Guidance for Industry
`Container Closure Systems for Packaging
`Human Drugs and Biologics
`
`CHEMISTRY, MANUFACTURING, AND CONTROLS DOCUMENTATION
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
`Center for Biologics Evaluation and Research (CBER)
`
`May 1999
`
`Regeneron Exhibit 1041.001
`
`

`

`Guidance for Industry
`Container Closure Systems for Packaging
`Human Drugs and Biologics
`
`CHEMISTRY, MANUFACTURING, AND CONTROLS DOCUMENTATION
`
`Additional copies are available from:
`
`Office of Training and Communications
`Division of Communications Management
`Drug Information Branch, HFD-210
`Center for Drug Evaluation and Research (CDER)
`5600 Fishers Lane
`Rockville, Maryland 20857
`(Tel) 301-827-4573
`(Internet) http://www.fda.gov/cder/guidance/index.htm
`
`or
`
`Office of Communications
`Training and Manufacturers Assistance, HFM-40
`Center for Biologics Evaluation and Research (CBER)
`1401 Rockville Pike
`Rockville, Mary land 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.htm
`
`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
`Center for Biologics Evaluation and Research (CBER)
`May 1999
`
`Regeneron Exhibit 1041.002
`
`

`

`Table of Contents
`
`I.
`
`11.
`
`III.
`
`INTRODUCTION ..................................................... I
`
`BACKGROUND ...................................................... 2
`A
`Definitions ..................................................... 2
`B.
`CGMP, CPSC and USP Requirements on Containers and Closures ........... 3
`C.
`Additional Considerations .......................................... 4
`
`QUALIFICATION AND QUALITY CONTROL OF PACKAGING COMPONENTS . 5
`A
`Introduction .................................................... 5
`B.
`General Considerations ............................................ 7
`C.
`Information That Should Be Submitted in Support of an Original
`Application for Any Drug Product .................................. 17
`Inhalation Drug Products ......................................... 23
`Drug Products for Injection and Ophthalmic Drug Products ............... 23
`Liquid-Based Oral and Topical Drug Products and Topical Delivery Systems .. 27
`Solid Oral Dosage Forms and Powders for Reconstitution ................ 33
`Other Dosage Forms ............................................ 37
`
`D.
`E.
`F.
`G.
`H.
`
`IV.
`
`POSTAPPROVALPACKAGINGCHANGES .............................. 37
`
`V.
`
`VI.
`
`TYPEIIIDRUGMASTERFILES ....................................... 37
`A
`General Comments .............................................. 3 7
`B.
`Information in a Type III DMF ..................................... 3 8
`
`BULK CONTAINERS ................................................ 39
`A
`Containers for Bulk Drug Substances ................................ 39
`B.
`Containers for Bulk Drug Products .................................. 40
`
`ATTACHMENT A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A-1
`REGULATORY REQUIREMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A-1
`
`ATTACHMENT B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B-1
`COMPLIANCE POLICY GUIDES THAT CONCERN PACKAGING . . . . . . . . . . B-1
`
`ATTACHMENT C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C-1
`EXTRACTION STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C-1
`
`ATTACHMENT D . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D-1
`ABBREVIATIONS ................................................. D-1
`
`ATTACHMENT E . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . E-1
`REFERENCES .................................................... E-1
`
`Regeneron Exhibit 1041.003
`
`

