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Drugs and Health Products

Draft Guidance Document - Drug Master Files (DMFs)

2008-09-05
Our file number: 08-124317-334

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Contact: Bureau of Pharmaceutical Sciences (BPS) Enquiries

Notice

The draft version of this Health Canada guidance document Drug Master Files (DMF) is now available for comment. This guidance document is a revised version of the guidance document Product Master Files published in 1994 which will replace the 1994 document when it is officially adopted.

The guidance document has been updated to incorporate revisions and terminology resulting from the adoption of International Conference on Harmonization (ICH) guidelines. Where terminology is defined in the ICH guidance documents, no definition is given and the reader is referred to these guidelines. The guidance document includes direction on biotechnological/biological products, veterinary drug products and natural health products in addition to pharmaceuticals. Administrative requirements and procedures have been updated and clarified, and content requirements for all types of DMFs are more detailed or cross-referenced to relevant ICH and Health Canada guidelines where they exist.

This guidance supplements other Health Canada and ICH guidances and as such, all appropriate guidance documents related to DMFs should be consulted prior to submission.

Stakeholders intending to file or use a DMF should be aware of the following initiatives:

  1. The Therapeutic Products Directorate (TPD) of the Health Products and Food Branch (HPFB) of Health Canada has initiated a pilot project to accept Certificates of Suitability (CEPs) issued by the European Directorate for the Quality of Medicines and Healthcare (EDQM) of the Council of Europe for Active Pharmaceutical Ingredients (APIs). Stakeholders are requested to consult the Health Canada website for current information on acceptance of CEPs.

  2. Health Canada is in the process of implementing the ICH Q7 guideline. Upon implementation, evidence of GMP compliance will be required for API manufacturers. Requirements for cGMPidence and Establishment Licencing already apply to sites fabricating Schedule D (Biologic) Drug Substances. Stakeholders are requested to consult the Health Canada website for current information on considerations for implementation of the ICH Q7 guideline.

  3. The Bureau of Pharmaceutical Sciences within TPD is considering preliminary evaluation of type I DMFs in the Integrated Review Process. Stakeholders are requested to consult the Health Canada website for current information on this initiative.

Health Canada will review the comments received during this consultation and revise the Guidance as necessary. A final version of this document will then be posted.

Comments on this document should be forwarded within 60 calendar days to:

Email: bps_enquiries@hc-sc.gc.ca

or by Fax at (613) 957-3989.

Foreword

Guidance documents are meant to provide assistance to industry and health care professionals on how to comply with governing statutes and regulations. Guidance documents also provide assistance to staff on how Health Canada mandates and objectives should be implemented in a manner that is fair, consistent and effective.

Guidance documents are administrative instruments not having force of law and, as such, allow for flexibility in approach. Alternate approaches to the principles and practices described in this document may be acceptable provided they are supported by adequate justification. Alternate approaches should be discussed in advance with the relevant program area to avoid the possible finding that applicable statutory or regulatory requirements have not been met.

As a corollary to the above, it is equally important to note that Health Canada reserves the right to request information or material, or define conditions not specifically described in this document, in order to allow the Department to adequately assess the safety, efficacy or quality of a therapeutic product. Health Canada is committed to ensuring that such requests are justifiable and that decisions are clearly documented.

This document should be read in conjunction with the accompanying notice and the relevant sections of other applicable guidance documents.

Table of Contents

1. Introduction

1.1 Policy Objective

To assist in the preparation and the filing of Drug Master Files (DMFs) and to ensure that DMFs have the information necessary to support a drug submission.

1.2 Scope and application

This guidance document applies to all DMF owners and their authorized agent, sponsors of pharmaceutical or biological drug submissions using a DMF to support their application and Health Canada employees involved in the DMF processes.

Drug Master Files may be classified according to the following categories:

  • Type I: Drug substance or intermediate in the manufacture of a drug substance. This can include Active Pharmaceutical Ingredients (API), vaccine antigens, excipients of biological origin (with the exception of gelatin), adjuvants (except for alum) or albumin;
  • Type II: Container closure systems or components;
  • Type III: Excipients, colourants, flavours and other additives, including alum and growth media;
  • Type IV: Dosage forms and drug product intermediates (e.g. blend of drug substance and excipients).

This guidance provides:

  1. a description of administrative procedures related to Type I to IV DMFs;
  2. definitions of terms related to DMFs;
  3. the requirements for the submission, amendment, closure, update, and transfer of ownership of a DMF or appointment/change of an Authorized DMF Agent (hereafter the Agent);
  4. a description of the procedures used by Health Canada to process DMFs;
  5. a description of the procedure used by Health Canada to review DMFs;
  6. guidance on the information which should be submitted for Type I to IV DMFs;
  7. appendices showing samples of a commitment letter, an agent authorization letter, a DMF update letter, a BSE/TSE statement, letters of authorization to access a DMF and a checklist for the submission of a DMF.

1.3 Background

A Drug Master File (DMF) is a reference that provides information about specific processes or components used in the manufacturing, processing, and packaging of a drug.

The DMF is a useful vehicle for providing information to Health Canada, where that information is of a proprietary nature and is not available to the manufacturer of the dosage form, or to a Sponsor of a submission when they are not the dosage form manufacturer.

The DMF can be referenced by drug manufacturers in support of their New Drug Submissions (NDSs), Abbreviated New Drug Submissions (ANDSs), Supplement to a New Drug Submission (SNDS) Supplement to an Abbreviated New Drug Submission (SANDS), DIN submissions, Notifiable Changes (NCs), New Product Number (NPN) applications and Clinical Trial Applications (CTAs). DMFs may be referenced by more than one drug manufacturer.

The guidance document has been updated to incorporate revisions resulting from the adoption of International Conference on Harmonization (ICH) guidelines. The terminology used in this guidance document is the same as used in the ICH guidelines. Where terminology is defined in the ICH guidance documents no definition is given and the reader is referred to these guidelines.

2. Guidance for Implementation

2.1 Administrative Information

To submit a DMF, forward it to the address shown in Section 2.1.1, below. The DMF should be complete, containing all the names and addresses indicated in Section 2.1.2, below.

