Guidance for IndustryContainer Closure Systems for PackagingHuman Drugs and BiologicsCHEMISTRY, MANUFACTURING, AND CONTROLS DOCUMENTATIONU.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)Center for Biologics Evaluation and Research (CBER)May 1999
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`Guidance for IndustryContainer Closure Systems for Packaging Human Drugs and BiologicsCHEMISTRY, MANUFACTURING, AND CONTROLS DOCUMENTATIONAdditional copies are available from:Office of Training and CommunicationsDivision of Communications ManagementDrug Information Branch, HFD-210Center for Drug Evaluation and Research (CDER)5600 Fishers LaneRockville, Maryland 20857(Tel) 301-827-4573(Internet) http://www.fda.gov/cder/guidance/index.htm orOffice of CommunicationsTraining and Manufacturers Assistance, HFM-40Center for Biologics Evaluation and Research (CBER)1401 Rockville PikeRockville, Maryland 20852-1448(Fax) 888-CBERFAX or 301-827-3844(Voice Information) 800-835-4709 or 301-827-1800(Internet) http://www.fda.gov/cber/guidelines.htmU.S. Department of Health and Human ServicesFood and Drug AdministrationCenter for Drug Evaluation and Research (CDER)Center for Biologics Evaluation and Research (CBER)May 1999
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`Table of ContentsI.INTRODUCTION.....................................................1II.BACKGROUND......................................................2A.Definitions.....................................................2B.CGMP, CPSC and USP Requirements on Containers and Closures...........3C.Additional Considerations..........................................4III.QUALIFICATION AND QUALITY CONTROL OF PACKAGING COMPONENTS.5A.Introduction....................................................5B.General Considerations............................................7C.Information That Should Be Submitted in Support of an Original Application for Any Drug Product..................................17D.Inhalation Drug Products.........................................23E.Drug Products for Injection and Ophthalmic Drug Products...............23F.Liquid-Based Oral and Topical Drug Products and Topical Delivery Systems..27G.Solid Oral Dosage Forms and Powders for Reconstitution................33H.Other Dosage Forms............................................37IV.POSTAPPROVAL PACKAGING CHANGES..............................37V.TYPE III DRUG MASTER FILES.......................................37A.General Comments..............................................37B.Information in a Type III DMF.....................................38VI.BULK CONTAINERS................................................39A.Containers for Bulk Drug Substances................................39B.Containers for Bulk Drug Products..................................40ATTACHMENT A....................................................... A-1REGULATORY REQUIREMENTS.................................... A-1ATTACHMENT B....................................................... B-1COMPLIANCE POLICY GUIDES THAT CONCERN PACKAGING.......... B-1ATTACHMENT C....................................................... C-1EXTRACTION STUDIES............................................ C-1ATTACHMENT D....................................................... D-1ABBREVIATIONS................................................. D-1ATTACHMENT E....................................................... E-1REFERENCES.................................................... E-1
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` This guidance has been prepared by the Packaging Technical Committee of the Chemistry, Manufacturing, and1Controls Coordinating Committee (CMC CC) in the Center for Drug Evaluation and Research (CDER) and inconjunction with the Center for Biologics Evaluation and Research (CBER) at the Food and Drug Administration. Thisguidance document represents the Agency's current thinking on container closure systems for the packaging of humandrugs and biological products. It does not create or confer any rights for or on any person and does not operate to bindFDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicablestatute, regulations, or both. In general, this guidance does not suggest specific test methods and acceptance criteria (except for references to The2United States Pharmacopia methods), nor does it suggest comprehensive lists of tests. These details should bedetermined based on good scientific principles for each specific container closure system for particular drug productformulations, dosage forms, and routes of administration. Acceptance criteria should be based on actual data forparticular packaging components and container closure systems, and they should be set to ensure batch-to-batchuniformity of packaging components. As used in this guidance, the terms drug and drug product include biologics unless otherwise noted.3 The policy statement is a document titled Container/Closure Information Which Should Be Provided In An4ANDA/AADA which was written by the Office of Generic Drugs/Packaging Advisory Group.GUIDANCE FOR INDUSTRY1CONTAINER CLOSURE SYSTEMS FOR PACKAGINGHUMAN DRUGS AND BIOLOGICSCHEMISTRY, MANUFACTURING, AND CONTROLS DOCUMENTATIONI.INTRODUCTIONThis document is intended to provide guidance on general principles for submitting information2on packaging materials used for human drugs and biologics. This guidance supersedes the FDA3Guideline for Submitting Documentation for Packaging for Human Drugs and Biologics, issuedin February 1987 and the packaging policy statement issued in a letter to industry dated June 30,1995 from the Office of Generic Drugs. This guidance is not intended to describe the4information that should be provided about packaging operations associated with drug productmanufacture.Approaches which differ from those described in this guidance may be followed, but the applicantis encouraged to discuss significant variations in advance with the appropriate CDER chemistryreview staff or CBER review staff. This is to prevent applicants or sponsors from spendingunnecessary time and effort in preparing a submission that the FDA may later determine to beunacceptable.
