Proposed Guidelines for the Content of Type III Drug Master Files Packaging Materials and Components

Revision 1 05/08/02 Additional copies are available from: School of Packaging Michigan State University East Lansing, MI 48824-1223 (Tel) 517-355-3604 (Internet) http://www.dmfworkshop.msu.edu/ Questions and comments may be submitted to the website.

Type III Drug Master File Subcommittee May 2002 CMC

Proposed Guidelines for the Content of Type III Drug Master Files (Packaging Materials and Components)
Introduction This Guideline was prepared by the Type III Drug Master File (DMF) Subcommittee1 and reflects their collective interpretation of the current requirements for a Type III DMF. While the information presented here is offered in good faith as reliable, the authors disclaim all liability for any loss or damage arising from reliance on such information by any party.

The purpose of this Guideline is to provide information related to the content of a Type III DMF used to support regulatory applications for drug and biologic products. Information pertaining to the packaging requirements for a drug product application has been inserted as a means of integrating guidance provided by FDA. This Guideline is also intended to serve as a discussion paper (White Paper) for the National DMF Workshop sponsored by Michigan State University scheduled for March 25-27, 2002 in Arlington, VA.

The Type III DMF Subcommittee was formed by the National DMF Workshop Steering Committee to focus on specific areas related to Type III DMFs. i Revision 1

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Acknowledgement
The membership of the Type III DMF Subcommittee consists of manufacturers of packaging components and drug products, consultants, the legal profession, and academia. We would like to acknowledge the following people who volunteered their time to write, review, and offer useful insight for the preparation of this Guideline. Name Company/Firm ** Robert Bergeson Pfizer Inc. * Julie Clifford * Amy Fortenberry * Maxine Gallagher * Aileen Gilbert * Arthur Jaeger *** Hugh Lockhart * Ed McKinley * Ron McManus * William Schmitt * Ralph Simmons * Dwain Sparks * Robert Swift Alcon Laboratories Paul, Hastings, Janofsky & Walker West Pharmaceutical Services Becton Dickinson Pharmaceutical Systems Division Merck Manufacturing Division Michigan State University Owens-Illinois Montesino Associates pharma center shelbyville, inc. (Alcan Packaging) Keller and Heckman LLP Eli Lilly and Company Schott Pharmaceutical Packaging Position Sr. Research Investigator, Stability Packaging Package Development, Manager Attorney, J.D. Global Regulatory Affairs, Vice President Regulatory Affairs Specialist Packaging Development Director Packaging Professor Regulatory Affairs, Manager Consultant Market Development Engineer Attorney, J.D. Associate Regulatory Consultant, RAC Scientific Services, Manager

* Type III DMF Subcommittee Members ** Subcommittee Chair *** Workshop Chair

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Table of Contents
Page I. II. III. IV. V. VI. VII. Background ......................................................................................................................1 Scope ................................................................................................................................3 Glossary ...........................................................................................................................5 Packaging Information that Should Be Submitted in Support of an Application ............7 Type III Drug Master Files ..............................................................................................8 Letters of Authorization .................................................................................................11 Drug Master File Practices .............................................................................................12

Appendices 1. References ............................................................................................................................17 2. Table 3 (FDA Container Closure Guidance) .......................................................................18 3. Packaging Requirements ......................................................................................................19 4. Example of Letter of Authorization for a Type III DMF .....................................................21 5. Example of Type III DMF ...................................................................................................22 6. Guideline for Drug Master Files ..........................................................................................41 7. Container Closure Systems for Packaging Human Drugs and Biologics: Chemistry, Manufacturing, and Controls Documentation (Section V., pages 37, 38, and 39) ..............58

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I.

Background

The DMF system was established as a route for manufacturers of drug and biologic substances or packaging components to submit confidential or proprietary information to the Food and Drug Administration (FDA) that may then be referenced in support of a regulatory application. The DMF is not used in the determination of the regulatory status of a substance or component used in a drug or biologic product. Rather, it is an administrative document used in support during the evaluation of the safety and the efficacy of the drug or biologic product. The submission of a DMF is a voluntary action not required by law or FDA regulation and is submitted solely at the discretion of the holder. The regulatory status of the DMF is further described in 21 CFR 314.420. There are currently four types of Drug Master Files.2 Type II DMFs provide information for active pharmaceutical ingredients, their intermediates, and materials used in their preparation, or drug products. Type III DMFs provide information for packaging materials. Type IV DMFs provide information for excipients, colors, flavors, essences, or materials used in their preparation. Type V DMFs provide reference information of the type that does not fit within one of the other categories. (Note: FDA discourages the use of Type V DMFs for miscellaneous
2

The use of Master Files for the purpose of referencing confidential information is not limited to drug and biologic applications. In addition, there are other master files held at other regulatory centers that are not be covered by this document. The FDA no longer accepts Type I DMFs and no longer allows information submitted in Type I DMFs to be incorporated by reference in any form of regulatory application. (65 Fed. Reg. 1776, January 12, 2000) 1 Revision 1

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information, duplicate information, or information that should be included in one of the other types of DMFs. If any holder wishes to submit information and supporting data in a DMF that is not covered by Types II through IV, a holder should first submit a letter of intent to the Drug Master File Staff.3)

The Federal Food, Drug, and Cosmetic Act (the Act) mandates the need for adequate information related to packaging materials. Section 501(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...." It is incumbent on the drug or biologic applicant or the associated DMF holder(s) to supply the requested information to adequately describe the safety of the container closure system.

September, 1989 Guideline for Drug Master Files. Section IV.C.1.e., Type V: FDA Accepted Reference Information. 2 Revision 1

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II.

Scope

This Guideline includes regulatory information and procedures that should be considered when establishing and maintaining a Type III DMF. The current FDA document, Guideline for Drug Master Files was issued in September 1989. (See Appendix 6.) Since that time, the FDA has released new guidance documents and incorporated changes that suggest this DMF Guideline should be updated. The supporting information expected for the packaging of a drug product contained in the Chemistry, Manufacturing, Controls section of a regulatory filing is described in these FDA Guidances. The May 1999 FDA Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics: Chemistry, Manufacturing, and Controls Documentation (Container Closure Guidance) is the most comprehensive regulatory guidance available for container closure systems for drug products. It details the information that should be submitted to FDA to support the primary container closure system used for specific dosage forms of drugs and biologics. This information includes a description of each component of the container closure system, its respective material(s) of construction, and relevant functional information. Generally, the Container Closure Guidance suggests including more detailed information in a DMF than has been requested in the past. Suppliers who are establishing or maintaining a Type III DMF are encouraged to become familiar with the Container Closure Guidance. An understanding of the basics of the regulatory process is essential to placing the respective roles of the DMF holder and applicant into perspective.

The regulatory approval process is significant to manufacturers of packaging components and the associated materials of construction because there is the potential for the container closure

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system to affect the safety and efficacy of the drug product. When preparing an application, the applicant should include or reference adequate data to demonstrate that the container closure system for the drug product will not in any way affect safety or efficacy. The applicant is restricted to the use of the container closure system and materials of construction described in the drug or biologic application, unless the applicant provides FDA with information on a new packaging material in accordance with the appropriate regulatory process.