2.1.1 Forwarding Address

Submit a DMF to:

Drug Master File Administration Unit,
Therapeutic Products Directorate,
Finance Building, AL: 0201D,
101 promenade Tunney's Pasture Driveway,
Tunney's Pasture
Ottawa, Ontario
K1A 0K9
Canada

Email: dmf_enquiries@hc-sc.gc.ca
Fax number:  613-957-3989

2.1.2 Name and Address

The DMF should include the following information:

  • the name and address of the Agent if applicable;
  • the name and address of the corporate headquarters (DMF Owner); and
  • the name and address of manufacturing, processing, and packaging facilities.

2.1.3 Official Language of Correspondence

The DMF can be submitted in either English or French.

2.1.4 Confidentiality

The Government of Canada receives many trade secrets and other types of confidential business information belonging to third parties, such as drug manufacturers or suppliers that submit DMFs for drug products licensing approval.

Trade secrets and other confidential business information are considered financially valuable to the companies that provide it to Health Canada, and the federal government is required by law to assure that such information is not used or disclosed for unauthorized purposes. Within Health Canada, DMFs are kept confidential and only officials of Health Canada have permission to access these records. Therefore, data and other scientific or technical information are reviewed and filed in strict confidence.

In legal terms, this confidential business information belongs to the suppliers that generate it and it has traditionally been protected by intellectual property law. In Canada, intellectual property includes, in part, patents, trademarks, copyright and trade secrets.

However, submitted information which objectively qualifies as confidential business information is subject to the federal Next link will take you to another website Access to Information Act when there is a formal request made under that Act. Section 20 of the Act protects information that qualifies as third party commercial, scientific or technical information and is a mandatory exemption, which means that government institutions must not disclose certain third party information. This is true whether the circumstance is the provision of information for the public, such as adverse drug reaction or for a regulatory decision document, or when the drug product information is subject to an access to information request.

Section 20 of the Access to Information Act gives the government the authority to refuse to disclose information that meets the requirements in this section as is often the case for sponsors and/or DMF owners information.

Section 20 of the Access to Information Act effectively defines the scope of "third party confidential information" that accords persons certain rights and protections with respect to information under the control of a government institution.

2.1.5 Agents

When the DMF Owner is not based in North America, it is strongly recommended that a North American Agent be used in order to expedite communications. Refer to Section 2.2.6 regarding appointment of agents.

2.2 Submission and File Maintenance Requirements

All correspondence (e.g. cover letters, letters of authorization to access a DMF) should come from the DMF Owner or the Agent where applicable.

2.2.1 Submission

A DMF is submitted by a company or their Agent. A DMF should be submitted only in cases where the company does not wish to disclose confidential business information/trade secrets to the Sponsor of the drug submission.

A single copy of the DMF is required, together with one signed original of the covering letter, a copy thereof and one copy of the statement of commitment (see Appendix A). The DMF should be well-organized, bound and paginated, and should include a table of contents. No loose leaf sheets should be provided for any information submitted.

The information in the DMF will be used to support a drug submission only if the DMF Owner or Agent provide Health Canada with a signed original letter of authorization to access the DMF (hereafter the letter of access; see Appendix D). A separate letter is required for each Sponsor who cross-references the DMF. A copy of the letter of access should be forwarded to the Sponsor.

When a DMF filed in support of a drug submission references another DMF, all necessary authorizations should be provided at the time of filing to avoid any unnecessary delay. The letter(s) of access should be submitted with the DMF correspondence/forms.

If applicable, e.g. for drug substances, excipients and drug products, certification that the product is free from risk of TSE/BSE should be provided (see Appendix E).

The submission should be accompanied by the form "Drug Master File Application" and the appropriate fees and Fee Forms, which are available on the Health Canada Website. Refer to the Health Canada document Drug Master File Fees for information on fees and to download the forms.

The guidance document on Cost Recovery-Veterinary Drug Submission Evaluation Fees should be consulted by DMF Owners intending to file a DMF to be cross-referenced in a veterinary drug submission only. An attestation that the component described in the DMF will be used for veterinary drugs only should be included in the cover letter.

A checklist of information to be submitted has been provided for your convenience in Appendix F.

2.2.2 Summary of the DMF

The DMF should be accompanied by a summary of the contents. For Type I and IV DMFs, the summary should be in the format of the Quality Overall Summary (QOS) as described by the ICH guidelines. Summaries should follow a similar QOS format for Type II and III DMFs. In addition, an electronic copy of the summary should be provided on a diskette or CD in either Word« or WordPerfect« Format.

2.2.3 Closure or Withdrawal of the DMF

Should a DMF be withdrawn by the Owner, the Owner should advise Health Canada in writing and provide a list of the Canadian customers using their DMF. Any company with a letter of access to the DMF should be informed of its withdrawal by the DMF Owner. Health Canada will retain the withdrawn DMF or will dispose of it according to appropriate procedures established by Health Canada for record retention and disposal in accordance with the Library and Archives of Canada Act. Health Canada will close a DMF that has not been updated within a 5 year period (refer to Section 2.2.4). Sponsors using material which is the subject of the DMF will be informed that the source is not acceptable. If the DMF Owner wishes to reactivate the closed DMF, fees in the same amount as for a new DMF will need to be submitted, however the same DMF number will be kept. An update to the DMF should be submitted when reactivating the closed DMF. Details on how to update a DMF are provided below.

The guidance document on Cost Recovery-Veterinary Drug Submission Evaluation Fees should be consulted by DMF Owners intending to reactivate a DMF cross-referenced in a veterinary drug submission. A confirmation that the component described in the DMF will be used for veterinary drugs only should be included in the cover letter.

2.2.4 Amending and Updating the DMF

All amendments and updates should come from the DMF Owner or Agent and should be addressed to the DMF Administration Unit (see 2.1). In addition, the DMF Owner should notify each company with letter of access to the DMF of the changes so that Sponsors can update their records and file the appropriate notifications to Health Canada (e.g. Supplement to a New Drug Submission, Notifiable Change or Annual update) in accordance with the applicable guidance documents on Post-Notice of Compliance (NOC) changes.

2.2.4.1 Amendments

Amendments are changes to a DMF and include trade name changes, DMF name changes, manufacturing site or manufacturing process changes or addition of a manufacturing site. Technical and administrative amendments should be filed separately with changes highlighted where appropriate (e.g. in a side by side comparison). Amendments should be submitted at the earliest opportunity when they pertain to the quality of a component described in a DMF in accordance with the applicable guideline on changes to marketed products, e.g. Changes to Marketed New Drug Products.

