© World Health Organization
`WHO Technical Report Series, No. 902, 2002
`
`Annex 9
`Guidelines on packaging for pharmaceutical
`products
`
`Introductory note
`
`Glossary
`
`1. Aspects of packaging
`1.1 General considerations
`1.2 Functions of packaging
`1.2.1 Containment
`1.2.2 Protection
`1.3 Presentation and information
`1.3.1 Labels
`1.3.2 Repacking, relabelling and dispensing
`1.3.3 Package inserts for patients (patient information leaflets)
`1.4 Compliance
`1.5 Protection of patients
`1.6 Detection of counterfeiting
`
`2. Packaging materials and closures
`2.1 Types of material
`2.1.1 Glass
`2.1.2 Plastics
`2.1.3 Metal
`2.2 Closures
`2.2.1 Rubber closures
`2.2.2 Caps or overseals
`2.2.3 Special types of closure
`
`3. Quality assurance aspects of packaging
`3.1 General considerations
`3.2 Quality control
`3.2.1 Sampling
`3.2.2 Testing programme
`Inspection and audit
`3.3.1 Rules
`3.3.2 Audits of suppliers
`
`3.3
`
`4. Protection of the environment
`4.1 Packaging waste
`4.2 Waste policies
`
`5. Quality specifications
`5.1 Requirements in The international pharmacopoeia
`5.1.1 Packaging materials
`5.1.2 Requirements for dosage form containers
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`5.2 Pharmacopoeial requirements for containers in Europe, Japan
`and the USA
`5.2.1 Glass containers
`5.2.2 Plastic containers
`5.2.3 Rubber closures
`5.3 International Standards
`
`References
`
`Bibliography
`
`Appendix 1
`Storage areas
`
`Appendix 2
`Labels
`
`Appendix 3
`Self-inspection and quality audits
`
`Appendix 4
`International Standards on packaging
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`Introductory note
`This review of the various elements of the packaging of a pharmaceu-
`tical product is aimed at ensuring that medicines arrive safely in the
`hands of the patients for whom they are prescribed.
`In the manufacture of pharmaceutical products, quality assurance is
`defined as “the totality of the arrangements made with the object of
`ensuring that pharmaceutical products are of the quality required for
`their intended use” (1).
`In addition, the system of quality assurance for the manufacture of
`pharmaceutical products should ensure that “arrangements are made
`for the manufacture, supply and use of the correct starting and pack-
`aging materials” (1).
`Public opinion sometimes considers packaging to be superfluous.
`However, it must be emphasized that packaging preserves the stabil-
`ity and quality of medicinal products and protects them against all
`forms of spoilage and tampering.
`All medicinal products need to be protected and “consequently need
`to be packaged in containers that conform to prescribed standards,
`particularly with respect to the exclusion of moisture and light and the
`prevention of leaching of extractable substances into the contents and
`of chemical interaction with the contents. . . . However, the limits of
`acceptability in these various respects depend, at least in part, on
`climatic variables. Recommendations in The international pharmaco-
`poeia can only be advisory; precise quantitative standards will have to
`be locally determined” (2).
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`The complexity of packaging materials and the highly technological
`nature of medicinal products is such that manufacturers are con-
`fronted with significant problems. Interaction between packaging and
`such products is possible due to the combination of a multiplicity of
`container components and active pharmaceutical ingredients, excipi-
`ents and solvents used in a variety of dosage forms.
`The quality of the packaging of pharmaceutical products plays a very
`important role in the quality of such products. It must:
`— protect against all adverse external influences that can alter the
`properties of the product, e.g. moisture, light, oxygen and tem-
`perature variations;
`— protect against biological contamination;
`— protect against physical damage;
`— carry the correct information and identification of the product.
`The kind of packaging and the materials used must be chosen in such
`a way that:
`— the packaging itself does not have an adverse effect on the product
`(e.g. through chemical reactions, leaching of packaging materials
`or absorption);
`— the product does not have an adverse effect on the packaging,
`changing its properties or affecting its protective function.