It is recognized that the reference to a Type III DMF for a material of construction (e.g., resin) within a Type III DMF for a component (e.g., bottle) is possible. Within this Guideline, it is presumed that the process for the reference to the material of construction DMF within the component DMF is similar to the process described herein for the reference to the component DMF within a drug product application. In most cases, cross-reference to the critical material of construction DMF(s) in the drug product application is expected.

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iii.

Glossary

The following definitions are not intended to supersede definitions contained in other references, but are intended to clarify certain terms used in this Guideline. Agency: the Food and Drug Administration (FDA). Agent or Representative: an organization appointed by a DMF holder to serve as the contact for the holder. Applicant: the organization submitting a regulatory document to the FDA in order to obtain FDA approval of a new drug or biological product and any organization owning an approved application. Application: any IND, NDA, ANDA, or BLA, including all amendments and supplements to the application. Certificate of Analysis (COA): a report for a given lot of an item, listing all of the applicable acceptance specification tolerances, together with the suppliers test result obtained for each listed specification. COAs are applicable to materials of construction and components. Certificate of Compliance (COC): a statement provided to a customer which certifies that an item has been or will be manufactured in accordance with established specifications an/or will comply with all applicable acceptance standards. cGMP: Current Good Manufacturing Practices as described in 21 CFR 210 and 211. Container closure system: the sum of packaging components that together contain and protect the dosage form. This includes primary and secondary packaging components, if the latter are intended to provide additional protection to the product. DMF Holder: a corporation and/or business that own a Drug Master File. Drug product: the dosage form in the final marketed package intended for sale. Extractable: a substance that may migrate from the package component and may be available to combine with the product. Letter of Authorization (LOA): a written statement by the DMF holder or designated agent or representative permitting FDA to refer to information in the DMF in support of another regulatory application.
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Materials of construction: the substances (e.g., glass, high-density polyethylene (HDPE) resin, metal) used to manufacture a packaging component. Packaging component: any single part of a container closure system. Packaging Material Name: simple general description of product discussed within the DMF. Packaging system: equivalent to a container closure system. Primary packaging component: a packaging component that is or may be in direct contact with the dosage form. Secondary packaging component: a packaging component that is not and will not be in direct contact with the dosage form. Sponsor: a person who takes responsibility for and initiates a clinical investigation. The sponsor may be an individual or pharmaceutical company, governmental agency, academic institution, private organization, or other organization. Sub-assembly component: a part of the package component that is added during some assembly process by the component supplier.

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iv.

Packaging Information that Should Be Submitted in Support of an Application

The Container Closure Guidance describes FDA requirements for packaging information to be contained in an application. This section applies to primary and secondary packaging components that provide protection to the drug. The type and extent of this information would depend on the dosage form and the route of administration. For example, packaging system information provided for an injectable dosage form or a drug product for inhalation is often more detailed and thorough than that which is provided for a solid oral dosage form. However, as outlined in Table 3 of the Container Closure guidance (See Appendix 2), there is general information that should be submitted in support of an original application for any drug product. The three primary categories of information expected are Description, Suitability, and Quality Control. This information may be submitted directly in the application by the applicant or by reference to a suppliers DMF.

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v.

Type III Drug Master Files

A. General Comments The responsibility for providing information about packaging components rests foremost with the applicant of a regulatory application. This information may be provided by the manufacturer of a packaging component or material of construction to the applicant who may include it directly in the application. The amount of information is dependent upon the dosage form. The appropriate guidance should be consulted.

Any information that a packaging component manufacturer does not wish to share with the applicant or sponsor (i.e., because it is considered proprietary) may be placed in a Type III DMF. It can then be incorporated by reference into the application by means of a letter from the DMF holder to FDA that authorizes reference to the DMF. Information in a Type III DMF is not restricted to data of a proprietary nature. DMF holders may include in their files as much or as little information as they choose. A manufacturer of a packaging component is not required to submit a Type III DMF. However, without a DMF there is no procedure for the Agency to review proprietary information except by submission in the drug product application. B. A Chain of Interlinked References 1. A drug or biologic application typically references the DMF(s) of the packaging component supplier(s) in the application to FDA for approval of a drug or biologic product. The application may also reference DMFs for suppliers of principal materials of construction (e.g., plastic resin).

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2. The DMF for a packaging component may reference one or more of the following additional DMFs: sub-assembly component (e.g., film, stopper) material of construction (e.g., plastic resin, coating, additive) treatment of a component

3. The DMF of a sub-assembly component may reference the DMF of material of construction. 4. The DMF for a material of construction may reference the DMF for ingredients of formulated material (e.g., additives). Basic raw materials (e.g., monomers of a resin, organic chemicals, inorganic fillers, etc.) are generally not covered by a DMF. 5. A model of the DMF system shows four options for providing required information for a packaging component. All four of these variations are in use as written or in combination. a. The supplier provides all necessary information to the applicant and the applicant incorporates the appropriate information into the application. b. The component supplier provides information to FDA in a DMF. The component supplier provides an LOA to the applicant. The applicant uses the LOA to cite the DMF. c. The component supplier provides information to FDA in a DMF. Likewise, ingredient and treatment suppliers provide information to FDA in their own DMFs. Ingredient and treatment suppliers provide LOAs to the component supplier who cites them in the component DMF. The component supplier provides an LOA for the component DMF, alone, to the applicant who uses that LOA to cite the DMF in the application. Therefore, the applicant does not provide LOAs for the ingredient and treatment suppliers DMFs.

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d. The component supplier provides information to FDA in a DMF. Likewise, ingredient and treatment suppliers provide information to FDA in their own DMFs. The component supplier provides an LOA to the applicant. Likewise, each ingredient and treatment supplier provides an LOA to the applicant. The applicant uses each of the LOAs to cite each DMF in the application. Points to consider 1. At any point in the chain, a supplier may choose to provide information directly to the applicant or a DMF Holder instead of using a DMF to protect the confidentiality of the information.

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VI. Letters of Authorization Before the FDA can review DMF information in support of an application, the DMF holder should submit to the Drug Master File Staff, in duplicate, a letter of authorization directing the FDA to review the DMF on behalf of the drug product applicant and in conjunction with the review of the application. The LOA should always be referred to as a Letter of Authorization. A copy of the LOA should be sent to the applicant to be submitted with the application. The LOA should include the following: 1. Date 2. Name of DMF holder 3. DMF number and Type (II, III, IV or V)
4.

Name of person(s) authorized to incorporate information in the DMF by reference4

5. Specific product(s) (e.g., packaging components) covered by the DMF 6. Original submission date and the dates of other relevant updates 7. Section numbers and/or pages numbers to be referenced 8. Statement of commitment that the DMF is current and that the DMF holder will comply with the statements made in it 9. Signature of authorizing official 10. Typed name and title of official authorizing reference to the DMF An example of a typical Letter of Authorization is provided in Appendix 4.

If the holder restricts the authorization to particular drug products, the list is required to include the name of each drug product and the application number, if known, to which the authorization applies. Reference: 21 CFR 314.420(d). 11 Revision 1

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VII. Drug Master File Practices The following highlights key points relevant to DMF practices as described in detail in the 1989 Guidance document. A. Drug Master File Review The agency will review information in a DMF When an applicant files an application and includes the appropriate LOA. Another DMF holder incorporates information in a subsequent DMF by reference.

NOTE: The FDA will notify the applicant when a deficiency has been found in the DMF.