A single copy of the amendments should be submitted, together with a signed original of the covering letter and a copy thereof. The covering letter should clearly indicate the DMF number, the Health Canada file number, the type of DMF (I, II, III or IV) and the sections of the DMF affected by the amendments. The form "Drug Master File Application" should accompany all amendments.

Amendments found in a Sponsor's submission are not added to the DMF. New data provided to the Sponsor by the DMF Owner should also be filed with the DMF.

Responses to a deficiency letter or clarification request (clarifax)

If the amendment is the result of deficiencies noted by Health Canada, the amendment should include a response to the deficiency comments in a question and answer format, along with an electronic copy of the response. The response should be filed with a signed original of the covering letter and a copy thereof.

DMF Owners and Agents should consult the TPD/BGTD/NHPD guidance to industry on Management of Drug Submissions or the VDD guidance to industry on Management of Regulatory Submissions where applicable as timeframes described therein will be applied to their response to Health Canada's correspondence (i.e. clarification request or a DMF deficiency notice/letter).

2.2.4.2 Updates

DMFs should be updated every five years from the date the original was submitted.

To update the DMF on the anniversary date the following information should be provided:

  1. Any recent changes not yet included in the DMF and a comparative table (see 2.2.4.1 Amendments). The accompanying cover letter should include a confirmation that this is to be considered as an update to the DMF and that no changes other than the ones described in the table have taken place since the last communication.

    or

  2. If no changes are made within five years, a letter indicating that the DMF remains current is considered satisfactory (see Appendix C).

An up-to-date list of all parties authorized to access the DMF should be submitted with each quinquennial update.

There is no need to resubmit an entire DMF at the time of updating unless changes to the DMF are extensive. In such an instance a completely revised DMF is to be submitted, the DMF should be revised according to the ICH CTD format.

All information submitted as an update should be bound (e.g. in basic 2 or 3 ring binders).

In the event that a DMF is not amended or correspondence is not received confirming that no changes have been made within 5 years, the file will be considered closed (see 2.2.3 Closure of DMFs).

2.2.5 Transfer of Ownership

The original DMF Owner should advise Health Canada in writing if ownership of the DMF is transferred for any reason, e.g. following a Buy-Out, a merger, a licensing agreement or a corporate restructuration. The notice should clearly indicate the name and address of the new DMF Owner. The new Owner should concurrently submit a letter accepting the transfer of ownership, confirmation that all letters of access remain valid, a new DMF Statement of Commitment, a DMF Fee Form and a DMF Application Form. It is not acceptable for Health Canada to receive notice of this transaction from only the new Owner.

Similarly, Health Canada should be advised of any company name change.

The guidance document on Cost Recovery-Veterinary Drug Submission Evaluation Fees should be consulted by DMF Owners intending to transfer ownership of a DMF cross-referenced in a veterinary drug submission. A confirmation that the component described in the DMF will be used for veterinary drugs only should be included in the cover letter.

2.2.6 Appointment or Change of the Authorized DMF Agent

If a company wishes to submit a DMF through an Agent, the company should clearly indicate the scope of that person's responsibility regarding:

  1. issuing letters of access,
  2. handling deficiencies in the file, and
  3. handling associated correspondence.

A sample Agent Authorization Letter is provided in Appendix B.

Health Canada should be notified in writing if the status of the Agent is changed. It is not the responsibility of Health Canada to provide duplicate information to a new appointee.

2.3 Processing of Drug Master Files

DMFs are processed in sequence according to date of receipt. A file number and DMF number are assigned only to a complete package. Within 30 days, a letter of acknowledgement is mailed to the DMF Owner or Agent, indicating that the DMF has been established.

The federal government is required by law to assure that confidential business information is not given to unauthorized recipients. As a result, Health Canada policy, outside the Access to Information Act context, prevents Health Canada from providing information about a DMF to anyone other than the DMF Owner or Agent (see section 2.1.4). In addition, correspondence concerning DMFs is not copied to sponsors.

2.4 Review of Drug Master Files

A DMF is reviewed only in connection with a specific drug submission. If a deficiency letter or clarifax has been sent to the Owner or Agent, as outlined below, the Sponsor will be notified in writing. However, the Sponsor will not be informed of the specific comments contained in the letter. DMF Owners and Agents should consult the TPD/BGTD/NHPD guidance to industry on Management of Drug Submissions or the VDD guidance to industry on Management of Regulatory Submissions where applicable as timeframes described therein will be applied to their response to Health Canada's correspondence. Failure to respond in the appropriate timeframe could result in the Sponsor's submission being rejected.

2.4.1 Type I

For Type I DMFs all confidential business information (Restricted Part)Footnote 1 is reviewed as part of the DMF. Non confidential business information (Sponsor's Part) is reviewed as part of the drug submission that the DMF supports.

All non confidential business information on the drug substance should be included in the drug submission (see Section 2.6). The Sponsor's Part of Type I DMFs may, therefore, be subject to discussions between Health Canada and the submission sponsor for whom you have authorized Health Canada to access your DMF.

Outside of the ATI regime, all communications with respect to the Restricted Part of the Type I DMF will be kept exclusively between the DMF Owner or Agent and Health Canada officials. If any comments are considered necessary concerning the Restricted Part of Type I DMF they will be forwarded directly to the DMF Owner or Agent in the form of a DMF deficiency letter or clarifax. If comments pertaining to the Sponsor's Part are considered to have an impact on the quality of the data generated by the DMF Owner (e.g. analytical methods supporting the stability data) they may also be forwarded to the DMF Owner or Agent.

When deficiencies are noted with the DMF Restricted Part, the Sponsor will be notified that there are outstanding issues that need to be addressed before the DMF can be considered acceptable to support their drug submission. Other Sponsors cross-referencing the deficient DMF for which a response to the DMF deficiency letter or clarifax has yet to be received will receive the same notice. No new deficiency letter will be issued to the DMF Owner or Agent unless new comments need to be forwarded (e.g. different requirements for API used in a different dosage form).

DMF Owners or Agents will not be informed that the DMF is acceptable to support the drug submission.

Type I DMF pre-evaluation

At the time a drug submission referencing the DMF is screened for completeness and acceptability for review, the DMF may be subjected to a preliminary evaluation. If deficiencies are noted during the preliminary evaluation a clarifax will be sent to the DMF Owner or Agent. The Health Canada website should be consulted for further details on the implementation of the Integrated Review Process.