`The resulting requirements must be met throughout the whole of the
`intended shelf-life of the product. Given the link between the quality
`of a pharmaceutical product and the quality of its packaging, phar-
`maceutical packaging materials and systems must be subject, in
`principle, to the same quality assurance requirements as pharmaceu-
`tical products.
`The appropriate system of quality assurance for the manufacture of
`pharmaceutical products should therefore follow the WHO guide-
`lines for good manufacturing practices (GMP) (1).
`The requirements to be met by pharmaceutical packaging and pack-
`aging materials as described in compendia (pharmacopoeias) and
`standards (e.g. those of the International Organization for Standard-
`ization (ISO)) must be considered only as general in character. The
`suitability of packaging or packaging material for any particular
`requirements and conditions can only be ascertained through detailed
`packaging and stability studies on the product concerned.
`Glossary
`The definitions given below apply specifically to the terms used in
`these guidelines. They may have different meanings in other contexts.
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`General
`bulk product
`Any product that has completed all the processing stages up to, but
`not including, final packaging (1).
`
`containers
`A container for pharmaceutical use is an article which holds or is
`intended to contain and protect a drug and is or may be in direct
`contact with it. The closure is a part of the container. The container
`and its closure must not interact physically or chemically with the
`substance within in any way that would alter its quality. The following
`terms include general requirements for the permeability of containers
`(3):
`• Well-closed containers must protect the contents from extraneous
`matter or from loss of the substance under normal conditions of
`handling, shipment or storage.
`• Tightly closed containers must protect the contents from extraneous
`matter, from loss of the substance, and from efflorescence, deli-
`quescence or evaporation under normal conditions of handling,
`shipment or storage. If the container is intended to be opened on
`several occasions, it must be designed to be airtight after reclosure.
`• Hermetically closed containers must protect the contents from ex-
`traneous matter and from loss of the substance, and be impervious
`to air or any other gas under normal conditions of handling, ship-
`ment or storage.
`Substances and dosage forms requiring protection from light should
`be maintained in a light-resistant container that — either by reason of
`the inherent properties of the material of which it is composed, or
`because a special coating has been applied to it — shields the contents
`from the effects of light. Alternatively, the container may be placed
`inside a suitable light-resistant (opaque) covering and/or stored in a
`dark place (3).
`
`labels
`All finished drug products should be identified by labelling, as
`required by the national legislation, bearing at least the following
`information:
`(a) the name of the drug product;
`(b) a list of the active ingredients (if applicable, with the Interna-
`tional Nonproprietary Names (INNs)), showing the amount of
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`each present, and a statement of the net contents, e.g. number of
`dosage units, mass or volume;
`(c) the batch number assigned by the manufacturer;
`(d) the expiry date in an uncoded form;
`(e) any special storage conditions or handling precautions that may
`be necessary;
`(f) the directions for use, and any warnings and precautions that may
`be necessary;
`(g) the name and address of the manufacturer or the company or
`person responsible for placing the product on the market.
`
`marketing authorization (product licence, registration certificate)
`A legal document issued by the competent drug regulatory authority
`that establishes the detailed composition and formulation of the prod-
`uct and the pharmacopoeial or other recognized specifications of
`its ingredients and of the final product itself, and includes details of
`packaging, information given on the label, product information and
`shelf-life (1).
`
`materials
`A term used to denote starting materials, process aids, intermediates,
`active pharmaceutical ingredients, packaging and labelling materials.
`
`packaging material
`Any material, including printed material, employed in the packaging
`of a pharmaceutical product, excluding any outer packaging used for
`transportation or shipment. Primary packaging materials are those
`that are in direct contact with the product (1).
`
`packaging process
`All operations, including filling and labelling, that a bulk product has
`to undergo in order to become a finished product (1).
`
`production
`All operations involved in the preparation of a pharmaceutical prod-
`uct, from receipt of the starting materials, through processing and
`packaging, to completion of the finished product (1).