Point to Consider 2. Often a contact at the applicant is unknown; therefore the DMF holder should be provided a contact person from the applicant, for the application, when the LOA is requested.

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B.

DMF Holder Obligations

Notification of change(s) to the Drug Master File Staff should include references to the volume(s), section(s), and page number(s) affected by the change. If the DMF holder makes a change that requires a change to the DMF, all persons authorized to reference the DMF section(s) affected by the change(s) should be notified. A Type III DMF is not approved or disapproved. However, a holder can receive a deficiency letter from the FDA. A deficiency generally indicates a lack of information in a specific area. Addressing deficiencies in the information provided in a DMF is typically the responsibility of the DMF holder. However, the FDA will notify the applicant when a deficiency has been found in a DMF Point to Consider 3. Other aspects of change control and timing of notification are outside of the scope of this Guideline. The appropriate guidance should be consulted regarding the timing and pertinence of changes with respect to notification to the applicant(s). The following is a list of common changes when notification should be considered. Practices that result in variation in any physical parameter Chemical composition of the materials of construction Introduction of new materials or changes to existing materials Manufacturing procedures Suppliers of materials of construction Manufacturing sites

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C. Annual Update Submitted on anniversary date of original submission. Includes the changes or additions previously discussed, unless previously submitted in a separate amendment. Includes an updated list of companies authorized to reference the DMF. Includes an updated list of persons authorized to incorporate information in the DMF including their name(s) and the type of information they are authorized to supply by reference. Point to Consider 4. Failure to update a DMF annually may result in a deficiency notice from FDA and may ultimately result in inactivation of the file by FDA. D. Appointment of an Agent International companies wanting to maintain a DMF may want to consider, although not required, appointing a US agent. The functions of an agent could include: Facilitating the original DMF submission Maintaining the DMF filing Issuing and tracking LOAs. Addressing deficiencies

When an agent is appointed, the holder should submit a signed letter of appointment to the DMF giving the agent's name, address, and scope of responsibility (administrative or scientific). Domestic DMF holders do not need to appoint an agent or representative.

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E. Responding to DMF Deficiencies The specific details of the deficiency will be communicated directly from the

FDA to the DMF holder. The FDA will notify the applicant when a deficiency has been found with a

specific DMF. The FDA may communicate the general area of deficiency to the applicant. Resolving a deficiency may require communication between the DMF holder and

the applicant. When the holder satisfactorily addresses FDA's deficiency letter, the holder

should notify the applicant that the deficiencies have been successfully addressed.

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Appendices Table of Contents

1. References ...............................................................................................................................17 2. Table 3 (FDA Container Closure Guidance) ..........................................................................18 3. Packaging Requirements .........................................................................................................19 4. Example of Letter of Authorization for a Type III DMF .......................................................21 5. Example of Type III DMF......................................................................................................22 6. Guideline for Drug Master Files.............................................................................................41 7. Container Closure Systems for Packaging Human Drugs and Biologics: Chemistry, Manufacturing, and Controls Documentation (Section V., pages 37, 38, and 39) ................58

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Appendix 1
References Part III - Guidance in Scientific and Technical Information http://www.fda.gov/cdrh/ode/338.pdf
1. 2. 3.

September, 1989 Guideline for Drug Master Files http://www.fda.gov/cder/guidance/dmf.htm

Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics http://www.fda.gov/cder/guidance/index.htm Guidance for Industry: Changes to an Approved NDA or ANDA (November 1999) and Questions and Answers (January 2001) http://www.fda.gov/cder/guidance/index.htm
4.

DRAFT Guidance for Industry: Submitting Type V Drug Master Files to the Center for Biologics Evaluation and Research http://www.fda/gov/cber/guidelines.htm
5.

6. Guideline for the Development of Type III Drug Master Files (DMFs). The Society of the Plastics Industry, Inc. (February, 1998)

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Appendix 2
Table 3 [See Reference 3.] Information That Should Be Submitted in an Original Application for Any Drug Product Description Overall general description of the container closure system, plus: For Each Packaging Component: Name, product code, manufacturer, physical description Materials of construction (for each: name, manufacturer, product code) Description of any additional treatments or preparations Suitability Protection: (By each component and/or the container closure system, as appropriate) Light exposure Reactive gases (e.g., oxygen) Moisture permeation Solvent loss or leakage Microbial contamination (sterility/container integrity, increased bioburden, microbial limits) Filth Other Safety: (for each material of construction, as appropriate) Chemical composition of all plastics, elastomers, adhesives, etc.a Extractables, as appropriate for the materialb Extraction/toxicological evaluation studies, as appropriate Appropriate USP testing Appropriate reference to the indirect food additive regulations (21 CFR 174-186) Other studies as appropriate Compatibility: (for each component and/or the packaging system, as appropriate) Component/dosage form interaction, USP methods are typically accepted May also be addressed in post-approval stability studies Performance: (for the assembled packaging system) Functionality and/or drug delivery, as appropriate For Each Packaging Component Received by the Applicant: Applicant's tests and acceptance criteriac Dimensional (drawing) and performance criteria Method to monitor consistency in composition, as appropriate

Quality Control

a b

For Each Packaging Component Provided by the Supplier: Manufacturer's acceptance criteria for release, as appropriate Brief description of the manufacturing process Stability See section III.C.4 Including any additives used in the manufacture of a packaging component See Attachment C for further discussion of extraction studies. Testing of plastics should be performed on the packaging component, not on the unformed resin. For a blow/fill/seal product, extractables should be evaluated on the formed drug product container itself. This also applies to a container closure system which is manufactured as part of the drug product manufacturing process.

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Note that an applicant's acceptance tests may include, among others, test parameters indicated under the description, suitability, and quality control sections of this table.

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Appendix 3
Packaging Requirements The following excerpt of Table 3 from the Container Closure Guidance is provided with comments on whether the information typically resides in the Type III DMF or drug product application and who is typically responsible for that information the Type III DMF holder or the drug product applicant. For the footnotes noted in this version of Table 3 from the Container Closure Guidance, please refer to Appendix 2. Point to Consider 5. The list provided below is not exhaustive. Additional information, such as manufacturing site(s) are typically provided in the DMF. In contrast, the address provided in an application is typically that of the administrative site (of the DMF).

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Appendix 3 Packaging Requirements (continued)

Item Description Overall general description of the container closure system, plus: For Each Packaging Component: Name, product code, manufacturer, physical description Materials of construction (for each: name, manufacturer, product code) Description of any additional treatments or preparations Protection: (By each component and/or the container closure system, as appropriate) Light exposure Reactive gases (e.g., oxygen) Moisture permeation Solvent loss or leakage Microbial contamination(sterility/container integrity, increased bioburden, microbial limits) Filth Other Safety: (for each material of construction, as appropriate) Chemical composition of all plastics, elastomers, adhesives, etc.a Extractables, as appropriate for the materialb Extraction/toxicological evaluation studies, as appropriate Appropriate USP testing Appropriate reference to the indirect food additive regulations (21 CFR 174-186) Other studies as appropriate Compatibility: (for each component and/or the packaging system, as appropriate) Component/dosage form interaction, USP methods are typically accepted May also be addressed in post-approval stability studies Performance: (for the assembled packaging system) Functionality and/or drug delivery, as appropriate For Each Packaging Component Received by the Applicant: Applicant's tests and acceptance criteriac Dimensional (drawing) and performance criteria Method to monitor consistency in composition, as appropriate Application DMF (Note 1) Required Required Required Required if performed by applicant Required If applicable If applicable If applicable If applicable If applicable Required If applicable Required Required Expected Optional if performed by the vendor Expected Expected Expected if performed by vendor

Suitability

Required Required Required

Quality Control

Required Required Required

For Each Packaging Component Provided by the Supplier: Expected Manufacturer's acceptance criteria for release, as appropriate Expected Brief description of the manufacturing process Note 1. The information provided by the DMF Holder is described as expected because DMFs are not required.

