and humidity at which Pharmacopeial articles shall be stored and distributed (including the shipment of articles to the consumer)when stability data indicate that storage and distribution at a lower or a higher temperature and a higher humidity produce undesirable results.Such directions apply except where the label on an article states a different storage temperature on the basis of stability studies of that particular formulation.Where no specific storage directions or limitations are provided in the individual monograph,but the label of an article states a storage temperature that is based on stability studies of that particular formulation,such labeled storage directions apply (see also Pharmaceutical Stability á1150ñ).The conditions are defined by the following terms.

Freezer— Aplace in which the temperature is maintained thermostatically between -25

and -10

(-13

and 14

F).

Cold— Any temperature not exceeding 8

(46

F).Arefrigeratoris a cold place in which the temperature is maintained thermostatically between 2

and 8

(36

and 46

F).

Cool— Any temperature between 8

and 15

(46

and 59

F).An article for which storage in a cool placeis directed may,alternatively,be stored and distributed in a refrigerator,unless otherwise specified by the individual monograph.

Room Temperature— The temperature prevailing in a working area.

Controlled Room Temperature— Atemperature maintained thermostatically that encompasses the usual and customary working environment of 20

to 25

(68

to 77

F);that results in a mean kinetic temperature calculated to be not more than 25

;and that allows for excursions between 15

and 30

(59

and 86

F)that are experienced in pharmacies,hospitals,and warehouses.Provided the mean kinetic temperature remains in the allowed range,transient spikes up to 40

are permitted as long as they do not exceed 24hours.Spikes above 40

may be permitted if the manufacturer so instructs.Articles may be labeled for storage at “controlled room temperature”or at “up to 25

”,or other wording based on the same mean kinetic temperature.The mean kinetic temperature is a calculated value that may be used as an isothermal storage temperature that simulates the nonisothermal effects of storage temperature variations.(See also Pharmaceutical Stability á1150ñ.)

An article for which storage at Controlled room temperatureis directed may,alternatively,be stored and distributed in a cool place,unless otherwise specified in the individual monograph or on the label.

Warm— Any temperature between 30

and 40

(86

and 104

F).

Excessive Heat— Any temperature above 40

(104

F).

Protection from Freezing— Where,in addition to the risk of breakage of the container,freezing subjects an article to loss of strength or potency,or to destructive alteration of its characteristics,the container label bears an appropriate instruction to protect the article from freezing.

Dry Place— The term “dry place”denotes a place that does not exceed 40%average relative humidity at Controlled Room Temperatureor the equivalent water vapor pressure at other temperatures.The determination may be made by direct measurement at the place or may be based on reported climatic conditions.Determination is based on not less than 12equally spaced measurements that encompass either a season,a year,or,where recorded data demonstrate,the storage period of the article.There may be values of up to 45%relative humidity provided that the average value is 40%relative humidity.

Storage in a container validated to protect the article from moisture vapor,including storage in bulk,is considered a dry place.

Storage under Nonspecific Conditions— Where no specific directions or limitations are provided in the Packaging and storagesection of individual monographs or in the article's labeling,the conditions of storage shall include storage at controlled room temperature,protection from moisture,and,where necessary,protection from light.Articles shall be protected from moisture,freezing,and excessive heat,and,where necessary,from light during shipping and distribution.Active pharmaceutical ingredients are exempt from this requirement.

Labeling— The term “labeling”designates all labels and other written,printed,or graphic matter upon an immediate container of an article or upon,or in,any package or wrapper in which it is enclosed,except any outer shipping container.The term “label”designates that part of the labeling upon the immediate container.

Ashipping container containing a single article,unless such container is also essentially the immediate container or the outside of the consumer package,is labeled with a minimum of product identification (except for controlled articles),lot number,expiration date,and conditions for storage and distribution.

Articles in this Pharmacopeia are subject to compliance with such labeling requirements as may be promulgated by governmental bodies in addition to the Pharmacopeial requirements set forth for the articles.