`
`quarantine
`The status of starting or packaging materials, intermediates, or bulk
`or finished products isolated physically or by other effective means
`while a decision is awaited on their release, rejection or reprocessing
`(1).
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`Containers for pharmaceuticals1
`ampoule
`A container sealed by fusion and to be opened exclusively by break-
`ing. The contents are intended for use on one occasion only.
`
`bag
`A container consisting of surfaces, whether or not with a flat bottom,
`made of flexible material, closed at the bottom and at the sides by
`sealing; the top may be closed by fusion of the material, depending on
`the intended use.
`
`blister
`A multi-dose container consisting of two layers, of which one is
`shaped to contain the individual doses. Strips are excluded.
`
`bottle
`A container with a more or less pronounced neck and usually a flat
`bottom.
`
`cartridge
`A container, usually cylindrical, suitable for liquid or solid pharma-
`ceutical dosage forms; generally for use in a specially designed appa-
`ratus (e.g. a prefilled syringe).
`
`gas cylinder
`A container, usually cylindrical, suitable for compressed, liquefied or
`dissolved gas, fitted with a device to regulate the spontaneous outflow
`of gas at atmospheric pressure and room temperature.
`
`injection needle
`A hollow needle with a locking device intended for the administration
`of liquid pharmaceutical dosage forms.
`
`injection syringe
`A cylindrical device with a cannula-like nozzle, with or without a fixed
`needle and a movable piston, used for the administration, usually
`parenteral, of an accurately measured quantity of a liquid pharmaceu-
`tical form. The syringe may be prefilled, and can be for single-dose or
`multi-dose use.
`
`1 Based on a list of terms drawn up in response to a request from the European
`Commission to revise and replace the guidelines of the Committee for Proprietary
`Medicinal Preparations (III/3593/91).
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`pressurized container
`A container suitable for compressed, liquefied or dissolved gas fitted
`with a device that, after its actuation, produces a controlled spon-
`taneous release of the contents at atmospheric pressure and room
`temperature.
`
`single-dose container
`A container for single doses of solid, semi-solid or liquid preparations.
`
`strip
`A multi-dose container consisting of two layers, usually provided with
`perforations, suitable for containing single doses of solid or semi-solid
`preparations. Blisters are excluded.
`
`tube
`A container for multi-dose semi-solid pharmaceutical forms consist-
`ing of collapsible material; the contents are released via a nozzle by
`squeezing the package.
`
`vial
`A small container for parenteral medicinal products, with a stopper
`and overseal; the contents are removed after piercing the stopper.
`Both single-dose and multi-dose types exist.
`
`1. Aspects of packaging
`1.1 General considerations
`Packaging may be defined as the collection of different components
`(e.g. bottle, vial, closure, cap, ampoule, blister) which surround the
`pharmaceutical product from the time of production until its use.
`The aspects of packaging to be considered (4) include:
`— the functions of packaging;
`— the selection of a packaging material;
`— the testing of the material selected;
`— filling and assembling;
`— sterilization;
`— storage and stability.
`Packaging materials (see section 2) include printed material em-
`ployed in the packaging of a pharmaceutical product, but not any
`outer packaging used for transportation or shipment. Examples of the
`types of materials used are shown in Table 1.
`A distinction must be made between primary and secondary packag-
`ing components. The primary packaging components (e.g. bottles,
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`Table 1
`Types of raw materials used in packaging
`
`Types of materials
`Cardboard
`
`Paper
`
`Glass
`
`Plastic
`
`Metal, e.g. aluminium
`
`Uses
`Boxes
`Display units
`
`Labels
`Leaflets
`
`Ampoules
`Bottles
`Vials
`Syringes
`Cartridges
`
`Closures
`Bottles
`Bags
`Tubes
`Laminates with paper or foil
`
`Collapsible tubes
`Rigid cans
`Foils
`Needles
`Gas cylinders
`Pressurized containers
`
`Rubber
`
`Closures, including plungers
`
`vials, closures, blisters) are in direct physical contact with the product,
`whereas the secondary components are not (e.g. aluminium caps,
`cardboard boxes). The choice of primary and/or secondary packaging
`materials will depend on the degree of protection required, compat-
`ibility with the contents, the filling method and cost, but also the
`presentation for over-the-counter (OTC) drugs and the convenience
`of the packaging for the user (e.g. size, weight, method of opening/
`reclosing (if appropriate), legibility of printing).