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Appendix 4
Example Letter of Authorization (Supplier Company Letterhead) Drug Master File Staff Central Document Room Food and Drug Administration 12229 Wilkins Avenue Rockville, Maryland 20852 Re: DMF 99999, Type III PVC resin abc123 PVC resin xyz456 Resin Maker and Company hereby authorizes Pharma Products Company to incorporate by reference DMF 99999 into any IND, NDA, or ANDA5 filed by Pharma Products Company. DMF 99999 was filed on October 24, 2001. Information about these materials is located in our initial submission in Sections I and IV and Amendment 001 submitted on January 15, 2002, in Section II, Pages 18-21. We hereby authorize your office to review the aforementioned specific information in DMF 99999 when considering any IND, IND Amendment, NDA, ANDA, or supplement filed by Pharma Products Company. We request that all information in this file be treated as confidential to the extent possible in accordance with 21 CFR 314.430 and 21 CFR 20.61, and that no information from this file be provided to any unauthorized persons without our written consent. The materials furnished will be manufactured in accordance with DMF 99999 and in compliance with good manufacturing practices. The DMF holder states that DMF 99999 is current and the holder will comply with the statements made within it. Notification to Pharma Products Company and an appropriate notification to FDA and this file will be made for changes that impact the subject materials of this letter. Sincerely, John Doe Manager, Regulatory Affairs Resin Maker and Company cc: Jane Smith, Packaging Engineer Pharma Products Company March 26, 2002

If the holder restricts the authorization to particular drug products, the list is required to include the name of each drug product and the application number, if known, to which the authorization applies. 22 Revision 1

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Appendix 5
Example of a Type III DMF The following appendix contains an example of a Type III DMF based on a closure intended for use with solid oral dosage and liquid oral dosage form products. In some cases, an example of a section is provided to assist the user of this Guideline.

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Binder Cover (Original Submission)

The binder cover (Available as Form FDA 3316a, blue review binder; and Form FDA 3316, red archive binder), includes the following information:

1. Name of company that is submitting the DMF 2. The type of DMF and subject matter title 3. Volume number and the total number of volumes

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[Example Binder Cover]

Volume _____________

DRUG MASTER FILE No. ___________ [Name of DMF Holder]

TYPE:

This submission: Volume ____ of ______ Volumes

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Statement of Commitment [Name of Company] closures division declares that the statements, manufacturing procedures, and controls provided in this Drug Master File will be followed in the manufacture and release of each component described herein. Further, [Name of Company] closures division manufacturers the components according to applicable regulations.

________________________________________________________ [Title and signature of appropriate company official]

___________________ [Date]

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Introduction

Examples of information included in the Introduction are the following:

1. Brief description of the packaging component and/or materials of construction 2. Brief description of the manufacturing process used to produce the product 3. Statement of confidentiality

[Example Introduction] Product Description: [Name of Company] closures division manufactures closure systems that are used in the food, drug, and chemical industries. The closure is then applied to a bottle, containing product by a food, drug or chemical company. The closure acts as barrier to contamination and may provide protective properties. Process Description: [Name of Company] closures division manufactures closure systems by injection molding and mechanized assembly of secondary components and liners. Products are manufactured of thermoplastics, colorants and chemical additives. Confidentiality: Information presented in this DMF is confidential and should be treated as confidential to the extent possible in accordance with 21 CFR 314.430 and 21 CFR 20.61. Information from this file should not be provided to any unauthorized persons without the written consent of [Name of Company or Agent].

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Table of Contents A Table of Contents in sufficient detail to allow the reviewer to find sections easily and quickly is recommended. The following example aligns with the subsequent examples in this Guideline. [Example Table of Contents] TYPE III DMF TABLE OF CONTENTS Section A. Page

Administrative Information ..........................................................................................28 1. DMF Holder 2. Corporate Headquarters 3. Manufacturing/Processing Facilities 4. Contact for FDA Correspondence 5. Assignment of Agent

B. Persons Authorized to Incorporate DMF by Reference .....................................................29 C. Descriptive Information .....................................................................................................30 D. Manufacturing Process .......................................................................................................33 E. Specifications .....................................................................................................................34 F. Test Methods ......................................................................................................................36 G. Quality Systems ..................................................................................................................37 H. Appendices .........................................................................................................................39

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A. Administrative Information 1. Name and address of the DMF holder 2. Address of corporate headquarters 3. Manufacturing or processing facility address(es) (Each manufacturing site may maintain a unique DMF) 4. Name and address of the contact for FDA correspondence and the title of that person 5. Name and address of Agent, if applicable (Refer to Appendix A.)

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B. Persons Authorized to Incorporate the DMF by Reference Provide the following information about persons authorized to incorporate information in the DMF by reference. The information should be in a list format and should identify by name (or code) the information that each person is authorized to incorporate and give the location of that information by date, volume, and page number. Authorized Person Company ABC Description and location of information referenced 2-piece Child Resistant Closures described in Sections 1, 2, 3 Referencing Drug Product and Application number6 Pharma Drug XYX, NDA 99-9999

If the holder restricts the authorization to particular drug products, the list is required to include the name of each drug product and the application number, if known, to which the authorization applies. Reference: 21 CFR 314.420(d) 30 Revision 1

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C. Descriptive Information
a.

Description of the package component. Identification by product name, product code (if

available), a physical description of the packaging component (e.g., type, size, shape, and color).
b.

Identification of the materials of construction: Identify plastics, paper, metal, glass,

elastomers, coatings, adhesives, and other such materials by a specific product designation (supplier/trade name or product number) and the source (name of the manufacturer). If applicable, an appropriate reference to other Type III Drug Master Files should be provided, and a letter of authorization should be included in an Appendix.
c.

Alternate, interchangeable materials of construction: Some DMFs identify and describe

alternate suppliers of materials of construction. Providing the appropriate data and information that will provide for use of alternate, interchangeable materials of construction should be considered. In some cases, an interchangeability protocol is provided.

Points to consider 6. Use of alternate suppliers or materials could pose significant issues to end users and may require reporting these changes to FDA in accordance with the Post Approval Change 7. Guidance. Some DMFs do not provide a specific product code or section for each component in the DMF; rather the components are classified by group or function. Specific information about the component may, then, be provided in a separate, auxiliary document (e.g., Materials Disclosure Memo) in which the component is described in a manner that allows the applicant to cross-reference more general information in the DMF.