`

`GUIDANCE FOR INDUSTRY1
`
`CONTAINER CLOSURE SYSTEMS FOR PACKAGING
`HUMAN DRUGS AND BIOLOGICS
`
`CHEMISTRY, MANUFACTURING, AND CONTROLS DOCUMENTATION
`
`I.
`
`INTRODUCTION
`
`This document is intended to provide guidance on general principles2 for submitting information
`on packaging materials used for human drugs and biologics.3 This guidance supersedes the FDA
`Guideline for Submitting Documentation for Packaging for Human Drugs and Biologics, issued
`in February 1987 and the packaging policy statement issued in a letter to industry dated June 30,
`1995 from the Office of Generic Drugs. 4 This guidance is not intended to describe the
`information that should be provided about packaging operations associated with drug product
`manufacture.
`
`Approaches which differ from those described in this guidance may be followed, but the applicant
`is encouraged to discuss significant variations in advance with the appropriate CDER chemistry
`review staff or CBER review staff This is to prevent applicants or sponsors from spending
`unnecessary time and effort in preparing a submission that the FDA may later determine to be
`unacceptable.
`
`1 This guidance has been prepared by the Packaging Technical Committee of the Chemistry, Manufacturing, and
`Controls Coordinating Committee (CMC CC) in the Center for Drug Evaluation and Research (CDER) and in
`conjunction with the Center for Biologics Evaluation and Research (CBER) at the Food and Drug Administration. This
`guidance document represents the Agency's current thinking on container closure systems for the packaging of human
`drugs and biological products. It does not create or confer any rights for or on any person and does not operate to bind
`FDA or the public. An alternative approach may be used if such approach satisfies the requirements of the applicable
`statute, regulations, or both.
`
`2 In general, this guidance does not suggest specific test methods and acceptance criteria ( except for references to The
`United States Pharmacopia methods), nor does it suggest comprehensive lists of tests. These details should be
`determined based on good scientific principles for each specific container closure system for particular drug product
`formulations, dosage forms, and routes of administration. Acceptance criteria should be based on actual data for
`particular packaging components and container closure systems, and they should be set to ensure batch-to-batch
`uniformity of packaging components.
`
`3 As used in this guidance, the terms drug and drug product include biologics unless otherwise noted.
`
`4 The policy statement is a document titled Container/Closure Information Which Should Be Provided In An
`ANDAIAADA which was written by the Office of Generic Drugs/Packaging Advisory Group.
`
`Regeneron Exhibit 1041.004
`
`

`

`II.
`
`BACKGROUND
`
`The Federal Food, Drug, and Cosmetic Act (the Act) mandates the need for adequate information
`related to packaging materials. Section 50l(a)(3) of the Act states that a drug is deemed to be
`adulterated "if its container is composed, in whole or in part, of any poisonous or deleterious
`substance which may render the contents injurious to health .... " In addition, section 502 of the
`Act states that a drug is considered misbranded if there are packaging omissions. Also, section
`505 of the Act requires a full description of the methods used in, and the facilities and controls
`used 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 the
`methods used in, the manufacturing, processing and packing of such drug. This includes facilities
`and controls used in the packaging a drug product.
`
`A.
`
`Definitions5
`
`Materials of construction6 refer to the substances ( e.g., glass, high density polyethylene
`(HDPE) resin, metal) used to manufacture a packaging component.
`
`A packaging component means any single part of a container closure system. Typical
`components are containers (e.g., ampules, vials, bottles), container liners (e.g., tube
`liners), closures ( e.g., screw caps, stoppers), closure liners, stopper overseals, container
`inner seals, administration ports (e.g., on large-volume parenterals (LVPs)), overwraps,
`administration accessories, and container labels. A primary packaging component means
`a packaging component that is or may be in direct contact with the dosage form. A
`secondary packaging component means a packaging component that is not and will not be
`in direct contact with the dosage form.
`
`A container closure system refers to the sum of packaging components that together
`contain and protect the dosage form. This includes primary packaging components and
`secondary packaging components, if the latter are intended to provide additional
`protection to the drug product. A packaging system is equivalent to a container closure
`system.
`
`5 These definitions are intended to clarify the use of certain terms in this guidance only and are not intended to supersede
`the definitions of container and package as provided for in 21 CFR 600.3.
`
`6 This term is used in a general sense for the basic material, which should be defined in the application in terms of its
`specific chemical composition for a given drug application (e.g., the specific polymer and any additives used to make the
`material).
`
`2
`
`Regeneron Exhibit 1041.005
`
`