`Containers may be referred to as primary or secondary, depending on
`whether they are for immediate use after production of the finished
`product or not. Both single-dose and multi-dose containers exist.
`Containers may be well-closed, tightly closed, hermetically closed or
`light-resistant, as defined in the glossary (3).
`The packaging process, as defined in the glossary, is the process
`that a bulk material must undergo to become a finished product. The
`properties and attributes of the product should be as specified by the
`manufacturer and required by the user. The packaging process con-
`sists of the following stages:
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`— filling and assembling;
`— sterilization in the final container, if applicable;
`— placing labels on the container;
`— storage at the manufacturing and shipping sites.
`Packaging documentation (1) includes aspects related to:
`— specifications and quality control, including batch records;
`— labels, inks and adhesive materials (e.g. glue);
`— package inserts for patients.
`Apart from primary and secondary packaging, two types of special
`packaging are currently in use, as follows:
`• Unit-dose packaging. This packaging guarantees safer medication
`by reducing medication errors; it is also more practical for the
`patient. It may be very useful in improving compliance with treat-
`ment and may also be useful for less stable products.
`• “Device” packaging. Packaging with the aid of an administration
`device is user-friendly and also improves compliance. This type
`of packaging permits easier administration by means of devices
`such as prefilled syringes, droppers, transdermal delivery systems,
`pumps and aerosol sprays. Such devices ensure that the medicinal
`product is administered correctly and in the right amount.
`
`1.2 Functions of packaging
`1.2.1 Containment
`The containment of the product is the most fundamental function of
`packaging for medicinal products. The design of high-quality packag-
`ing must take into account both the needs of the product and of the
`manufacturing and distribution system. This requires the packaging:
`— not to leak, nor allow diffusion and permeation of the product;
`— to be strong enough to hold the contents when subjected to nor-
`mal handling;
`— not to be altered by the ingredients of the formulation in its final
`dosage form.
`
`1.2.2 Protection
`The packaging must protect the product against all adverse external
`influences that may affect its quality or potency, such as:
`— light
`— moisture
`— oxygen
`— biological contamination
`— mechanical damage.
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`The compatibility of the packaging with the active pharmaceutical
`ingredients is very important in maintaining the integrity of the
`product.
`
`Stability. Information on stability is given in the guidelines for stabil-
`ity testing of pharmaceutical products containing well-established
`drug substances in conventional dosage forms (4).
`
`For primary packaging, it is necessary to know the possible interac-
`tions between the container and the contents. Normally, product/
`component stability and compatibility are confirmed during the pri-
`mary research and development stage.
`
`While excluding the effect of external factors on the product, the
`packaging itself should not interact with it so as to introduce unac-
`ceptable changes. There are numerous possibilities of interactions
`between (primary) packaging materials and pharmaceutical products,
`such as:
`
`— the release of chemicals from components of the packaging
`materials;
`— the release of visible and/or subvisible particles;
`— the absorption or adsorption of pharmaceutical components by
`the packaging materials;
`— chemical reactions between the pharmaceutical product and the
`packaging materials;
`— the degradation of packaging components in contact with the
`pharmaceutical products;
`— the influence of the manufacturing process (e.g. sterilization) on
`the container.
`
`The active pharmaceutical ingredients should remain within their
`specification limits over the shelf-life of the pharmaceutical product.