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[Example of Descriptive Information] Component Description Product Name XYZ Two Piece Closure XYZ Two Piece Closure Product Designation XYZ 28-400 XYZ 33-400

Materials of Construction All materials are in compliance with Federal Regulation 21 CFR, Paragraph(s) xxx.xxx. Refer to Appendix B for supplier letters of compliance and Appendix C for letters of authorization to DMFs. Plastic Resins: Outer and Inner Shells The outer shell is molded from high density polyethylene with the tensile strength of xxxx to xxxx psi and the specific gravity of .xxx to xxx. The primary supplier of the polyethylene resin meeting these specifications is: Company [Company Name and Address] Product Name [Product Name] Product Designation [Product Designation] DMF Reference [DMF number]

Alternate suppliers of the polyethylene resin meeting these specifications are: Company [Company Name and Address] Product Name [Product Name] Product Designation [Product Designation] DMF Reference [DMF number]

The inner shell is molded from polypropylene with the tensile strength of xxxx to xxxx psi and the specific gravity of .xxx to xxx. The primary supplier of the polypropylene resin meeting these specifications is: Company [Company Name and Address] Product Name [Product Name] Product Designation [Product Designation] DMF Reference [DMF number]

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[Example of Descriptive Information, continued] The alternate supplier of the polypropylene resin meeting these specifications is: Company [Company Name and Address] Product Name [Product Name] Product Designation [Product Designation] DMF Reference [DMF number]

Colorants: White #xxxx The outer shell includes a white colorant supplied by: XXXX that contains a carrier, XXX and lubricant XXX, which may meet Federal Regulation 21 CFR XXX.XXX. The primary supplier of the colorant meeting these specifications is: Company [Company Name and Address] Product Name [Product Name] Product Designation [Product Designation] DMF Reference [DMF number]

Closure Liner(s) Material(s): The liner <material> is supplied by XXXX and is constructed of the following laminations, which may meet Federal Regulation 21 CFR XXX.XXX. The primary supplier of the liner meeting these specifications is: Company [Company Name and Address] Product Name [Product Name] Product Designation [Product Designation] DMF Reference [DMF number]

[Or, the following, separate section may be appropriate for alternate suppliers] Alternate Suppliers Currently, no alternate suppliers have been identified for any of the materials of construction.

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D. Manufacturing Process Description This description should include the appropriate detail so that the process is adequately described. Each process covered by the DMF should be described separately. Additional treatments performed as part of the process or after the process, such as processes for cleaning, washing, or treating the final packaging component or material of construction should be included.

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E. Specifications 1. Characterization of the key properties 2. If toxicological and safety data are not readily available by cross-reference, appropriate data should be provided.
3.

General description of the acceptance, in process, and release controls for materials of

construction and the finished product (component part or assembled component). Point to Consider 8. Data on packaging generated in accordance with a compendium (e.g., USP <381>, <661>, or <671>) are provided to FDA in regulatory applications. The applications also include references documenting the FDA food-contact compliance of the packaging (e.g., references to the applicable food additive regulations, 21 CFR 174-186). This may be accomplished by including the data or appropriate references in the application or by providing references to DMFs. Applicants may request a letter of compliance from a vendor with respect to food-contact compliance, but will, generally, not provide the letter to FDA, unless requested. Applicants also expect DMF holders to obtain appropriate information from suppliers of components and materials of construction for the products covered by the DMF, that is, references to the applicable food-contact status. The specific nature of the compendial data will vary according to the dosage form and the packaging material, and the references to food-contact status will vary according to the packaging material. Applicants prefer that DMF holders include in the DMF any compendial data generated by the holder and data pertaining to or references to the food-contact status of the products covered by the DMF. Changes in this type of information, if it is included in the DMF, must be reflected in amendments to the DMF with appropriate notice to applicants authorized to reference the information.

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[Example of Specifications] XYZ 33-400 Two Piece Closure [Characterization of the key properties] The two-piece closures are molded from resins that vendors certify to be in compliance with 21 CFR XXX.XXX. The key properties of the closure and the materials of construction are to provide sealing requirements for use with glass and plastic containers. [Supporting data] When applied properly the two-piece closure has shown to provide excellent sealing qualities as determined by xxxx leak testing. The closure also has excellent torque retention based on xxxx torque testing. All materials of construction comply with xxxxx safety standards. [Product Acceptance Criteria] Incoming Raw Materials All materials of construction are tested in accordance with our quality standards and are certified to be in compliance with xxxx. a. [Resin] each lot used for xxxx is verified by certificate of analysis, xxx identification and xxx tests to assure correct material and that xxx are within specifications. b. [Additive 1..] is verified by certificate of analysis and xxx for each lot received. c. Additional materials, e.g., liners, etc. Final product inspection and release a. Specifications [may be stated in accordance with current MIL STD or ANSI/ASQC Z1.4]. (For example, dimensional, particulates, extractables, etc.) b. Final inspections are performed by xxx personnel at the xxx process by verifying product, product quantities, labeling, and packaging parameters.

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F. Test Methods 1. Test methods for materials of construction 2. Test methods for in-process materials (e.g., sub-assemblies, treatments, etc.) 3. Test methods for supplier products, (incoming materials) or appropriate reference to contract lab methods 4. Test methods for packaging component

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G. Quality Systems 1. Dimensional and performance criteria (Provide drawings, dimensional information, performance test data, as appropriate.) 2. General Description of Quality Control Systems

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3. [Example of Quality Systems] Xxx Company has an established and maintained system of complete traceability of all raw materials used in the manufacture of products produced by process xxxx. Product xxx is typically packaged in [corrugated boxes using a polyethylene bag liner and twist ties unless otherwise specified by the customer. Cartons are sealed with gum backed tape. Each carton is identified with a 5 by 5 inch gum backed label listing the appropriate information. 1. Product xxx is manufactured in accordance with xxxx Manufacturing Specifications. This includes all manufacturing processes. All Manufacturing Specifications are derived from customer, industry specific, state, and federal requirements. 2. Xxxx Company Manufacturing Quality Systems include the following; a. b. c. d. e. Bills of materials Specified tooling and part drawings Packaging requirements and configurations Special operating instructions Inspection plans

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H. Appendices Provide as appropriate to the DMF. Example Appendices [Example TOC of Appendices] A. B. C. Agent letter Letters of Compliance Letters of Authorization

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Appendix 6

Guideline for Drug Master Files

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GUIDELINE FOR DRUG MASTER FILES

Center for Drug Evaluation and Research Food and Drug Administration Department of Health and Human Services September 1989

For further information regarding the guideline please contact: Food and Drug Administration Center for Drug Evaluation and Research Office of Drug Evaluation I (HFD-100) 5600 Fishers Lane Rockville, Maryland 20857 (301-827-7310)

Note: This Guideline was prepared by Dr. Arthur Shaw, Food and Drug Administration, for a Course offered by the Center for Professional Advancement in March of 1994. There have been no changes in the text from the printed version of the Guideline. However the text has been reformatted to reduce the number of pages.