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` These definitions are intended to clarify the use of certain terms in this guidance only and are not intended to supersede5the definitions of container and package as provided for in 21 CFR 600.3. This term is used in a general sense for the basic material, which should be defined in the application in terms of its6specific chemical composition for a given drug application (e.g., the specific polymer and any additives used to make thematerial).2II.BACKGROUNDThe Federal Food, Drug, and Cosmetic Act (the Act) mandates the need for adequate informationrelated to packaging materials. Section 501(a)(3) of the Act states that a drug is deemed to beadulterated "if its container is composed, in whole or in part, of any poisonous or deleterioussubstance which may render the contents injurious to health...." In addition, section 502 of theAct states that a drug is considered misbranded if there are packaging omissions. Also, section505 of the Act requires a full description of the methods used in, and the facilities and controlsused for, the packaging of drugs (see Attachment A).Section 505(b)(1)(D) of the Act states that an application shall include a full description of themethods used in, the manufacturing, processing and packing of such drug. This includes facilitiesand controls used in the packaging a drug product. A.Definitions5Materials of construction refer to the substances (e.g., glass, high density polyethylene6(HDPE) resin, metal) used to manufacture a packaging component.A packaging component means any single part of a container closure system. Typicalcomponents are containers (e.g., ampules, vials, bottles), container liners (e.g., tubeliners), closures (e.g., screw caps, stoppers), closure liners, stopper overseals, containerinner seals, administration ports (e.g., on large-volume parenterals (LVPs)), overwraps,administration accessories, and container labels. A primary packaging component meansa packaging component that is or may be in direct contact with the dosage form. Asecondary packaging component means a packaging component that is not and will not bein direct contact with the dosage form.A container closure system refers to the sum of packaging components that togethercontain and protect the dosage form. This includes primary packaging components andsecondary packaging components, if the latter are intended to provide additionalprotection to the drug product. A packaging system is equivalent to a container closuresystem.
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` The materials of construction used in the labeling are a concern from a packaging perspective if they affect the7protection and/or safety of the drug product.3A package or market package refers to the container closure system and labeling,7associated components (e.g., dosing cups, droppers, spoons), and external packaging(e.g., cartons or shrink wrap). A market package is the article provided to a pharmacist orretail customer upon purchase and does not include packaging used solely for the purposeof shipping such articles.Quality refers to the physical, chemical, microbiological, biological, bioavailability, andstability attributes that a drug product should maintain if it is to be deemed suitable fortherapeutic or diagnostic use. In this guidance, the term is also understood to convey theproperties of safety, identity, strength, quality, and purity (see 21 CFR 211.94(a)).An extraction profile refers to the analysis (usually by chromatographic means) of extractsobtained from a packaging component. A quantitative extraction profile is one in whichthe amount of each detected substance is determined.B.CGMP, CPSC and USP Requirements on Containers and ClosuresCurrent good manufacturing practice (CGMP) requirements for the control of drugproduct containers and closures are included in 21 CFR Parts 210 and 211. A listing ofthe relevant sections is provided in Attachment A. In addition, a listing of CompliancePolicy Guides that deal with packaging issues is provided in Attachment B. References inthis guidance to CGMP regulations are provided for completeness. For additionalinformation, refer to the FDA Compliance Program Guidance Manual for Pre-ApprovalInspections/Investigations (7346.832) which describes specific responsibilities for CDERscientists and for field investigators.The FDA requirement for tamper-resistant closures is included in 21 CFR 211.132 and theConsumer Product Safety Commission (CPSC) requirements for child-resistant closuresare included in 16 CFR 1700. An outline of these and other applicable regulatoryrequirements is provided in Attachment A.The United States Pharmacopeial Convention has established requirements for containerswhich are described in many of the drug product monographs in The United StatesPharmacopeia/National Formulary (USP/NF). For capsules and tablets, theserequirements generally relate to the design characteristics of the container (e.g., tight,well-closed or light-resistant). For injectable products, materials of construction are alsoaddressed (e.g., "Preserve in single-dose or in multiple-dose containers, preferably of TypeI glass, protected from light"). These requirements are defined in the "General Noticesand Requirements" (Preservation, Packaging, Storage, and Labeling) section of the USP. The requirements for materials of construction are defined in the "General Chapters" of