`The question of whether a packaging will provide the required protec-
`tion for the pharmaceutical product and the required stability over
`a certain time period can only be answered by means of real-time
`stability studies. Such studies must evaluate the changes in the quality
`of the product, in contact with its packaging, during a period equiva-
`lent to its intended shelf-life.
`
`In addition, packaging must meet the following requirements:
`
`— it must preserve the physical properties of all dosage forms and
`protect them against damage or breakage;
`— it must not alter the identity of the product;
`— it must preserve the characteristic properties of the product, so
`that the latter complies with its specifications;
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`— it must protect the product against undesirable or adulterating
`chemical, biological or physical entities.
`Storage. Packaging materials should be stored in accordance with
`GMP for storage areas (1; see Appendix 1). The characteristics of the
`active pharmaceutical ingredients will determine whether different
`packaging will be needed. For example, the packaging requirements
`of medicinal products kept at temperatures between 2 and 8°C may
`differ from those of products intended for tropical countries or light-
`sensitive products. If the contents are sterile, sterility must be main-
`tained, including that of any unused remaining product.
`The shelf-life and utilization period are always determined in relation
`to storage conditions and the stability of the active pharmaceutical
`ingredient.
`Normal storage conditions are defined as “storage in dry, well-
`ventilated premises at temperatures of 15–25 °C or, depending on
`climatic conditions, up to 30°C. Extraneous odours, other indications
`of contamination, and intense light have to be excluded” (5).
`
`1.3 Presentation and information
`Packaging is also an essential source of information on medicinal
`products. Such information is provided by labels and package inserts
`for patients.
`The information provided to the patient may include the following:
`— the name of the patient;
`— the identification number for dispensing records;
`— the name, strength, quantity and physical description or identifica-
`tion of the medicinal product;
`— directions for use and cautionary statements, if applicable;
`— the storage instructions;
`— the date of dispensing and period of use (related to the expiry
`date);
`— the name and address of the dispenser.
`
`1.3.1 Labels
`Throughout manufacturing, a succession of specific outer labels are
`applied to the container of the medicinal product. The level of pro-
`cessing is indicated by the following words:
`— quarantine
`— storage
`— distribution.
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`Specifications for labels for finished drug products are defined in
`the WHO guidelines on GMP for pharmaceutical products (1; see
`Appendix 2).
`
`Written labels on the packaging:
`
`• Permit the identification of each active ingredient by means of its
`INN, and also give the dosage form and the trade name/trademark.
`All information concerning the medicinal product, as required by
`national legislation, must be stated on the packaging.
`
`• Preserve the stability of the medicinal product by giving advice on
`its storage (4):
`
`After the stability of the product has been evaluated, one of the following
`recommendations as to storage conditions can be prominently indicated on
`the label:
`
`— store under normal storage conditions;
`— store between 2 and 8 °C (under refrigeration, no freezing);
`— store below 8 °C (under refrigeration);
`— store between -5 and -20 °C (in a freezer);
`— store below -18 °C (in a deep freezer).
`
`• Permit the follow-up of a specific medicinal product by means of
`the batch number on the labels. It must be possible to follow the
`route of distribution of a product from the manufacturing process
`to its administration to the patient with the aim of locating and
`identifying products that are of potential risk (e.g. blood products,
`blood-derived products).
`
`• Mask the real identity of the medicinal product in clinical studies.
`This is extremely important in clinical trials in determining the real
`efficacy of a medicinal product in blinded studies. If the identity is
`masked by a code, it must be possible to disclose it at any time in a
`medical emergency.
`
`National legislation must be followed with regard to the information
`provided to the patient, as well as the record-keeping and packaging
`instructions.
`
`1.3.2 Repacking, relabelling and dispensing
`In some countries, it is common practice not to dispense drugs in the
`original packaging, but rather in a personalized manner to each pa-
`tient. This applies especially to solid oral dosage forms, and involves
`the “repacking” and “relabelling” of drugs in small quantities. Differ-
`ent drugs may even be included in “customized” medication pack-
`ages, also referred to as “patient med packs”. The quantities of drugs
`supplied in this way are usually enough only for a short period of time,
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`i.e. to provide drugs for immediate use. It should be remembered,
`however, that data obtained in stability studies undertaken by the
`manufacturer are no longer valid for drugs removed from the original
`package.