`

`A package or market package 7 refers to the container closure system and labeling,
`associated 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 or
`retail customer upon purchase and does not include packaging used solely for the purpose
`of shipping such articles.
`
`Quality refers to the physical, chemical, microbiological, biological, bioavailability, and
`stability attributes that a drug product should maintain if it is to be deemed suitable for
`therapeutic or diagnostic use. In this guidance, the term is also understood to convey the
`properties of safety, identity, strength, quality, and purity (see 21 CFR 21 l.94(a)).
`
`An extraction profile refers to the analysis (usually by chromatographic means) of extracts
`obtained from a packaging component. A quantitative extraction profile is one in which
`the amount of each detected substance is determined.
`
`B.
`
`CGMP, CPSC and USP Requirements on Containers and Closures
`
`Current good manufacturing practice (CGMP) requirements for the control of drug
`product containers and closures are included in 21 CFR Parts 210 and 211. A listing of
`the relevant sections is provided in Attachment A In addition, a listing of Compliance
`Policy Guides that deal with packaging issues is provided in Attachment B. References in
`this guidance to CGMP regulations are provided for completeness. For additional
`information, refer to the FDA Compliance Program Guidance Manual for Pre-Approval
`Inspections/Investigations (7346.832) which describes specific responsibilities for CDER
`scientists and for field investigators.
`
`The FDA requirement for tamper-resistant closures is included in 21 CFR 211.132 and the
`Consumer Product Safety Commission (CPSC) requirements for child-resistant closures
`are included in 16 CFR 1700. An outline of these and other applicable regulatory
`requirements is provided in Attachment A
`
`The United States Pharmacopeial Convention has established requirements for containers
`which are described in many of the drug product monographs in The United States
`Pharmacopeia/National Formulary (USP/NF). For capsules and tablets, these
`requirements generally relate to the design characteristics of the container ( e.g., tight,
`well-closed or light-resistant). For injectable products, materials of construction are also
`addressed ( e.g., "Preserve in single-dose or in multiple-dose containers, preferably of Type
`I glass, protected from light"). These requirements are defined in the "General Notices
`and Requirements" (Preservation, Packaging, Storage, and Labeling) section of the USP.
`The requirements for materials of construction are defined in the "General Chapters" of
`
`7 The materials of construction used in the labeling are a concern from a packaging perspective if they affect the
`protection and/or safety of the drug product.
`
`3
`
`Regeneron Exhibit 1041.006
`
`

`

`the USP (see Attachment A).
`
`C.
`
`Additional Considerations
`
`1.
`
`Submissions of INDs
`
`The packaging information in the chemistry, manufacturing, and controls section
`of an IND usually includes a brief description of the components, the assembled
`packaging system and any precautions needed to ensure the protection and
`preservation of the drug substance and drug product during their use in the clinical
`trials.
`
`For general guidance regarding the container closure system information to be
`submitted for phase 1 studies, refer to the FDA guidance for industry Content and
`Format of investigational New Drug Applications(INDs) for Phase I Studies of
`Drugs, Including Well-Characterized, Therapeutic, Biotechnology-derived
`Products (November 1995).
`
`General guidance regarding the container closure system information to be
`submitted for phase 2 or phase 3 studies will be provided in the FDA guidance for
`industry INDs for Phase 2 and 3 Studies of Drugs, Including Specified
`Therapeutic Biotechnology-Derived Products, Chemistry, Manufacturing, and
`Controls Content and Format, when finalized (draft guidance published April 21,
`1999).
`
`2.
`
`Submissions on Packaging of a Drug Product by Another Firm
`
`a.
`
`Contract Packager
`
`A contract packager is a firm retained by the applicant to package a drug
`product. The applicant remains responsible for the quality of the drug
`product during shipping, storage, and packaging.
`
`The information regarding the container closure system used by a contract
`packager that should be submitted in the CMC section of an application
`(NDA, ANDA, or BLA), or in a DMF which is referenced in the
`application, is no different from that which would be submitted if the
`applicant performed its own packaging operations. If the information is
`provided in a DMF, then a copy of the letter of authorization (LOA) for
`the DMF should be provided in the application (see section V.A).
`
`4
`
`Regeneron Exhibit 1041.007
`
`