2.4.2 Types II and III

For Types II and III Drug Master Files, all information is reviewed as part of the DMF. DMF Owners or Agents will not be informed that the DMF is acceptable to support the submission.

Comments concerning deficiencies in Types II and III DMFs are sent directly, in writing, to the Owner or Agent.

Outside of the ATI regime, all communications with respect to the Types II and III DMFs will be kept exclusively between the DMF Owner or Agent and Health Canada officials.

2.4.3 Type IV

For Type IV DMFs, all confidential business information (Restricted Part) is reviewed as part of the DMF. Non confidential business information (Sponsor's Part) is reviewed as part of the drug submission.

All non confidential business information on the drug product should be included in the drug submission (see Section 2.9). The Sponsor's Part of Type IV DMFs may, therefore, be subject to discussions between Health Canada and the Sponsor.

Outside of the ATI regime, all communications with respect to the Restricted Part of the Type IV DMF will be kept exclusively between the DMF Owner or Agent and Health Canada officials. If any comments are considered necessary concerning the Restricted Part of Type IV DMF they will be forwarded directly to the DMF Owner or Agent. In this case, the Sponsor will be notified that there are outstanding issues that need to be addressed before the DMF can be considered acceptable to support their drug submission. The DMF Owner or Agent will not be informed that the DMF is acceptable to support the drug submission.

2.5 Naming of the DMF

The preferred name of the DMF should be the generic name (e.g. the International Nonproprietary Name (INN) for an active pharmaceutical ingredient) followed by any brand names or codes to identify a particular product. If the company has more than one DMF for a similar product, the cover letter should state this explicitly and provide information to distinguish the different products, e.g. different polymorphic forms, different manufacturing processes. A single DMF may contain information on different forms of a drug substance, or for type IV DMFs, more than one strength of the product. However in such cases, the information in the DMFs for each form should be clearly differentiated.

2.6 Type I - Drug Substances or Intermediates in the Production of Drug Substances

DMFs concerning the manufacture of a drug substance should be prepared according to the ICH Common Technical Document (CTD) format and as described in Draft Quality (Chemistry and Manufacturing) Guidance: New Drug Submissions (NDSs) and Abbreviated New Drug Submissions (ANDSs), Evidence for Quality of Natural Health Products, Preparation of Veterinary New Drug Submissionsor other guidelines outlined in the scope section (1.2- (f)) where applicable. The DMF should be accompanied by a copy of the QOS. It is recommended that Health Canada templates for the QOS be used to expedite review. Only the sections relevant to the drug substance need to be completed. Other sections should be deleted.

The DMF should contain complete information on the drug substance. This information should be submitted as two separately bound volumes and labelled the "Sponsor's Part" and the "Restricted Part." The Restricted Part should contain exclusively confidential business information/trade secret. The Sponsor's Part should contain all other required information, as well as a brief outline of the manufacturing method, as indicated in Table 2-6-1. A copy of the Sponsor's Part should be provided to the Sponsor. This data, supplemented by the Sponsor's own information on the drug substance, should be included in the submission. Submissions that lack this information will not be accepted for review.

The division of information between the Sponsor's and Restricted Parts of the DMF is outlined in Table 2-6-1. Information should appear in CTD format. For further details refer to the ICH Guideline M4 and other Health Canada Guidance Documents.

Table 2-6-1 : Overview of Type I (Drug Substance) DMF Contents
Module Sponsor's ("Open") Part Restricted ("Closed") Part

Table 1 footnotes

Table 1 footnote 1

A separate QOS for each part or a single QOS to cover both parts can be provided, deleting all sections of the QOS not relevant to the DMF. In cases when a single QOS is provided, the confidential business information/trade secret sections should be clearly identified.

Return to table 1 footnote 1 referrer

Table 1 footnote 2

A flow chart (including molecular structures and all reagents/solvents) and a short description can be sufficient, if additional detailed information is presented in the Restricted Part. However, for sterile drug substances full validation data on the sterilisation process should be provided in the Sponsor's Part.

Return to table 1 footnote 2 referrer

Table 1 footnote 3

Detailed information.

Return to table 1 footnote 3 referrer

Table 1 footnote 4

Insofar as the information is also relevant for the Sponsor.

Return to table 1 footnote 4 referrer

Table 1 footnote 5

Insofar as this information is not relevant for the Sponsor.

Return to table 1 footnote 5 referrer

Table 1 footnote 6

Insofar as the information is related to the detailed description of the manufacturing process and the DMF Owner sufficiently justifies that there is no need to control these impurities in the final drug substance, e.g. solvents which are tested and not detected in the drug substance.

Return to table 1 footnote 6 referrer

Table 1 footnote 7

Insofar as the information is related to the detailed description of the manufacturing process, control of materials and process validation.

Return to table 1 footnote 7 referrer

1 Administrative information    
1.1 Table of Contents x x
1.2 Application Information
1.2.1 Cover letter and DMF Application and Amendment Form
1.2.2 Fee form
1.2.3 Application Certification Form
1.2.5 GMP Information
1.2.6 Letters of Access
1.2.8 Agent Authorisation
  x
1.6 Electronic Review Documentation   x
2.3 Quality Overall Summary (QOS) x Table 1 footnote 1) x Table 1 footnote 1)
3.2.S Drug Substance x x
3.2.S.1 General Information x  
3.2.S.1.1 Nomenclature x  
3.2.S.1.2 Structure x  
3.2.S.1.3 General Properties x  
3.2.S.2 Manufacture x x
3.2.S.2.1 Manufacturer(s) x  
3.2.S.2.2 Description of Manufacturing Process and Process Controls Table 1 footnote 2) Table 1 footnote 3)
3.2.S.2.3 Control of Materials   x
3.2.S.2.4 Controls of Critical Steps and Intermediates Table 1 footnote 4) Table 1 footnote 5)
3.2.S.2.5 Process Validation and/or Evaluation   x
3.2.S.2.6 Manufacturing Process Development   x
3.2.S.3 Characterisation x  
3.2.S.3.1 Elucidation of Structure and other Characteristics x  
3.2.S.3.2 Impurities x Table 1 footnote 6)
3.2.S.4 Control of the Drug Substance x  
3.2.S.4.1 Specification x  
3.2.S.4.2 Analytical Procedures x  
3.2.S.4.3 Validation of Analytical Procedures x  
3.2.S.4.4 Batch Analyses x  
3.2.S.4.5 Justification of Specification x Table 1 footnote 7)
3.2.S.5 Reference Standards or Materials x  
3.2.S.6 Container Closure System x  
3.2.S.7 Stability x  
3.2.S.7.1 Stability Summary and Conclusions x  
3.2.S.7.2 Post-approval Stability Protocol and Stability Commitment x  
3.2.S.7.3 Stability Data x  
3.2.A Appendices   x
3.2.A.1 Facilities and Equipment   x
3.2.A.2 Adventitious Agents Safety Evaluation   x

2.6.1 Submission of DMFs for Similar Active Pharmaceutical Ingredients

Health Canada allows for identical medicinal ingredientsFootnote 2 manufactured by the same company to be filed in a single DMF (e.g. different manufacturing sites or manufacturing processes for APIs or different polymorphic forms of the API) provided they have the same specifications or are clearly distinguished.