`Where repacking and relabelling are necessary, the WHO guidelines
`on GMP for pharmaceutical products (1) should be followed to avoid
`any mix-up or contamination of the product, which could place the
`patients’ safety at risk.
`
`1.3.3 Package inserts for patients (patient information leaflets)
`Product information must help patients and other users to understand
`the medication. The patient package insert, together with the label,
`provides the patient with key information concerning the proper use
`of the product, potential adverse drug reactions and interactions,
`storage conditions and the expiry date.
`In OTC medicinal products, the package insert, together with the
`label, may constitute the only pharmaceutical advice that the patient
`receives.
`
`1.4 Compliance
`Packaging and labelling may help to reinforce the instructions given
`by the physician or the pharmacist, and improve compliance with
`drug therapy. In this respect, packaging becomes a compliance aid.
`The design of pharmaceutical packaging should be such that the
`product can easily be administered in a safe manner to the patient. If
`the patient feels at ease with the packaging and route of administra-
`tion, the design of the packaging may become a key factor in increas-
`ing compliance. This is also an important factor in clinical trials.
`
`1.5 Protection of patients
`Packaging must not only increase compliance through its design, but
`must also protect the patient and indicate the integrity of the product.
`Packaging equipped with a tamper-evident device protects against
`incidental and accidental poisoning. To protect children, several
`child-resistant closures have been developed (see section 2.2.3).
`
`1.6 Detection of counterfeiting
`The Forty-first World Health Assembly, after reviewing the report of
`the Executive Board on the implementation of WHO’s revised drug
`strategy, requested: “. . . governments and pharmaceutical manufac-
`turers to cooperate in the detection and prevention of the increasing
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`incidence of the export or smuggling of falsely labelled, spurious,
`counterfeited or substandard pharmaceutical preparations” (6).
`Several documents (2, 6–9) show that counterfeit pharmaceutical
`products are in wide circulation. In November 1985, during the WHO
`Conference of Experts on the Rational Use of Drugs in Nairobi,
`Kenya, concern was expressed regarding the extent to which counter-
`feit pharmaceutical products were in circulation in developing coun-
`tries (10). In view of the importance of this issue, a text has been drafted
`to provide model provisions to deal with counterfeit drugs (11).
`The design of the packaging must therefore contribute to preventing
`tampering with, or the counterfeiting of, certain medicinal products.
`Such tamper-evident containers can allow the visual inspection of the
`medicinal product before use, and this may serve as a first stage in
`detecting counterfeit drugs.
`
`2.
`
`Packaging materials and closures
`In accordance with the methods of use and administration of medici-
`nal products, packaging materials, closures and containers vary a
`great deal and have to meet a wide variety of different requirements.
`All the routes used for systemic access have demanding requirements,
`which often can only be met by complex structured and formulated
`medicinal products. This is particularly true of the new medicinal
`products that are now appearing, such as those administered via
`transdermal delivery systems.
`To ensure the efficacy of a product during its total shelf-life, pharma-
`ceuticals must be regarded as a combination of the medicinal product
`itself and the packaging.
`
`2.1 Types of material
`Only the most commonly used packaging materials and containers
`are described here.
`
`2.1.1 Glass
`For a large number of pharmaceuticals, including medicinal products
`for oral and local administration, glass containers are usually the first
`choice (e.g. bottles for tablets, injection syringes for unit- or multi-
`dose administration). Different types of glass may be necessary,
`depending on the characteristics and the intended use of the medici-
`nal products concerned.
`Manufacturers should arrange with their suppliers to obtain the
`appropriate type of glass container for the intended use. Suppliers
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`should provide the raw and packaging materials in conformity with
`industrial norms. Classifications of types of glass are given in the
`European and United States pharmacopoeias, whereas no such
`classification exists in the Japanese pharmacopoeia.