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`4the USP (see Attachment A).C.Additional Considerations1.Submissions of INDsThe packaging information in the chemistry, manufacturing, and controls sectionof an IND usually includes a brief description of the components, the assembledpackaging system and any precautions needed to ensure the protection andpreservation of the drug substance and drug product during their use in the clinicaltrials.For general guidance regarding the container closure system information to besubmitted for phase 1 studies, refer to the FDA guidance for industry Content andFormat of investigational New Drug Applications(INDs) for Phase 1 Studies ofDrugs, Including Well-Characterized, Therapeutic, Biotechnology-derivedProducts (November 1995).General guidance regarding the container closure system information to besubmitted for phase 2 or phase 3 studies will be provided in the FDA guidance forindustry INDs for Phase 2 and 3 Studies of Drugs, Including SpecifiedTherapeutic Biotechnology-Derived Products, Chemistry, Manufacturing, andControls Content and Format, when finalized (draft guidance published April 21,1999).2.Submissions on Packaging of a Drug Product by Another Firma.Contract PackagerA contract packager is a firm retained by the applicant to package a drugproduct. The applicant remains responsible for the quality of the drugproduct during shipping, storage, and packaging.The information regarding the container closure system used by a contractpackager that should be submitted in the CMC section of an application(NDA, ANDA, or BLA), or in a DMF which is referenced in theapplication, is no different from that which would be submitted if theapplicant performed its own packaging operations. If the information isprovided in a DMF, then a copy of the letter of authorization (LOA) forthe DMF should be provided in the application (see section V.A).
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` This discussion does not apply to the repackaging of drug products for dispensing under the practice of pharmacy.8 FDA Compliance Policy Guides, “Expiration Dating of Unit Repackaged Drugs,” 480.200, February 1, 1984, rev.9March 1995 (CPG 7132b.11). FDA Compliance Policy Guides, "Regulatory Action Regarding Approved New Drugs and Antibiotic Drug Products10Subjected to Additional Processing or Other Manipulation," 446.100, January 18, 1991 (CPG 7132c.06).5b.Repackager8A repackager is a firm that buys drug product from the drug productmanufacturer or distributor and repackages it for sale under a labeldifferent from that of the manufacturer. The repackager is responsible forensuring the quality and stability of the repackaged drug prpoduct. Therepackaging operation is required to e in compliance with CGMPs (21 CFRPart 211), and there are limits to the expiration period that may be usedwith the repackaged product unless the repackager conducts stabilitystudies. Packaging qualification information is not required if the9repackager uses the same container closure system approved in the originalapplication.All significant phases of the manufacturing and processing of a drugproduct (including packaging) should be described as part of the CMCsection of an application (NDA, ANDA or BLA), or in a DMF referencedin the application. The only exception is the repackaging of solid oral drugproducts for which an approved application already exists. For biologics,10repackaging is considered a step in the manufacturing process for whichlicensing is required (21 CFR 600.3(u) and 601). III.QUALIFICATION AND QUALITY CONTROL OF PACKAGINGCOMPONENTSA.IntroductionCDER and CBER approve a container closure system to be used in the packaging of ahuman drug or biologic as part of the application (NDA, ANDA or BLA) for the drug orbiologic. A packaging system found acceptable for one drug product is not automaticallyassumed to be appropriate for another. Each application should contain enoughinformation to show that each proposed container closure system and its components aresuitable for its intended use.The type and extent of information that should be provided in an application will dependon the dosage form and the route of administration. For example, the kind of informationthat should be provided about a packaging system for an injectable dosage form or a drug
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`6product for inhalation is often more detailed than that which should be provided about apackaging system for a solid oral dosage form. More detailed information usually shouldbe provided for a liquid-based dosage form than for a powder or a solid, since a liquid-based dosage form is more likely to interact with the packaging components.Table 1 illustrates the correlation between the degree of concern regarding the route ofadministration with the likelihood of packaging component-dosage form interactions fordifferent classes of drug products. Table 1Examples of Packaging Concerns for Common Classes of Drug ProductsDegree of ConcernLikelihood of Packaging Component-Dosage Form InteractionAssociated with theRoute ofAdministrationHighMediumLowHighestInhalation AerosolsSterile Powders andand Solutions;Powders forInjections andInjection; InhalationInjectablePowders SuspensionsaHighOphthalmic Solutionsand Suspensions;TransdermalOintments andPatches; NasalAerosols and SpraysLowTopical Solutions andTopical Powders;Oral Tablets and OralSuspensions; TopicalOral powders(Hard and Softand Lingual Aerosols;Gelatin) CapsulesOral Solutions andSuspensionsFor the purposes of this table, the term suspension is used to mean a mixture of twoaimmiscible phases (e.g., solid in liquid or liquid in liquid). As such, it encompasses a widevariety of dosage forms such as creams, ointments, gels, and emulsions, as well assuspensions in the pharmaceutical sense.For the purpose of this guidance, container closure systems for the most common types ofdosage forms will be discussed in terms of five general categories: Inhalation DrugProducts (section III.D); Drug Products for Injection and Ophthalmic Drug Products(Section III.E); Liquid-based Oral and Topical Drug Products and Topical DeliverySystems (section III.F); Solid Oral Dosage Forms and Powders for Reconstitution (section