It is at the discretion of the DMF Owner whether a single DMF or separate DMFs are filed. If separate DMFs are filed for the same API, the cover letter accompanying each DMF should clearly specify it is a new DMF and not an update to the other DMF already on file. Additionally a side-by-side description of differences between each DMF should be provided.

When similar APIs are submitted in separate DMFs, the names of the DMFs should allow for easy identification of each substance, e.g. Drug Substance, Polymorphic Form A and Drug Substance, Polymorphic Form B.

2.7 Type II - Container Closure Systems and Components

The following information should be provided for Type II Drug Master Files:

  1. general information concerning the container and closure system;
  2. specific information about any plastic components that come in contact with the drug product;
  3. complete descriptions of the glass container;
  4. complete descriptions of the closure system by the elastomer manufacturer;
  5. descriptions of the compositions of the valve components for pressurized containers; and
  6. the suitability of the packaging material with respect to the nature of the drug product, dosing regimen, manufacturing process and sterilization process, where applicable.

2.7.1 General Requirements

Although the requirement for packaging material varies according to the type of container and closure system, DMFs should provide the following general information:

  1. intended uses of components;
  2. technical properties of the packaging material;
  3. acceptance specifications and test methods including physical dimensions or drawings or both; and
  4. test results for light and moisture transmission, extractable components, leaching and migration, where applicable.

Additional information on packaging can be found in Draft Quality (Chemistry and Manufacturing) Guidance: New Drug Submissions (NDSs) and Abbreviated New Drug Submissions (ANDSs). Information for specific pharmaceutical products can be found in, Pharmaceutical Quality of Aqueous Solutions and Pharmaceutical Quality of Inhalation and Nasal Products.

General requirements for materials used in the manufacture of containers and containers used for packaging of pharmaceutical products can be found in the general chapters of the European Pharmacopoeia and the United States Pharmacopeia.

2.7.2 Plastics

When plastic components come into contact with drug products, the following additional information should be provided where applicable:

  1. Quantitative composition. This information includes ingredients added to the resin in order to perform a specific function during fabrication, such as plasticizers, lubricants, pigments, colourants, stabilizers, and antioxidants.
  2. Method of manufacture. This information includes a brief description of how the packaging material is manufactured and a statement of the maximum percentage of reground material permitted in processing.
  3. Information on the toxicity of all added substances. (published information is acceptable).
  4. Additional quality control testing. Although physical and chemical techniques may be used to identify and characterize plastics, additional tests should be performed according to the applicable pharmacopoeial recommendations to ensure that the plastic material is suitable for packaging drugs. Such tests should include light transmission, vapour permeation, etc.
  5. Results of all extraction studies. The tests should investigate the aqueous (and other applicable solvents) extraction of the plastic to characterize or determine the presence of impurities or extractables. If possible, the extraction media should also include the drug vehicle to be used. Testing should meet the requirements of the USP General Chapters <87/88> Biological Reactivity, and the Health Canada guides, Pharmaceutical Quality of Aqueous Solutions or Pharmaceutical Quality of Inhalation and Nasal Products Guidance as applicable for the intended dosage form.

2.7.3 Glass containers

Complete information on the composition and description of glass vials, syringes or ampuls should be submitted. Complete specifications, including tests and acceptance criteria for any glass treatment, and drawings should be provided.

2.7.4 Closure Systems

2.7.4.1 Elastomers

The elastomer manufacturer should provide complete descriptions of the components and compositions of elastomers used in closure systems as well as

  1. specifications;
  2. test methods;
  3. cleaning procedures; and
  4. any additional treatments such as siliconization or coating procedures.

Also provided should be the results of applicable pharmacopoeial test, including biological safety, and the relevant extraction and coring studies.

2.7.4.2 Caps, Liners, Inner Seal, Dropper Tips

Complete composition, specifications (including drop size for tips) and test methods should be provided for the materials used in caps, liners, inner seals, and dropper tips that are part of the closure system.

Studies on vapour permeation and torque (where applicable) should be provided for caps.

2.7.5 Pressurized Containers

Complete information on the composition and description of valve components (including valve closure, valve actuator and aerosolizing device) should be submitted. The chemical composition of all rubber components should be included. Complete specifications, including drawings for valve and actuator components, spray characteristics of the valve closure system, the results of leak testing, and results of leaching and migration tests should be provided.

2.7.6 Suitability of the Packaging Material

The manufacturer of the packaging material should conduct reasonable studies to demonstrate the suitability of the packaging material for its intended use. Examples of this are uniformity of delivered dose for metered dose valves and deliverable volume for calibrated syringes.

2.8 Type III - Excipients

Type III Excipient DMFs include DMFs for colourants, flavours, capsule shells, alum and growth media, coating ingredients. Information on the manufacture and composition of gelatin capsules should also be described in a Type III DMF.

The amount of information required in a Type III DMF will vary depending on the excipient and the inherent risk. Health Canada should be contacted prior to submitting a Type III DMF in order to determine the content requirements.

The following information should generally be provided for Type III Drug Master Files:

  1. complete formulation and brief method of manufacture, where applicable;
  2. appropriate and sufficiently detailed specifications and test methods that adequately control the material's identity, strength, quality, and purity with respect to the intended use;
  3. depending on the nature of the material, tests such as residue on ignition, heavy metals, arsenic, and percent of total solid;
  4. safety data for novel excipients; and
  5. a certificate of analysis.

It is advised to enquire about additional information that may be required for components cross-referenced in submissions for biologics and to be filed as a type III DMF.