`Glass can be tested for light transmission and hydrolytic resistance. In
`the Japanese pharmacopoeia, such tests are described only for glass
`containers for injection, whereas in the European and United States
`pharmacopoeias they are given for all types of glass containers.
`
`2.1.2 Plastics
`Some containers are now being made of plastics; the main use is for
`bags for parenteral solutions. Plastic containers have several advan-
`tages compared with glass containers:
`— they are unbreakable
`— they are collapsible
`— they are light.
`The European, Japanese and United States pharmacopoeias all de-
`scribe materials of the same type, but there are considerable differ-
`ences in the classification and presentation.
`As far as tests are concerned, the three pharmacopoeias are
`extremely difficult to compare. The European pharmacopoeia is the
`most detailed and requires tests in relation to the use and routes of
`administration of the medicinal product. Moreover, the same concept
`is extended to bulk containers for active ingredients.
`
`2.1.3 Metal
`Metal containers are used solely for medicinal products for non-
`parenteral administration. They include tubes, packs made from foil
`or blisters, cans, and aerosol and gas cylinders. Aluminium and stain-
`less steel are the metals of choice for both primary and secondary
`packaging for medicinal products. They have certain advantages and
`provide excellent tamper-evident containers.
`Since metal is strong, impermeable to gases and shatterproof, it is the
`ideal packaging material for pressurized containers.
`Descriptions and tests can be found in the norms and standards of the
`ISO; these have been established in collaboration with manufactur-
`ers. Requirements are not given in pharmacopoeias; the suitability of
`a particular material for a container is normally established by con-
`ducting stability studies in which the material is in contact with the
`drug in question.
`
`133
`
`Novartis Exhibit 2174.0015
`Regeneron v. Novartis, IPR2021-00816
`
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`

`2.2 Closures
`Closures used for the purpose of covering drug containers after the
`filling process should be as inert as possible. They should not give rise
`to undesired interactions between the contents and the outside envi-
`ronment, and should provide a complete seal. Besides their protective
`function, closures must also allow the easy and safe administration of
`the drug.
`Depending on the application, closures may have to be pierced with a
`needle for intravenous sets. Such closures are made from elastomeric
`materials (rubbers), while those that cannot be pierced are generally
`made from plastics such as polyethylene or polypropylene.
`Depending on the type of container, closures may have different
`shapes and sizes, e.g. stoppers for infusion or injection bottles or
`plungers for prefilled syringes. A special design of stopper may also
`be required for some pharmaceutical production processes such as
`lyophilization.
`Closures, as primary packaging components, are of critical impor-
`tance and must be carefully selected. They are an essential compo-
`nent of the container and, as such, an integral part of the drug
`preparation.
`A container type which does not require a removable closure at the
`time of administration is usually preferred since such a container/
`closure system avoids, or at least minimizes, the risk of biological and
`other contamination as well as tampering.
`For parenteral preparations, the combination of glass containers and
`elastomeric closures, usually secured by an aluminium cap, is widely
`used. Typical examples are infusion bottles, injection vials and
`prefilled syringes. The rubber closures used within such a system must
`be carefully selected in accordance with the intended purpose. Most
`often, improper rubber closures are the cause of incompatibility
`between the packaging and the drug.
`
`2.2.1 Rubber closures
`Rubber consists of several ingredients, one of which is elastomer.
`Modern rubber compounds used in packaging pharmaceuticals con-
`tain only a limited number of ingredients, which are very difficult to
`extract. Closures made from such materials generally do not pose any
`problems, and can be used in contact with a large number of drug
`preparations.
`Rubber closures for pharmaceutical use must meet the relevant re-
`quirements of the most important pharmacopoeias (the European,
`
`134
`
`Novartis Exhibit 2174.0016
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Japanese and United States pharmacopoeias). International stan-
`dards have also been establ