Amount of Ingredient per Dosage Unit— The strength of a drug product is expressed on the container label in terms of micrograms or milligrams or grams or percentage of the therapeutically active moiety or drug substance,whichever form is used in the title,unless otherwise indicated in an individual monograph.Both the active moiety and drug substance names and their equivalent amounts are then provided in the labeling.

Pharmacopeial articles in capsule,tablet,or other unit dosage form shall be labeled to express the quantity of each active ingredient or recognized nutrient contained in each such unit;except that,in the case of unit-dose oral solutions or suspensions,whether supplied as liquid preparations or as liquid preparations that are constituted from solids upon addition of a designated volume of a specific diluent,the label shall express the quantity of each active ingredient or recognized nutrient delivered under the conditions prescribed in Deliverable Volume á698ñ.Pharmacopeial drug products not in unit dosage form shall be labeled to express the quantity of each active ingredient in each milliliter or in each gram,or to express the percentage of each such ingredient (see Percentage Measurements),except that oral liquids or solids intended to be constituted to yield oral liquids may,alternatively,be labeled in terms of each 5-mLportion of the liquid or resulting liquid.Unless otherwise indicated in a monograph or chapter,such declarations of strength or quantity shall be stated only in metric units (see also Units of Potencyin these General Notices).

Use of Leading and Terminal Zeros— In order to help minimize the possibility of errors in the dispensing and administration of drugs,the quantity of active ingredient when expressed in whole numbers shall be shown without a decimal point that is followed by a terminal zero (e.g.,express as 4mg [not 4.0mg]).The quantity of active ingredient when expressed as a decimal number smaller than 1shall be shown with a zero preceding the decimal point (e.g.,express as 0.2mg [not .2mg]).

Labeling of Salts of Drugs— It is an established principle that Pharmacopeial articles shall have only one official name.For purposes of saving space on labels,and because chemical symbols for the most common inorganic salts of drugs are well known to practitioners as synonymous with the written forms,the following alternatives are permitted in labeling official articles that are salts:HCl for hydrochloride;HBr for hydrobromide;Na for sodium;and Kfor potassium.The symbols Na and Kare intended for use in abbreviating names of the salts of organic acids;but these symbols are not used where the word Sodium or Potassium appears at the beginning of an official title (e.g.,Phenobarbital Na is acceptable,but Na Salicylate is not to be written).

Labeling Vitamin-Containing Products— The vitamin content of an official drug product shall be stated on the label in metric units per dosage unit.The amounts of vitamins A,D,and Emay be stated also in USP Units.Quantities of vitamin Adeclared in metric units refer to the equivalent amounts of retinol (vitamin Aalcohol).The label of a nutritional supplement shall bear an identifying lot number,control number,or batch number.

Labeling Botanical-Containing Products— The label of an herb or other botanical intended for use as a dietary supplement bears the statement,“If you are pregnant or nursing a baby,seek the advice of a health professional before using this product.”

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Labeling Parenteral and Topical Preparations— The label of a preparation intended for parenteral or topical use states the names of all added substances (see Added Substancesin these General Notices and Requirements,and see Labelingunder Injections á1ñ),and,in the case of parenteral preparations,also their amounts or proportions,except that for substances added for adjustment of pHor to achieve isotonicity,the label may indicate only their presence and the reason for their addition.

Labeling Electrolytes— The concentration and dosage of electrolytes for replacement therapy (e.g.,sodium chloride or potassium chloride)shall be stated on the label in milliequivalents (mEq).The label of the product shall indicate also the quantity of ingredient(s)in terms of weight or percentage concentration.

Labeling Alcohol— The content of alcohol in a liquid preparation shall be stated on the label as a percentage (v/v)of C2H5OH.

Special Capsules and Tablets— The label of any form of Capsule or Tablet intended for administration other than by swallowing intact bears a prominent indication of the manner in which it is to be used.