2.9 Type IV - Dosage Forms

DMFs concerning the manufacture of the dosage form should be prepared in the manner described in Draft Quality (Chemistry and Manufacturing) Guidance: New Drug Submissions (NDSs) and Abbreviated New Drug Submissions (ANDSs), Evidence for Quality of Natural Health Products, Preparation of Veterinary New Drug Submissionsor other guidelines outlined in the scope section (1.2- (f)) where applicable.

All information regarding the drug substance used should be filed in a separate Type I DMF and cross-referenced in the Type IV DMF.

The DMF should be divided into a Sponsor's Part and a Restricted Part. The contents of each part are described in Table 2-9-1.

A QOS and Certified Product Information Document (CPID) summarizing all information should be provided in the DMF as well.

Table 2-9-1: Overview of Type IV (Drug Product) DMF Contents
Module Sponsor's ("Open") Part Restricted ("Closed") Part

Table 2 footnotes

Table 2 footnote 1

A separate QOS for each part or a single QOS to cover both parts can be provided, deleting all sections of the QOS not relevant to the DMF. In cases when a single QOS is provided, the confidential business information/trade secret sections should be clearly identified.

Return to table 2 footnote 1 referrer

Table 2 footnote 2

Flow chart and short description can be sufficient, if additional detailed information is presented in the Restricted Part.

Return to table 2 footnote 2 referrer

Table 2 footnote 3

Detailed information.

Return to table 2 footnote 3 referrer

Table 2 footnote 4

Insofar as the information is also relevant for the Sponsor.

Return to table 2 footnote 4 referrer

Table 2 footnote 5

Complete qualitative composition is provided to the sponsor.

Return to table 2 footnote 5 referrer

Table 2 footnote 6

Insofar as this information is not relevant for the Sponsor.

Return to table 2 footnote 6 referrer

Table 2 footnote 7

Insofar as the information is related to the detailed description of the manufacturing process and the DMF Owner sufficiently justifies that there is no need to control these impurities in the final drug product.

Return to table 2 footnote 7 referrer

Table 2 footnote 8

Insofar as the information is related to the detailed description of the manufacturing process, control of materials and process validation.

Return to table 2 footnote 8 referrer

1 Administrative information    
1.1 Table of Contents x x
1.2 Application Information
1.2.1 Cover letter and DMF Application and Amendment Form
1.2.2 Fee form
1.2.3 Application Certification Form
1.2.5 GMP Information
1.2.6 Letters of Access
1.2.8 Agent Authorisation
  x
1.4.2 Certified Product Information Document (CPID)   x
1.6 Electronic Review Documentation   x
2.3 Quality Overall Summary (QOS) x Table 2 footnote 1 x Table 2 footnote 1
3.2.P Drug Product x x
3.2.P.1 Description and Composition of the Drug Product x Table 2 footnote 3
3.2.P.2 Pharmaceutical Development Table 2 footnote 4 Table 2 footnote 3
3.2.P.2.1 Components of the Drug Product Table 2 footnote 5 x
3.2.P.2.2 Drug Product   x
3.2.P.2.3 Manufacturing Process Development   x
3.2.P.2.4 Container Closure System   x
3.2.P.2.5 Microbiological Attributes   x
3.2.P.2.6 Compatibility   x
3.2.P.3 Manufacture x x
3.2.P.3.1 Manufacturer(s) x x
3.2.P.3.2 Batch Formula x x
3.2.P.3.3 Description of Manufacturing Process and Process Controls Table 2 footnote 2 Table 2 footnote 3
3.2.P.3.4 Controls of Critical Steps and Intermediates Table 2 footnote 4 Table 2 footnote 6
3.2.P.3.5 Process Validation and/or Evaluation   x
3.2.P.4 Control of Excipients Table 2 footnote 4 Table 2 footnote 6
3.2.P.4.1 Specifications   x
3.2.P.4.2 Analytical Procedures   x
3.2.P.4.3 Validation of Analytical Procedures   x
3.2.P.4.4 Justification of Specifications   x
3.2.P.4.5 Excipients of Human or Animal Origin   x
3.2.P.4.6 Novel Excipients   x
3.2.P.5 Control of Drug Product x  
3.2.P.5.1 Specification(s) x  
3.2.P.5.2 Analytical Procedures x  
3.2.P.5.3 Validation of Analytical Procedures x  
3.2.P.5.4 Batch Analyses x  
3.2.P.5.5 Characterisation of Impurities x Table 2 footnote 7
3.2.P.5.6 Justification of Specification(s) x Table 2 footnote 8
3.2.P.6 Reference Standards or Materials x  
3.2.P.7 Container Closure System x  
3.2.P.8 Stability x  
3.2.P.8.1 Stability Summary and Conclusions x  
3.2.P.8.2 Post-approval Stability Protocol and Stability Commitment x  
3.2.P.8.3 Stability Data x  
3.2.A Appendices   x
3.2.A.1 Facilities and Equipment   x
3.2.A.2 Adventitious Agents Safety Evaluation   x
3.2.A.3 Excipients   x
3.2.R Regional Information   x
3.2.R.1 Production Documentation   x
3.2.R.1.1 Executed Production Documents   x
3.2.R.1.2 Master Production Documents   x

If another DMF is cross-referenced in a Type IV DMF, then the Type IV DMF should contain letters of access for the cross-referenced DMF. The Sponsor need only be provided with a letter of access to the Type IV DMF. However, if the Sponsor requires specific access to the DMFs cross-referenced in the Type IV DMF, then the sponsor should obtain a letter of access as well.

2.9.1 Drug Master files for Clinical Trial Applications

The information provided in a DMF for a CTA is dependant on the phase of the CTA.

Active DMFs for on-going clinical trials should be kept updated. After the clinical trial(s) is (are) complete, the DMF can be closed as long as no further reference is to be made to the DMF. If the DMF Owner wishes to update the DMF for use in later phase clinical trials, then the DMF should be updated on a quinquennial basis as per this guidance or as needed (see section 2.2.4).

When updating a DMF with additional information to use for later phase trials, fully revised summaries (QOS) should be provided according to the Health Canada document Quality (Chemistry and Manufacturing) Guidance: Clinical Trial Applications (CTA's). A side-by-side comparison of all information amended should be provided with the updated DMF.