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TABLE OF CONTENTS
I. INTRODUCTION II. DEFINITIONS III. TYPES OF DRUG MASTER FILES IV. SUBMISSIONS TO DRUG MASTER FILES
A. Transmittal Letters 1. Original Submissions 2. Amendments B. Administrative Information 1. Original Submissions 2. Amendments C. Drug Master File Contents 1. Types of Drug Master Files a. Type I: Manufacturing Site, Facilities, Operating Procedures, and Personnel b. Type II: Drug Substance, Drug Substance Intermediate, and Material Used in Their Preparation, or Drug Product c. Type III: Packaging Material d. Type IV: Excipient, Colorant, Flavor, Essence, or Material Used in Their Preparation e. Type V: FDA Accepted Reference Information 2. General Information and Suggestions a. Environmental Assessment b. Stability D. Format, Assembly, and Delivery

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V. AUTHORIZATION TO REFER TO A DRUG MASTER FILE

A. Letter of Authorization to FDA B. Copy to Applicant, Sponsor, or Other Holder

VI. PROCESSING AND REVIEWING POLICIES

A. Policies Related to Processing Drug Master Files B. Drug Master File Review

VII. HOLDER OBLIGATIONS

A. Notice Required for Changes to a Drug Master File B. Listing of Persons Authorized To Refer to a Drug Master File C. Annual Update D. Appointment of an Agent E. Transfer of Ownership

VIII. MAJOR REORGANIZATION OF A DRUG MASTER FILE IX. CLOSURE OF A DRUG MASTER FILE

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GUIDELINE FOR DRUG MASTER FILES

I. INTRODUCTION
A Drug Master File (DMF) is a submission to the Food and Drug Administration (FDA) that may be used to provide confidential detailed information about facilities, processes, or articles used in the manufacturing, processing, packaging, and storing of one or more human drugs. The submission of a DMF is not required by law or FDA regulation. A DMF is submitted solely at the discretion of the holder. The information contained in the DMF may be used to support an Investigational New Drug Application (IND), a New Drug Application (NDA), an Abbreviated New Drug Application (ANDA), another DMF, an Export Application, or amendments and supplements to any of these. A DMF is NOT a substitute for an IND, NDA, ANDA, or Export Application. It is not approved or disapproved. Technical contents of a DMF are reviewed only in connection with the review of an IND, NDA, ANDA, or an Export Application. This guideline does not impose mandatory requirements (21 CFR 10.90(b)). It does, however, offer guidance on acceptable approaches to meeting regulatory requirements. Different approaches may be followed, but the applicant is encouraged to discuss significant variations in advance with FDA reviewers to preclude spending time and effort in preparing a submission that FDA may later determine to be unacceptable. Drug Master Files are provided for in 21 CFR 314.420. This guideline is intended to provide DMF holders with procedures acceptable to the agency for preparing and submitting a DMF. The guideline discusses types of DMF's, the information needed in each type, the format of submissions to a DMF, the administrative procedures governing review of DMF's, and the obligations of the DMF holder. DMF's are generally created to allow a party other than the holder of the DMF to reference material without disclosing to that party the contents of the file. When an applicant references its own material, the applicant should reference the information contained in its own IND, NDA, or ANDA directly rather than establishing a new DMF.

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II. DEFINITIONS
For the purposes of this guideline, the following definitions apply: 1. Agency means the Food and Drug Administration. 2 Agent or representative means any person who is appointed by a DMF holder to serve as the contact for the holder. 3. Applicant means any person who submits an application or abbreviated application or an amendment or supplement to them to obtain FDA approval of a new drug or an antibiotic drug and any other person who owns an approved application (21 CFR 314.3 (b)). 4. Drug product means a finished dosage form, for example, tablet, capsule, or solution, that contains a drug substance, generally, but not necessarily, in association with one or more other ingredients (21 CFR 314.3 (b)). 5. Drug substance means an active ingredient that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of the human body, but does not include intermediates used in the synthesis of such ingredient (21 CFR 314.3 (b)). 6. Export application means an application submitted under section 802 of the Federal Food, Drug, and Cosmetic Act to export a drug that is not approved for marketing in the United States. 7. Holder means a person who owns a DMF. 8. Letter of authorization means a written statement by the holder or designated agent or representative permitting FDA to refer to information in the DMF in support of another person's submission. 9. Person includes individual, partnership, corporation, and association. (Section 201(e) of the Federal Food, Drug, and Cosmetic Act.) 10. Sponsor means a person who takes responsibility for and initiates a clinical investigation. The sponsor may be an individual or pharmaceutical company, governmental agency, academic institution, private organization, or other organization (21 CFR 312.3 (b)).

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III.TYPES OF DRUG MASTER FILES

There are five types of DMF's: Type I Type II Manufacturing Site, Facilities, Operating Procedures, and Personnel Drug Substance, Drug Substance Intermediate, and Material Used in Their Preparation, or Drug Product Type III Packaging Material Type IV Excipient, Colorant, Flavor, Essence, or Material Used in Their Preparation Type V FDA Accepted Reference Information Each DMF should contain only one type of information and all supporting data. See Section IV.C of the guideline for more detailed descriptions of the kind of information desired in each type. Supporting information and data in a DMF can be cross referenced to any other DMF (see Part V).

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IV. SUBMISSIONS TO DRUG MASTER FILES

Each DMF submission should contain a transmittal letter, administrative information about the submission, and the specific information to be included in the DMF as described in this section. The DMF must be in the English language. Whenever a submission contains information in another language, an accurate certified English translation must also be included. Each page of each copy of the DMF should be dated and consecutively numbered. An updated table of contents should be included with each submission.

A. Transmittal Letters
The following should be included:

1. Original Submissions
a.

Identification of submission: Original, the type of DMF as classified in Section III, and its subject. b. Identification of the applications, if known, that the DMF is intended to support, including the name and address of each sponsor, applicant, or holder, and all relevant document numbers. c. Signature of the holder or the authorized representative. d. Typewritten name and title of the signer.

2. Amendments
a. Identification of submission: Amendment, the DMF number, type of DMF, and the subject of the amendment. b. A description of the purpose of submission, e.g., update, revised formula, or revised process. c. Signature of the holder or the authorized representative. d. Typewritten name and title of the signer.

B. Administrative Information
Administrative information should include the following:

1. Original Submissions
a. Names and addresses of the following: (1) DMF holder. (2) Corporate headquarters. (3) Manufacturing/processing facility. (4) Contact for FDA correspondence. (5) Agent(s), if any. b. The specific responsibilities of each person listed in any of the categories in Section a. c. Statement of commitment. A signed statement by the holder certifying that the DMF is current and that the DMF holder will comply with the statements made in it.

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2. Amendments
a. b. c. d. e. Name of DMF holder. DMF number. Name and address for correspondence. Affected section and/or page numbers of the DMF. The name and address of each person whose IND, NDA, ANDA, DMF, or Export Application relies on the subject of the amendment for support. f. The number of each IND, NDA, ANDA, DMF, and Export Application that relies on the subject of the amendment for support, if known. g. Particular items within the IND, NDA, ANDA, DMF, and Export Application that are affected, if known.

C. Drug Master File Contents 1. Types of Drug Master Files a. Type I: Manufacturing Site, Facilities, Operating Procedures, and Personnel
A Type I DMF is recommended for a person outside of the United States to assist FDA in conducting on site inspections of their manufacturing facilities. The DMF should describe the manufacturing site, equipment capabilities, and operational layout. A Type I DMF is normally not needed to describe domestic facilities, except in special cases, such as when a person is not registered and not routinely inspected. The description of the site should include acreage, actual site address, and a map showing its location with respect to the nearest city. An aerial photograph and a diagram of the site may be helpful. A diagram of major production and processing areas is helpful for understanding the operational layout. Major equipment should be described in terms of capabilities, application, and location. Make and model would not normally be needed unless the equipment is new or unique. A diagram of major corporate organizational elements, with key manufacturing, quality control, and quality assurance positions highlighted, at both the manufacturing site and corporate headquarters, is also helpful.

b. Type II: Drug Substance, Drug Substance Intermediate, and Material Used in Their Preparation, or Drug Product
A Type II DMF should, in general, be limited to a single drug intermediate, drug substance, drug product, or type of material used in their preparation.