`

`b.
`
`Repackager8
`
`A repackager is a firm that buys drug product from the drug product
`manufacturer or distributor and repackages it for sale under a label
`different from that of the manufacturer. The repackager is responsible for
`ensuring the quality and stability of the repackaged drug prpoduct. The
`repackaging operation is required to e in compliance with CGMPs (21 CFR
`Part 211), and there are limits to the expiration period that may be used
`with the repackaged product unless the repackager conducts stability
`studies. 9 Packaging qualification information is not required if the
`repackager uses the same container closure system approved in the original
`application.
`
`All significant phases of the manufacturing and processing of a drug
`product (including packaging) should be described as part of the CMC
`section of an application (NDA, ANDA or BLA), or in a DMF referenced
`in the application. The only exception is the repackaging of solid oral drug
`products for which an approved application already exists. 1° For biologics,
`repackaging is considered a step in the manufacturing process for which
`licensing is required (21 CFR 600.3(u) and 601).
`
`III. QUALIFICATION AND QUALITY CONTROL OF PACKAGING
`COMPONENTS
`
`A.
`
`Introduction
`
`CDER and CBER approve a container closure system to be used in the packaging of a
`human drug or biologic as part of the application (NDA, ANDA or BLA) for the drug or
`biologic. A packaging system found acceptable for one drug product is not automatically
`assumed to be appropriate for another. Each application should contain enough
`information to show that each proposed container closure system and its components are
`suitable for its intended use.
`
`The type and extent of information that should be provided in an application will depend
`on the dosage form and the route of administration. For example, the kind of information
`that should be provided about a packaging system for an injectable dosage form or a drug
`
`8 This discussion does not apply to the repackaging of drug products for dispensing under the practice of pharmacy.
`
`9 FDA Compliance Policy Guides, "Expiration Dating of Unit Repackaged Drugs," 480.200, February 1, 1984, rev.
`March 1995 (CPG7132b.ll).
`
`1° FDA Compliance Policy Guides, "Regulatory Action Regarding Approved New Drugs and Antibiotic Drug Products
`Subjected to Additional Processing or Other Manipulation," 446.100, January 18, 1991 (CPG 7132c.06).
`
`5
`
`Regeneron Exhibit 1041.008
`
`

`

`product for inhalation is often more detailed than that which should be provided about a
`packaging system for a solid oral dosage form. More detailed information usually should
`be provided for a liquid-based dosage form than for a powder or a solid, since a liquid(cid:173)
`based dosage form is more likely to interact with the packaging components.
`
`Table I illustrates the correlation between the degree of concern regarding the route of
`administration with the likelihood of packaging component-dosage form interactions for
`different classes of drug products.
`
`Table 1
`. C
`E xamp1es o fP k
`t
`oncerns or ommon Cl asses o fD ru2 p d
`f C
`ro uc s
`ac a2m2
`Degree of Concern
`Likelihood of Packaging Component-Dosage Form Interaction
`Associated with the
`Route of
`Administration
`
`High
`
`Medium
`
`Low
`
`Highest
`
`High
`
`Sterile Powders and
`Powders for
`Injection; Inhalation
`Powders
`
`Inhalation Aerosols
`and Solutions;
`Injections and
`Injectable
`Suspensionsa
`
`Ophthalmic Solutions
`and Suspensions;
`Transdermal
`Ointments and
`Patches; Nasal
`Aerosols and Sprays
`
`Low
`
`a
`
`Topical Solutions and Topical Powders;
`Suspensions; Topical Oral powders
`and Lingual Aerosols;
`Oral Solutions and
`Suspensions
`For the purposes of this table, the term suspension is used to mean a mixture of two
`immiscible phases ( e.g., solid in liquid or liquid in liquid). As such, it encompasses a wide
`variety of dosage forms such as creams, ointments, gels, and emulsions, as well as
`suspensions in the pharmaceutical sense.
`
`Oral Tablets and Oral
`(Hard and Soft
`Gelatin) Capsules
`
`For the purpose of this guidance, container closure systems for the most common types of
`dosage forms will be discussed in terms of five general categories: Inhalation Drug
`Products (section III.D); Drug Products for Injection and Ophthalmic Drug Products
`(Section 111.E); Liquid-based Oral and Topical Drug Products and Topical Delivery
`Systems (section 111.F); Solid Oral Dosage Forms and Powders for Reconstitution (section
`
`6
`
`Regeneron Exhibit 1041.009
`
`