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`7III.G); and Other Dosage Forms (section III.H).B.General ConsiderationsSuitability refers to the tests and studies used and accepted for the initial qualification of acomponent or a container closure system for its intended use. Quality control (QC) refersto the tests typically used and accepted to establish that, after the application is approved,the components and the container closure system continue to possess the characteristicsestablished in the suitability studies. The subsections on associated components andsecondary components describe the tests and studies for establishing suitability and qualitycontrol for these types of components. However, the ultimate proof of the suitability ofthe container closure system and the packaging process is established by full shelf lifestability studies.1.Suitability for the Intended UseEvery proposed packaging system should be shown to be suitable for its intendeduse: it should adequately protect the dosage form; it should be compatible withthe dosage form; and it should be composed of materials that are considered safefor use with the dosage form and the route of administration. If the packagingsystem has a performance feature in addition to containing the product, theassembled container closure system should be shown to function properly.Information intended to establish suitability may be generated by the applicant, bythe supplier of the material of construction or the component, or by a laboratoryunder contract to either the applicant or the firm. An adequately detaileddescription of the tests, methods, acceptance criteria, reference standards, andvalidation information for the studies should be provided. The information may besubmitted directly in the application or indirectly by reference to a DMF. If aDMF is used, a letter authorizing reference (i.e., letter of authorization (LOA)) tothe DMF must be included in the application (see section V.A).General issues concerning protection, compatibility, safety and performance ofpackaging components and/or systems are discussed below. In this guidance,component functionality and drug delivery will also be addressed in connectionwith specific dosage forms and routes of administration (see sections III.D, III.E,III.F, III.G, and III.H).a.ProtectionA container closure system should provide the dosage form with adequateprotection from factors (e.g., temperature, light) that can cause adegradation in the quality of that dosage form over its shelf life. Commoncauses of such degradation are: exposure to light, loss of solvent, exposure
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` For further information regarding photostability studies, see the FDA Guideline for the Photostability Testing of New11Drug Substances and Products (May 1997).8to reactive gases (e.g., oxygen), absorption of water vapor, and microbialcontamination. A drug product can also suffer an unacceptable loss inquality if it is contaminated by filth.Not every drug product is susceptible to degradation by all of these factors. Not all drug products are light sensitive. Not all tablets are subject to lossof quality due to absorption of moisture. Sensitivity to oxygen is mostcommonly found with liquid-based dosage forms. Laboratory studies canbe used to determine which of these factors actually have an influence on aparticular drug product.Light protection is typically provided by an opaque or amber-colored11container or by an opaque secondary packaging component (e.g., cartonsor overwrap). The USP test for light transmission (USP <661>) is anaccepted standard for evaluating the light transmission properties of acontainer. Situations exist in which solid and liquid-based oral drugproducts have been exposed to light during storage because the opaquesecondary packaging component was removed, contrary to the approvedlabeling and the USP monograph recommendation. A firm, therefore, maywant to consider using additional or alternate measures to provide lightprotection to these drug products when necessary.Loss of solvent can occur through a permeable barrier (e.g., a polyethylenecontainer wall), through an inadequate seal, or through leakage. Leaks candevelop through rough handling or from inadequate contact between thecontainer and the closure (e.g., due to the buildup of pressure duringstorage). Leaks can also occur in tubes due to a failure of the crimp seal.Water vapor or reactive gases (e.g., oxygen) may penetrate a containerclosure system either by passing through a permeable container surface(e.g., the wall of a low density polyethylene (LDPE) bottle) or by diffusingpast a seal. Plastic containers are susceptible to both routes. Althoughglass containers would seem to offer better protection, because glass isrelatively impermeable, glass containers are more effective only if there is agood seal between the container and the closure. Protection from microbial contamination is provided by maintainingadequate container integrity after the packaging system has been sealed. An adequate and validated procedure should be used for drug productmanufacture and packaging.