Expiration Date and Beyond-Use Date— The label of an official drug product or nutritional or dietary supplement product shall bear an expiration date.All articles shall display the expiration date so that it can be read by an ordinary individual under customary conditions of purchase and use.The expiration date shall be prominently displayed in high contrast to the background or sharply embossed,and easily understood (e.g.,“EXP6/89,”“Exp.June 89,”or “Expires 6/89”).[NOTE—For additional information and guidance,refer to the Nonprescription Drug Manufacturers Association's Voluntary Codes and Guidelines of the OTC Medicines Industry.]

The monographs for some preparations state how the expiration date that shall appear on the label is to be determined.In the absence of a specific requirement in the individual monograph for a drug product or nutritional supplement,the label shall bear an expiration date assigned for the particular formulation and package of the article,with the following exception:the label need not show an expiration date in the case of a drug product or nutritional supplement packaged in a container that is intended for sale without prescription and the labeling of which states no dosage limitations,and which is stable for not less than 3years when stored under the prescribed conditions.

Where an official article is required to bear an expiration date,such article shall be dispensed solely in,or from,a container labeled with an expiration date,and the date on which the article is dispensed shall be within the labeled expiry period.The expiration date identifies the time during which the article may be expected to meet the requirements of the Pharmacopeial monograph,provided it is kept under the prescribed storage conditions.The expiration date limits the time during which the article may be dispensed or used.Where an expiration date is stated only in terms of the month and the year,it is a representation that the intended expiration date is the last day of the stated month.The beyond-use date is the date after which an article must not be used.The dispenser shall place on the label of the prescription container a suitable beyond-use date to limit the patient's use of the article based on any information supplied by the manufacturer and the General Notices and Requirementsof this Pharmacopeia.The beyond-use date placed on the label shall not be later than the expiration date on the manufacturer's container.

For articles requiring constitution prior to use,a suitable beyond-use date for the constituted product shall be identified in the labeling.

For all other dosage forms,in determining an appropriate period of time during which a prescription drug may be retained by a patient after its dispensing,the dispenser shall take into account,in addition to any other relevant factors,the nature of the drug;the container in which it was packaged by the manufacturer and the expiration date thereon;the characteristics of the patient's container,if the article is repackaged for dispensing;the expected storage conditions to which the article may be exposed;any unusual storage conditions to which the article may be exposed;and the expected length of time of the course of therapy.The dispenser shall,on taking into account the foregoing,place on the label of a multiple-unit container a suitable beyond-use date to limit the patient's use of the article.Unless otherwise specified in the individual monograph,or in the absence of stability data to the contrary,such beyond-use date shall be not later than (a)the expiration date on the manufacturer's container,or (b)1year from the date the drug is dispensed,whichever is earlier.For nonsterile solid and liquid dosage forms that are packaged in single-unit and unit-dose containers,the beyond-use date shall be 1year from the date the drug is packaged into the single-unit or unit-dose container or the expiration date on the manufacturer’s container,whichever is earlier,unless stability data or the manufacturer’s labeling indicates otherwise.

The dispenser must maintain the facility where the dosage forms are packaged and stored,at a temperature such that the mean kinetic temperature is not greater than 25

.The plastic material used in packaging the dosage forms must afford better protection than polyvinyl chloride,which does not provide adequate protection against moisture permeation.Records must be kept of the temperature of the facility where the dosage forms are stored,and of the plastic materials used in packaging.

Pharmaceutical Compounding— The label on the container or package of an official compounded preparation shall bear a beyond-use date.The beyond-use date is the date after which a compounded preparation is not to be used.Because compounded preparations are intended for administration immediately or following short-term storage,their beyond-use dates may be assigned based on criteria different from those applied to assigning expiration dates to manufactured drug products.

The monograph for an official compounded preparation typically includes a beyond-use requirement that states the time period following the date of compounding during which the preparation,properly stored,is to be used.In the absence of stability information that is applicable to a specific drug and preparation,recommendations for maximum beyond-use dates have been devised for nonsterile compounded drug preparations that are packaged in tight,light-resistant containers and stored at controlled room temperature unless otherwise indicated (see Stability Criteria and Beyond-Use Datingunder Stability of Compounded Preparationsin the general tests chapter Pharmaceutical Compounding—Nonsterile Preparations á795ñ).