`

`111.G); and Other Dosage Forms (section 111.H).
`
`B.
`
`General Considerations
`
`Suitability refers to the tests and studies used and accepted for the initial qualification of a
`component or a container closure system for its intended use. Quality control (QC) refers
`to 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 characteristics
`established in the suitability studies. The subsections on associated components and
`secondary components describe the tests and studies for establishing suitability and quality
`control for these types of components. However, the ultimate proof of the suitability of
`the container closure system and the packaging process is established by full shelf life
`stability studies.
`
`1.
`
`Suitability for the Intended Use
`
`Every proposed packaging system should be shown to be suitable for its intended
`use: it should adequately protect the dosage form; it should be compatible with
`the dosage form; and it should be composed of materials that are considered safe
`for use with the dosage form and the route of administration. If the packaging
`system has a performance feature in addition to containing the product, the
`assembled container closure system should be shown to function properly.
`
`Information intended to establish suitability may be generated by the applicant, by
`the supplier of the material of construction or the component, or by a laboratory
`under contract to either the applicant or the firm. An adequately detailed
`description of the tests, methods, acceptance criteria, reference standards, and
`validation information for the studies should be provided. The information may be
`submitted directly in the application or indirectly by reference to a DMF. If a
`DMF is used, a letter authorizing reference (i.e., letter of authorization (LOA)) to
`the DMF must be included in the application (see section V.A).
`
`General issues concerning protection, compatibility, safety and performance of
`packaging components and/or systems are discussed below. In this guidance,
`component functionality and drug delivery will also be addressed in connection
`with specific dosage forms and routes of administration (see sections 111.D, 111.E,
`111.F, 111.G, and 111.H).
`
`a.
`
`Protection
`
`A container closure system should provide the dosage form with adequate
`protection from factors (e.g., temperature, light) that can cause a
`degradation in the quality of that dosage form over its shelf life. Common
`causes of such degradation are: exposure to light, loss of solvent, exposure
`
`7
`
`Regeneron Exhibit 1041.010
`
`

`

`to reactive gases (e.g., oxygen), absorption of water vapor, and microbial
`contamination. A drug product can also suffer an unacceptable loss in
`quality 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 loss
`of quality due to absorption of moisture. Sensitivity to oxygen is most
`commonly found with liquid-based dosage forms. Laboratory studies can
`be used to determine which of these factors actually have an influence on a
`particular drug product.
`
`Light protection11 is typically provided by an opaque or amber-colored
`container or by an opaque secondary packaging component ( e.g., cartons
`or overwrap). The USP test for light transmission (USP <661>) is an
`accepted standard for evaluating the light transmission properties of a
`container. Situations exist in which solid and liquid-based oral drug
`products have been exposed to light during storage because the opaque
`secondary packaging component was removed, contrary to the approved
`labeling and the USP monograph recommendation. A firm, therefore, may
`want to consider using additional or alternate measures to provide light
`protection to these drug products when necessary.
`
`Loss of solvent can occur through a permeable barrier ( e.g., a polyethylene
`container wall), through an inadequate seal, or through leakage. Leaks can
`develop through rough handling or from inadequate contact between the
`container and the closure ( e.g., due to the buildup of pressure during
`storage). 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 container
`closure system either by passing through a permeable container surface
`( e.g., the wall of a low density polyethylene (LDPE) bottle) or by diffusing
`past a seal. Plastic containers are susceptible to both routes. Although
`glass containers would seem to offer better protection, because glass is
`relatively impermeable, glass containers are more effective only if there is a
`good seal between the container and the closure.
`
`Protection from microbial contamination is provided by maintaining
`adequate container integrity after the packaging system has been sealed.
`An adequate and validated procedure should be used for drug product
`manufacture and packaging.
`
`11 For further information regarding photostability studies, see the FDA Guideline for the Photostability Testing of New
`Drug Substances and Products (May 1997).
`
`8
`
`Regeneron Exhibit 1041.011
`
`