2.10 DMFs with Multiple Components

Multiple components may be included in a single DMF provided that the components are similar (e.g. the DMF consists of different stopper formulations or multiple flavours, the DMF consists of one complete container closure system). Type II and III DMFs typically contain multiple related components. Information on each component should be included in a separate section with a tab to differentiate the component. If it is expected that new components will be added to the DMF in the future, then the DMF should be provided in a form to allow easy addition of the new information (e.g. in a ring binder). New components will only be accepted if the DMF meets this criteria. Otherwise, the DMF Owner will be requested to submit the components as a new DMF. A limit of 50 components will be enforced per DMF. Additional components should be filed in a new DMF.

The DMF should be accompanied by a table listing all components in the DMF along with the companies authorised to use those specific components (e.g. bromobutyl stopper type A : company A, company X). If either the components or the companies with letters of access are changed then the table should be updated in its entirety.

DMFs should be updated every five years. If no changes have been made, a simple statement confirming this would be sufficient to update the DMF. If many components are included in the DMF, an attestation listing all components which have not been modified is acceptable. For the components where changes have been made, an amendment should be filed at the earliest opportunity, highlighting the changes (e.g. in a side-by-side comparison).

3 References

3.1 Health Canada Documents

Health Canada Documents can be found on the website.

  • Food and Drugs Act, Food and Drug Regulations, and Medical Devices Regulations
  • Drug Master File Application Form
  • Draft Quality (Chemistry and Manufacturing) Guidance: New Drug Submissions (NDSs) and Abbreviated New Drug Submissions (ANDSs)
  • Evidence for Quality of Natural Health Products
  • Preparation of Veterinary New Drug Submissions
  • Changes to Marketed New Drug Products
  • Stability requirements for Changes to Marketed New Drug Products
  • Impurities in Existing Drug Substances and Products
  • Pharmaceutical Quality of Aqueous Solutions
  • Pharmaceutical Quality of Inhalation and Nasal Products
  • Quality (Chemistry and Manufacturing) Guidance: Clinical Trial Applications (CTA's)
  • Stability Testing of Existing Drugs
  • Stereochemical Issues in Chiral Drug Development
  • Management of Drug Submissions
  • Preparation of NDS in the CTD format
  • Bureau of Biologics and Radiopharmaceuticals, Guidance to Industry Product-Specific Facility Information
  • Preparation of the Quality Information for Drug Submissions in the CTD Format: Biotechnological/ Biological (Biotech) Products
  • Preparation of the Quality Information for Drug Submissions in the CTD Format: Conventional Biotherapeutic Products
  • Preparation of the Quality Information for Drug Submissions in the CTD Format: Blood Products
  • Preparation of the Quality Information for Drug Submissions in the CTD Format: Vaccines
  • Access to Information Act
  • Library and Archives of Canada Act

3.2 ICH Documents

  • Q1A(R2): Stability Testing of New Drug Substances and Products
  • Q1B: Photostability Testing of New Drug Substances and Products
  • Q1C: Stability Testing Requirements for New Dosage Forms
  • Q1D: Bracketing and Matrixing Designs for Stability Testing of Drug Substances and Drug Products
  • Q1E: Evaluation of Stability Data
  • Q3A(R): Impurities in New Drug Substances
  • Q3B(R): Impurities in New Drug Products
  • Q3C: Impurities: Guideline for Residual Solvents
  • Q6A: Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances
  • Q7: Good Manufacturing Practices Guide for Active Pharmaceutical Ingredients
  • M4: Common Technical Document (CTD)
  • M4Q: The Common Technical Document - Quality (CTD-Q)

3.3 VICH Documents

  • GL3(R): Stability Testing of New Veterinary Drug Substances and Medicinal Products
  • GL4: Stability Testing: Requirements for New Dosage Forms
  • GL5: Stability Testing: Photostability Testing of New Drug Substances and Products
  • GL8: Stability Testing for Medicated Premixes
  • GL10(R): Impurities in New Veterinary Drug Substances
  • GL11(R): Impurities in New Veterinary Medicinal Products
  • GL17: Stability Testing of New Biotechnological / Biological Veterinary Medicinal Products
  • GL18: Impurities: Residual Solvents in New Veterinary Medicinal Products, Active Substances and Excipients
  • GL39: Test Procedures and Acceptance Criteria for New Veterinary Drug Substances and New Medicinal Products: Chemical Substances
  • GL40: Test Procedures and Acceptance Criteria for New Biotechnological / Biological Veterinary Medicinal Products
  • GL45: Bracketing and Matrixing Designs for Stability Testing of New Veterinary Drug Substances and Medicinal Products (Step 4)

4. Glossary

ANDS
Abbreviated New Drug Submission.
Authorized DMF Agent
Any person appointed by the owner of the DMF to submit a DMF or serve on behalf of the owner. An authorized agent may not be the DMF Owner.
BSE
Bovine Spongiform Encephalopathy
Confidential Business Information
Information which provides a business advantage as a result of the fact that it is kept confidential. This is true whether the information is tangible or intangible. Confidential business information is broad enough to encompass trade-secrets.
Covering Letter
The letter accompanying the DMF.
CTA
Clinical Trial Application.
Dosage Form
The finished product (e.g., tablets, capsules, injections, etc.).
Dosage Form Manufacturer
The company which manufactures the finished drug product for pharmaceutical use.
DMF Amendment
Changes to the DMF filed between the 5 year updates.
DMF Owner
The company who owns the DMF. This may be the manufacturer of the product described in the DMF and/or the owner of the confidential business information.
DMF Update
either an amendment filed on the DMF anniversary date, a letter of confirmation of no changes (See Appendix C) or a complete resubmission of the DMF volumes. The Drug Master File Administration Unit should receive correspondence a minimum of every 5 years from the time of the original application for the DMF. Refer to Section 2.2.4 for further information on updating a DMF
Drug Substance
A pharmacologically active ingredient.
Letter of Access
A letter written by the DMF Owner or authorized Agent permitting Health Canada to reference information in the DMF on behalf of the Sponsor (See Appendix D).
Manufacturer
The company that manufactures the product covered by the DMF. This may be a manufacturer of a drug substance, an excipient, a packaging material or container closure system or a drug product/finished dosage form.
NDS
New Drug Submission.
NPN
Natural Product Number
Person(s)
Individuals, partnerships, corporations or associations.
Product Line
A group of drug products containing the same API, irrespective of the dosage form, and manufactured/marketed by the company to which authorization to access the DMF is granted.
Proprietary Information
Privately owned knowledge or data, such as that protected by a registered patent, copyright, or trademark, i.e., any information that is not generally known to the public, which may have commercial or competitive value. Examples of proprietary information are intellectual property, operating and marketing plans, student and employee information.
Restricted Part
The confidential business information contained in a DMF. Formerly called the Closed Part (see Section 2.6).
SANDS
Supplement to an Abbreviated New Drug Submission.
Significant Change
A change that may impact on purity or performance or necessitates a change in specifications.
SNDS
Supplement to a New Drug Submission
Sponsor
The person submitting an NDS, ANDS, SNDS, SANDS, DIN submission or CTA. This may or may not be the dosage form manufacturer.
Sponsor's Part
The non confidential business information contained in a DMF. Formerly called the Open Part (See Section 2.6).
Statement of Commitment
A declaration from the Owner that the information provided in the DMF is true and accurate (see Appendix A).
Trade Secrets
Trade secrets are a category of highly confidential business information. A trade secret is any formula, pattern, device, or information belonging to a certain owner that is used in a business and which gives a competitive advantage. A trade-secret constitutes information which involves proprietary information relating to more technical matters such as processes or specification and methods of production, or formulae.
TSE
Transmissible Spongiform Encephalopathies.