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(1) Drug Substance Intermediates, Drug Substances, and Material Used in Their Preparation
Summarize all significant steps in the manufacturing and controls of the drug intermediate or substance. Detailed guidance on what should be included in a Type II DMF for drug substances and intermediates may be found in the following guidelines: Guideline for Submitting Supporting Documentation in Drug Applications for the Manufacture of Drug Substances. Guideline for the Format and Content of the Chemistry, Manufacturing, and Controls Section of an Application.

(2) Drug Product

Manufacturing procedures and controls for finished dosage forms should ordinarily be submitted in an IND, NDA, ANDA, or Export Application. If this information cannot be submitted in an IND, NDA, ANDA, or Export Application, it should be submitted in a DMF. When a Type II DMF is submitted for a drug product, the applicant/sponsor should follow the guidance provided in the following guidelines: Guideline for the Format and Content of the Chemistry, Manufacturing, and Controls Section of an Application. Guideline for Submitting Documentation for the Manufacture of and Controls for Drug Products Guideline for Submitting Samples and Analytical Data for Methods Validation

c. Type III: Packaging Material

Each packaging material should be identified by the intended use, components, composition, and controls for its release. The names of the suppliers or fabricators of the components used in preparing the packaging material and the acceptance specifications should also be given. Data supporting the acceptability of the packaging material for its intended use should also be submitted as outlined in the "Guideline for Submitting Documentation for Packaging for Human Drugs and Biologics." Toxicological data on these materials would be included under this type of DMF, if not otherwise available by cross reference to another document.

d. Type IV: Excipient, Colorant, Flavor, Essence, or Material Used in Their Preparation
Each additive should be identified and characterized by its method of manufacture, release specifications, and testing methods.

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Toxicological data on these materials would be included under this type of DMF, if not otherwise available by cross reference to another document. Usually, the official compendia and FDA regulations for color additives (21 CFR Parts 70 through 82), direct food additives (21 CFR Parts 170 through 173), indirect food additives (21 CFR Parts 174 through 178), and food substances (21 CFR Parts 181 through 186) may be used as sources for release tests, specifications, and safety. Guidelines suggested for a Type II DMF may be helpful for preparing a Type IV DMF. The DMF should include any other supporting information and data that are not available by cross reference to another document.

e. Type V: FDA Accepted Reference Information

FDA discourages the use of Type V DMF's for miscellaneous information, duplicate information, or information that should be included in one of the other types of DMF's. If any holder wishes to submit information and supporting data in a DMF that is not covered by Types I through IV, a holder must first submit a letter of intent to the Drug Master File Staff (for address, see D.5.a. of this section). FDA will then contact the holder to discuss the proposed submission.

2. General Information and Suggestions a. Environmental Assessment

Type II, Type III, and Type IV DMF's should contain a commitment by the firm that its facilities will be operated in compliance with applicable environmental laws. If a completed environmental assessment is needed, see 21 CFR Part 25.

b. Stability
Stability study design, data, interpretation, and other information should be submitted, when applicable, as outlined in the "Guideline for Submitting Documentation for the Stability of Human Drugs and Biologics."

D. Format, Assembly, and Delivery 1. An original and duplicate are to be submitted for all DMF submissions.
Drug Master File holders and their agents/representatives should retain a complete reference copy that is identical to, and maintained in the same chronological order as, their submissions to FDA.

2. The original and duplicate copies must be collated, fully assembled, and individually jacketed.
Each volume of a DMF should, in general, be no more than 2 inches thick. For multivolume submissions, number each volume. For example, for a 3 volume submission, the volumes would be numbered 1 of 3, 2 of 3, and 3 of 3.

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3. U.S. Standard Paper

U.S. standard paper size (8-1/2 by 11 inches) is preferred. Paper length should not be less than 10 inches nor more than 12 inches. However, it may occasionally be necessary to use individual pages larger than standard paper size to present a floor plan, synthesis diagram, batch formula, or manufacturing instructions. Those pages should be folded and mounted to allow the page to be opened for review without disassembling the jacket and refolded without damage when the volume is shelved. See Figures 1 and 2 [in the original guidance].

4. The Agency's System

The agency's system for filing DMF's provides for assembly on the left side of the page. The left margin should be at least three fourths of an inch to assure that text is not obscured in the fastened area. The right margin should be at least one half of an inch. The submitter should punch holes 8 1/2 inches apart in each page. See the page measurements shown in Figure 3 [in the original guidance].

5. Delivery to FDA a. Drug Master File submissions and correspondence should be addressed as follows:
Drug Master File Staff Food and Drug Administration 12229 Wilkins Avenue Rockville MD 20852

b. Delivery charges to the above address must be prepaid.

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V. AUTHORIZATION TO REFER TO A DRUG MASTER FILE A. Letter of Authorization to FDA

Before FDA can review DMF information in support of an application, the DMF holder must submit in duplicate to the DMF a letter of authorization permitting FDA to reference the DMF. If the holder cross references its own DMF, the holder should supply in a letter of authorization the information designated by items 3, 5, 6, 7, and 8 of this section. The holder does not need to send a transmittal letter with its letter of authorization. The letter of authorization should include the following: 1. The date. 2. Name of DMF holder. 3. DMF number. 4. Name of person(s) authorized to incorporate information in the DMF by reference. 5. Specific product(s) covered by the DMF. 6. Submission date(s) of 5, above. 7. Section numbers and/or page numbers to be referenced. 8. Statement of commitment that the DMF is current and that the DMF holder will comply with the statements made in it. 9. Signature of authorizing official. 10. Typed name and title of official authorizing reference to the DMF.

B. Copy to Applicant, Sponsor, or Other Holder

The holder should also send a copy of the letter of authorization to the affected applicant, sponsor, or other holder who is authorized to incorporate by reference the specific information contained in the DMF. The applicant, sponsor, or other holder referencing a DMF is required to include a copy of the DMF holder's letter of authorization in the application.

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VI. PROCESSING AND REVIEWING POLICIES A. Policies Related to Processing Drug Master Files
1. Public availability of the information and data in a DMF is determined under 21 CFR Part 20, 21 CFR 314.420(e), and 21 CFR 314.430. 2. An original DMF submission will be examined on receipt to determine whether it meets minimum requirements for format and content. If the submission is administratively acceptable, FDA will acknowledge its receipt and assign it a DMF number. If the submission is administratively incomplete or inadequate, it will be returned to the submitter with a letter of explanation from the Drug Master File Staff, and it will not be assigned a DMF number.