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`9b.CompatibilityPackaging components that are compatible with a dosage form will notinteract sufficiently to cause unacceptable changes in the quality of eitherthe dosage form or the packaging component.Examples of interactions include loss of potency due to absorption oradsorption of the active drug substance, or degradation of the active drugsubstance induced by a chemical entity leached from a packagingcomponent; reduction in the concentration of an excipient due toabsorption, adsorption or leachable-induced degradation; precipitation;changes in drug product pH; discoloration of either the dosage form or thepackaging component; or increase in brittleness of the packagingcomponent.Some interactions between a packaging component and dosage form willbe detected during qualification studies on the container closure system andits components. Others may not show up except in the stability studies. Therefore, any change noted during a stability study that may beattributable to interaction between the dosage form and a packagingcomponent should be investigated and appropriate action taken, regardlessof whether the stability study is being conducted for an original application,a supplemental application, or as fulfillment of a commitment to conductpostapproval stability studies.c.SafetyPackaging components should be constructed of materials that will notleach harmful or undesirable amounts of substances to which a patient willbe exposed when being treated with the drug product. This considerationis especially important for those packaging components which may be indirect contact with the dosage form, but it is also applicable to anycomponent from which substances may migrate into the dosage form (e.g.,an ink or adhesive).Making the determination that a material of construction used in themanufacture of a packaging component is safe for its intended use is not asimple process, and a standardized approach has not been established. There is, however, a body of experience which supports the use of certainapproaches that depend on the route of administration and the likelihood ofinteractions between the component and the dosage form (see Table 1).For a drug product such as an injection, inhalation, ophthalmic, ortransdermal, a comprehensive study is appropriate. This involves two
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` See Attachment C for discussion of extraction studies.12 FDA/CFSAN, Recommendations for Chemistry Data for Indirect Food Additive Petitions, Version 1.2, Chemistry13Review Branch, Office of Pre-Market Approval, June 1995.10parts: first, an extraction study on the packaging component to determine12which chemical species may migrate into the dosage form (and at whatconcentration); and, second, a toxicological evaluation of those substanceswhich are extracted to determine the safe level of exposure via the labelspecified route of administration. This technique is used by the Center forFood Safety and Applied Nutrition (CFSAN) to evaluate the safety ofsubstances that are proposed as indirect food additives (e.g., polymers oradditives that may be used in for packaging foods).13The approach for toxicological evaluation of the safety of extractablesshould be based on good scientific principles and take into account thespecific container closure system, drug product formulation, dosage form,route of administration, and dose regimen (chronic or short-term dosing).For many injectable and ophthalmic drug products (see sections III.E andIII.F), data from the USP Biological Reactivity Tests and USP ElastomericClosures for Injections tests will typically be considered sufficient evidenceof material safety.For many solid and liquid oral drug products, an appropriate reference tothe indirect food additive regulations (21 CFR 174-186) promulgated byCFSAN for the materials of construction used in the packaging componentwill typically be considered sufficient. Although these regulations do notspecifically apply to materials for packaging drug products, they includepurity criteria and limitations pertaining to the use of specific materials forpackaging foods that may be acceptable for the evaluation of drug productpackaging components. Applicants are cautioned that this approach maynot be acceptable for liquid oral dosage forms intended for chronic use (seesection III.F.1).For drug products that undergo clinical trials, the absence of adversereactions traceable to the packaging components is considered supportingevidence of material safety.Safety assessments for specific dosage forms are discussed further insection III of this guidance.d.Performance
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`11Performance of the container closure system refers to its ability to functionin the manner for which it was designed. A container closure system isoften called upon to do more than simply contain the dosage form. Whenevaluating performance, two major considerations are container closuresystem functionality and drug delivery.i.Container Closure System FunctionalityThe container closure system may be designed to improve patientcompliance (e.g., a cap that contains a counter), minimize waste(e.g., a two-chamber vial or IV bag), improve ease of use (e.g., aprefilled syringe), or have other functions.ii.Drug DeliveryDrug delivery refers to the ability of the packaging system todeliver the dosage form in the amount or at the rate described in thepackage insert. Some examples of a packaging system for whichdrug delivery aspects are relevant are a prefilled syringe, atransdermal patch, a metered tube, a dropper or spray bottle, a drypowder inhaler, and a metered dose inhaler.Container closure system functionality and/or drug delivery arecompromised when the packaging system fails to operate asdesigned. Failure can result from misuse, faulty design,manufacturing defect, improper assembly, or wear and tear duringuse. Tests and acceptance criteria regarding dosage form deliveryand container closure system functionality should be appropriate tothe particular dosage form, route of administration, and designfeatures.e.SummaryTable 2 summarizes typical packaging suitability considerations forcommon classes of drug products.