`

`b.
`
`Compatibility
`
`Packaging components that are compatible with a dosage form will not
`interact sufficiently to cause unacceptable changes in the quality of either
`the dosage form or the packaging component.
`
`Examples of interactions include loss of potency due to absorption or
`adsorption of the active drug substance, or degradation of the active drug
`substance induced by a chemical entity leached from a packaging
`component; reduction in the concentration of an excipient due to
`absorption, adsorption or leachable-induced degradation; precipitation;
`changes in drug product pH; discoloration of either the dosage form or the
`packaging component; or increase in brittleness of the packaging
`component.
`
`Some interactions between a packaging component and dosage form will
`be detected during qualification studies on the container closure system and
`its components. Others may not show up except in the stability studies.
`Therefore, any change noted during a stability study that may be
`attributable to interaction between the dosage form and a packaging
`component should be investigated and appropriate action taken, regardless
`of whether the stability study is being conducted for an original application,
`a supplemental application, or as fulfillment of a commitment to conduct
`postapproval stability studies.
`
`c.
`
`Safety
`
`Packaging components should be constructed of materials that will not
`leach harmful or undesirable amounts of substances to which a patient will
`be exposed when being treated with the drug product. This consideration
`is especially important for those packaging components which may be in
`direct contact with the dosage form, but it is also applicable to any
`component 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 the
`manufacture of a packaging component is safe for its intended use is not a
`simple process, and a standardized approach has not been established.
`There is, however, a body of experience which supports the use of certain
`approaches that depend on the route of administration and the likelihood of
`interactions between the component and the dosage form (see Table 1).
`
`For a drug product such as an injection, inhalation, ophthalmic, or
`transdermal, a comprehensive study is appropriate. This involves two
`
`9
`
`Regeneron Exhibit 1041.012
`
`

`

`parts: first, an extraction study 12 on the packaging component to determine
`which chemical species may migrate into the dosage form (and at what
`concentration); and, second, a toxicological evaluation of those substances
`which are extracted to determine the safe level of exposure via the label
`specified route of administration. This technique is used by the Center for
`Food Safety and Applied Nutrition (CFSAN) to evaluate the safety of
`substances that are proposed as indirect food additives (e.g., polymers or
`additives that may be used in for packaging foods ). 13
`
`The approach for toxicological evaluation of the safety of extractables
`should be based on good scientific principles and take into account the
`specific 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 111.E and
`III.F), data from the USP Biological Reactivity Tests and USP Elastomeric
`Closures for Injections tests will typically be considered sufficient evidence
`of material safety.
`
`For many solid and liquid oral drug products, an appropriate reference to
`the indirect food additive regulations (21 CFR 174-186) promulgated by
`CF SAN for the materials of construction used in the packaging component
`will typically be considered sufficient. Although these regulations do not
`specifically apply to materials for packaging drug products, they include
`purity criteria and limitations pertaining to the use of specific materials for
`packaging foods that may be acceptable for the evaluation of drug product
`packaging components. Applicants are cautioned that this approach may
`not be acceptable for liquid oral dosage forms intended for chronic use (see
`section 111.F .1 ).
`
`For drug products that undergo clinical trials, the absence of adverse
`reactions traceable to the packaging components is considered supporting
`evidence of material safety.
`
`Safety assessments for specific dosage forms are discussed further in
`section III of this guidance.
`
`d.
`
`Performance
`
`12 See Attachment C for discussion of extraction studies.
`
`13 FDA/CF SAN, Recommendations for Chemistry Data for Indirect Food Additive Petitions, Version 1.2, Chemistry
`Review Branch, Office of Pre-Market Approval, June 1995.
`
`10
`
`Regeneron Exhibit 1041.013
`
`