B. Drug Master File Review

A DMF IS NEVER APPROVED OR DISAPPROVED. The agency will review information in a DMF only when an IND sponsor, an applicant for an NDA, ANDA, or Export Application, or another DMF holder incorporates material in the DMF by reference. As noted, the incorporation by reference must be accompanied by a copy of the DMF holder's letter of authorization. If FDA reviewers find deficiencies in the information provided in a DMF, a letter describing the deficiencies is sent to the DMF holder. At the same time, FDA will notify the person who relies on the information in the deficient DMF that additional information is needed in the supporting DMF. The general subject of the deficiency is identified, but details of the deficiency are disclosed only to the DMF holder. When the holder submits the requested information to the DMF in response to the agency's deficiency letter, the holder should also send a copy of the accompanying transmittal letter to the affected persons relying on the DMF and to the FDA reviewing division that identified the deficiencies. The transmittal letter will provide notice that the deficiencies have been addressed.

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VII. HOLDER OBLIGATIONS

Any change or addition, including a change in authorization related to specific customers, should be submitted in duplicate and adequately cross referenced to previous submission(s). The reference should include the date(s), volume(s), section(s), and/or page number(s) affected.

A. Notice Required for Changes to a Drug Master File

A holder must notify each affected applicant or sponsor who has referenced its DMF of any pertinent change in the DMF (21 CFR 314. 420(c)). Notice should be provided well before making the change in order to permit the sponsor/applicant to supplement or amend any affected application(s) as needed.

B. Listing of Persons Authorized To Refer to a Drug Master File

1. A DMF is required to contain a complete list of persons authorized to incorporate information in the DMF by reference [21 CFR 314.420(d)]. The holder should update the list in the annual update. The updated list should contain the holder's name, DMF number, and the date of the update. The update should identify by name (or code) the information that each person is authorized to incorporate and give the location of that information by date, volume, and page number. 2. Any person whose authorization has been withdrawn during the previous year should be identified under a suitable caption. 3. If the list is unchanged on the anniversary date, the DMF holder should also submit a statement that the list is current.

C. Annual Update
The holder should provide an annual report on the anniversary date of the original submission. This report should contain the required list as described in B.1., and should also identify all changes and additional information incorporated into the DMF since the previous annual report on the subject matter of the DMF. If the subject matter of the DMF is unchanged, the DMF holder should provide a statement that the subject matter of the DMF is current. Failure to update or to assure FDA annually that previously submitted material and lists in the DMF remain current can cause delays in FDA review of a pending IND, NDA, ANDA, Export Application, or any amendment or supplement to such application; and FDA can initiate procedures for closure of the DMF (see Section IX).

D. Appointment of an Agent
When an agent is appointed, the holder should submit a signed letter of appointment to the DMF giving the agent's name, address, and scope of responsibility (administrative and/or scientific). Domestic DMF holders do not need to appoint an agent or representative, although foreign DMF holders are encouraged to engage a U.S. agent.

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E. Transfer of Ownership
To transfer ownership of a DMF to another party, the holder should so notify FDA and authorized persons in writing. The letter should include the following: 1. 2. 3. 4. 5. 6. Name of transferee Address of transferee Name of responsible official of transferee Effective date of transfer Signature of the transferring official Typewritten name and title of the transferring official.

The new holder should submit a letter of acceptance of the transfer and an update of the information contained in the DMF, where appropriate. Any change relating to the new ownership (e.g., plant location and methods) should be included.

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VIII. MAJOR REORGANIZATION OF A DRUG MASTER FILE

A holder who plans a major reorganization of a DMF is encouraged to submit a detailed plan of the proposed changes and request its review by the Drug Master File Staff. The staff should be given sufficient time to comment and provide suggestions before a major reorganization is undertaken.

IX. CLOSURE OF A DRUG MASTER FILE

A holder who wishes to close a DMF should submit a request to the Drug Master File Staff stating the reason for the closure. See Section IV.D.5.a for the address. The request should include a statement that the holder's obligations as detailed in Section VII have been fulfilled. The Agency may close a DMF that does not contain an annual update of persons authorized to incorporate information in the DMF by reference and a list of changes made since the previous annual report. The holder will be notified of FDA's intent to close the DMF. Many of the guidelines referred to in the text and a current list of available guidelines may be obtained from the following: Legislative, Professional, and Consumer Affairs Branch (HFD-365) Center for Drug Evaluation and Research Food and Drug Administration 5600 Fishers Lane Rockville, MD 20857 Copies of the Code of Federal Regulations (CFR) may be purchased from the following: Superintendent of Documents U.S. Government Printing Office Washington, D.C. 20402 FDA/Center for Drug Evaluation and Research Last Updated:June 28, 2001 Originator: CDER HTML by PKS

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Appendix 7

Container Closure Systems for Packaging Human Drugs and Biologics: Chemistry, Manufacturing, and Controls Documentation

(Section V., pages 37, 38, and 39)

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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 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, 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.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

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V. TYPE III DRUG MASTER FILES A. General Comments The responsibility for providing information about packaging components rests foremost with the applicant of an NDA, ANDA or BLA, or the sponsor of an IND. This information may be provided to the applicant by the manufacturer of a packaging component or material of construction and may be included directly in the application. Any information that a manufacturer does not wish to share with the applicant or sponsor (i.e., because it is considered proprietary) may be placed in a Type III DMF and incorporated into the application by a letter from the manufacturer to the applicant that authorizes reference to the DMF. The letter of authorization should specify the firm to whom authorization is granted, the component or material of construction being described, and where the information and/or data is located in the file by page number and/or date of submission. This last item is especially important for files that contain information on multiple components or have several volumes. Information in a Type III DMF is not restricted to data of a proprietary nature. DMF holders may include in their files as much or as little information as they choose. In addition, a manufacturer of a packaging component is not required to maintain a Type III DMF. Without a DMF there is no procedure for the Agency to review proprietary information except by submission to the application. The Agency ordinarily reviews a DMF only in connection with an application (IND, NDA, ANDA, or BLA). If the combined information from the application and the DMF is not adequate to support approval of the application or safety for the IND, then the Agency may request additional information from the applicant and/or the DMF holder, as appropriate. In the event of a change in the DMF, the holder of a DMF must notify the holder of each application supported by the DMF (21 CFR 314.420(c)). Notice should be provided well before the change is implemented to allow the applicant or sponsor enough time to file a supplement or an amendment to the affected application. General information on format and content of a DMF and a LOA may be found in the CDER Guideline for Drug Master Files (September 1989). B. Information in a Type III DMF Section III of this guidance describes the kind of descriptive, suitability, and quality control information which the Agency usually reviews concerning packaging components and materials of construction for drug products. The following are examples of the items that have been submitted via a Type III DMF.

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1. Descriptive Information: a. General description of the component and the address of the manufacturing site b. Description of the manufacturing process for a packaging component and operations performed after manufacture, but prior to shipment (washing, coating, sterilization or depyrogenation) c. Description of the acceptance, in-process, and release controls for materials of construction, the manufacturing process, and the finished product (component part or assembled component) d. Characterization of the key properties 2. Information About Suitability a. Protection provided by the component b. Safety information on the materials of construction or the finished component c. Compatibility of the materials of construction or the finished component with the specific dosage form, the specific drug product, or equivalent materials 3. Information About Quality Control: a. Dimensional (an engineering drawing) and performance criteria for the component b. A description of the quality control measures used to maintain consistency in the physical and chemical characteristics of packaging components c. A summary of the quality assurance/quality control criteria when release of the component is based on statistical process control

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