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`12Table 2Typical Suitability Considerations for Common Classes of Drug Products(This table is a general guide, and is not comprehensive. See sections III.C through III.H for amore detailed discussion.)Route ofAdministration/Dosage FormSUITABILITYaProtectionCompatibilitySafetyDrugPerformance/DeliveryInhalation Aerosols andSolutions, Nasal SpraysL, S, M, W, GCase 1cCase 1sCase 1dInhalation PowdersL, W, MCase 3cCase 5sCase 1dInjections, InjectableSuspensionsbL, S, M, GCase 1cCase 2sCase 2dSterile Powders andPowders for InjectionL, M, WCase 2cCase 2sCase 2dOphthalmic Solutionsand SuspensionsL, S, M, GCase 1cCase 2sCase 2dTopical DeliverySystemsL, SCase 1cCase 3sCase 1dTopical Solutions andSuspensions, andTopical and LingualAerosolsL, S, MCase 1cCase 3sCase 2dTopical PowdersL, M, WCase 3cCase 4sCase 3dOral Solutions andSuspensionsL, S, MCase 1cCase 3sCase 2dOral PowdersL, WCase 2cCase 3sCase 3dOral Tablets and Oral(Hard and Soft Gelatin)L, WCase 3cCase 4sCase 3dCapsulesIf there is a special performance function built into the drug product (e.g., counter cap), itais of importance for any dosage form/route of administration to show that the containerclosure system performs that function properly.For definition of the term suspension, see footnote a to Table 1.bExplanation of Codes in Table 2:
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`13Protection:L (protects from light, if appropriate)S (protects from solvent loss/leakage)M (protects sterile products or those with microbial limits frommicrobial contamination)W (protects from water vapor, if appropriate)G (protects from reactive gases, if appropriate)Compatibility:Case 1c: Liquid-based dosage form that conceivably could interact with itscontainer closure system components (see examples described in sectionIII.B.1).Case 2c: Solid dosage form until reconstituted; greatest chancefor interacting with its container closure system componentsoccurs after it is reconstituted.Case 3c: Solid dosage form with low likelihood of interactingwith its container closure system components.Safety:Case 1s: Typically provided are USP Biological Reactivity Testdata, extraction/toxicological evaluation, limits on extractables,and batch-to-batch monitoring of extractables.Case 2s: Typically provided are USP Biological Reactivity Testdata and possibly extraction/toxicological evaluation.Case 3s: Typically, an appropriate reference to the indirect foodadditive regulations is sufficient for drug products with aqueous-based solvents. Drug products with non-aqueous based solventsystems or aqueous based systems containing co-solventsgenerally require additional suitability information (see sectionIII.F).Case 4s: Typically, an appropriate reference to the indirect foodadditive regulations is sufficient.Case 5s: Typically, an appropriate reference to the indirect foodadditive regulations for all components except the mouthpiece forwhich USP Biological Reactivity Test data is provided.Performance:Case 1d: Frequently a consideration.Case 2d: May be a consideration.Case 3d: Rarely a consideration.2.Quality Control of Packaging ComponentsIn addition to providing data to show that a proposed container closure system issuitable for its intended use, an application should also describe the quality controlmeasures that will be used to ensure consistency in the packaging components (seesection III.C.3). These controls are intended to limit unintended postapproval
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` These are substances