`

`Performance of the container closure system refers to its ability to function
`in the manner for which it was designed. A container closure system is
`often called upon to do more than simply contain the dosage form. When
`evaluating performance, two major considerations are container closure
`system functionality and drug delivery.
`
`1.
`
`Container Closure System Functionality
`
`The container closure system may be designed to improve patient
`compliance ( 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., a
`prefilled syringe), or have other functions.
`
`11.
`
`Drug Delivery
`
`Drug delivery refers to the ability of the packaging system to
`deliver the dosage form in the amount or at the rate described in the
`package insert. Some examples of a packaging system for which
`drug delivery aspects are relevant are a prefilled syringe, a
`transdermal patch, a metered tube, a dropper or spray bottle, a dry
`powder inhaler, and a metered dose inhaler.
`
`Container closure system functionality and/or drug delivery are
`compromised when the packaging system fails to operate as
`designed. Failure can result from misuse, faulty design,
`manufacturing defect, improper assembly, or wear and tear during
`use. Tests and acceptance criteria regarding dosage form delivery
`and container closure system functionality should be appropriate to
`the particular dosage form, route of administration, and design
`features.
`
`e.
`
`Summary
`
`Table 2 summarizes typical packaging suitability considerations for
`common classes of drug products.
`
`11
`
`Regeneron Exhibit 1041.014
`
`

`

`Inhalation Aerosols and
`Solutions, Nasal Sprays
`Inhalation Powders
`Injections, Injectable
`Suspensionsb
`Sterile Powders and
`Powders for Injection
`Ophthalmic Solutions
`and Suspensions
`Topical Delivery
`Systems
`Topical Solutions and
`Suspensions, and
`Topical and Lingual
`Aerosols
`Topical Powders
`Oral Solutions and
`Suspensions
`Oral Powders
`Oral Tablets and Oral
`(Hard and Soft Gelatin)
`Caosules
`If there is a special performance function built into the drug product ( e.g., counter cap), it
`is of importance for any dosage form/route of administration to show that the container
`closure system performs that function properly.
`For definition of the term suspension, see footnote a to Table 1.
`
`L,M,W
`
`Case 2c
`
`Case 2s
`
`Case 2d
`
`L,S,M,G
`
`Case le
`
`Case 2s
`
`Case 2d
`
`L, S
`
`Case le
`
`Case 3s
`
`Case Id
`
`L,S,M
`
`Case le
`
`Case 3s
`
`Case 2d
`
`L,M,W
`
`L,S,M
`
`L,W
`
`L,W
`
`Case 3c
`
`Case le
`
`Case 2c
`
`Case 4s
`
`Case 3s
`
`Case 3s
`
`Case 3d
`
`Case 2d
`
`Case 3d
`
`Case 3c
`
`Case 4s
`
`Case 3d
`
`Table 2
`Typical Suitability Considerations for Common Classes of Drug Products
`(This table is a general guide, and is not comprehensive. See sections III.C through 111.H for a
`more detailed discussion.)
`
`Route of
`Administration/
`Dosage Form
`
`SUITABILITYa
`
`Protection
`
`Compatibility
`
`Safety
`
`Performance/
`Drug
`Delivery
`
`L, S,M, W, G
`
`Case le
`
`Case ls
`
`L,W,M
`
`Case 3c
`
`L,S,M,G
`
`Case le
`
`Case 5s
`
`Case 2s
`
`Case Id
`
`Case Id
`
`Case 2d
`
`a
`
`b
`
`Explanation of Codes in Table 2:
`
`12
`
`Regeneron Exhibit 1041.015
`
`

`

`Protection:
`
`L (protects from light, if appropriate)
`S (protects from solvent loss/leakage)
`M (protects sterile products or those with microbial limits from
`microbial contamination)
`W (protects from water vapor, if appropriate)
`G (protects from reactive gases, if appropriate)
`
`Compatibility:
`
`Case le: Liquid-based dosage form that conceivably