Appendix A Sample Application Certification Form / Statement of Commitment

Health Canada
DMF Application Certification Form

We (DMF Owner's name) certify that, to the best of our knowledge and belief, with reference to the application pertaining to (product name) manufactured in our plant at (location)

  1. All the information and material included in the application and solicited information are accurate and complete, and that the summary documents correctly represent the information and material referred to in the application. No information is false or misleading and no omissions have been made that may affect its accuracy and completeness.
  2. The product is manufactured in accordance with the process described herein and each lot of the product released will conform to the specifications if tested by the methods described in the DMF.

In addition, we agree to maintain the DMF in order to keep the file open and active by updating the information contained in this document by:

  1. Submitting an amendment to the DMF when significant changes3 are made
  2. By providing a quinquennial update describing all minor changes made since the previous submission
  3. or by providing a quinquennial confirmation that no changes have been made to the DMF.

(Authorized Signature)
(Signee's Name and Title)

Date

Appendix B Sample Agent Authorization Letter

(Date)

(File Number)

Drug Master File Administration Unit,
Therapeutic Products Directorate,
Finance Building, AL: 0201D,
101 promenade Tunney's Pasture Driveway,
Ottawa, Ontario
K1A 0K9

Dear Sir or Madam:
RE: (name of DMF) DMF XXXX-XXXFootnote 4 or To Be Assigned

Please be advised that we have appointed (Agent name) to be our authorized DMF agent for the Canadian market. (Agent name) will be responsible for:

  1. issuing letters of access,
  2. handling deficiencies in the file, and
  3. handling associated correspondence.

Yours sincerely,

(Authorized signature)
(Signee's Name and Title)

Appendix C Sample Quinquennial Update Letter

(Date)

(File Number)

Drug Master File Administration Unit,
Therapeutic Products Directorate,
Finance Building, AL: 0201D,
101 Tunney's Pasture Driveway,
Ottawa, Ontario
K1A 0K9

Dear Sir or Madam:

RE: Update (name of DMF) - DMF XXXX-XXX

In accordance with our commitment to keep the drug master file for (name of DMF) DMF XXXX-XXX,open and active, please accept this letter as confirmation that no changes have been made in the drug master file since our communication dated (date).

Yours sincerely,

(Authorized signature)
(Signee's Name and Title)

Appendix D Sample Letters of Authorization

Appendix D1 Access to entire DMF for Type I and IV only

(Date)

(File Number)

Drug Master File Administration Unit,
Therapeutic Products Directorate,
Finance Building, AL: 0201D,
101 Tunney's Pasture Driveway,
Ottawa, Ontario
K1A 0K9

Dear Sir or Madam:

RE: (name of DMF) - DMF XXXX-XXX5 or To Be Assigned

Please accept this letter as authorization for (company name) to make reference to our drug master file, (state specific name of DMF and DMF number) in support of the (S)(A) NDS/NC for (state Product Line )Footnote 6 to be filed with Health Canada.

This authorization is, however, subject to all applicable regulations regarding confidentiality of such information.

Yours sincerely,

(Authorized signature)
(Signee's Name and Title)

Appendix D2 - DMFs with multiple components for Type II and Type III DMF only

(Date)

(File Number)

Drug Master File Administration Unit,
Therapeutic Products Directorate,
Finance Building, AL: 0201D,
101 Tunney's Pasture Driveway,
Ottawa, Ontario
K1A 0K9

Dear Sir or Madam:

RE: (name of DMF) - DMF XXXX-XXX or To Be AssignedFootnote 7

Please accept this letter as authorization for (company name) to make reference to our drug master file, (state name of DMF and DMF number) for the following components in support of their drug submission(s) to be filed with Health Canada.

Component 1 (e.g. name of formulation, grade of excipient, packaging component)Footnote 8
Component 2

This authorization is, however, subject to all applicable regulations regarding confidentiality of such information.

Yours sincerely,

(Authorized signature)
(Signee's Name and Title)

Appendix E Sample BSE/TSE Certification

We (DMF Owner's name) declare that the (product name) manufactured in our plant at (location) is not manufactured using any material of animal originFootnote 9.

(Authorized Signature)
(Signee's Name and Title)

Date

Appendix F DMF Application Checklist

For new submissions:

  • One signed original cover letter and 1 additional copy
  • Drug Master File Application or Amendment form Fee form10
  • Signed Application Certification Form/Statement of Commitment
  • Agent Authorization Letter (if appropriate)
  • BSE/TSE Certification
  • Single copy of DMF (no duplicates required)

    *For Type I and IV DMFs:

    • Sponsor's Part of DMF (a copy of what has been provided to the sponsor)
    • Restricted Part of DMF
  • Electronic copy of Quality Overall Summary (and CPID for Type IV DMF)

For Letters of Authorization:

  • One Letter of Authorization per company
  • Fee formFootnote 10

Additionally for Amendments and Updates:

  • Drug Master File Application or Amendment form
  • Complete side-by-side listing of changes

For Response to Deficiency Letters, Clarifaxes

  • Hard copy of question and answer response (see Section 3.4)
  • Electronic copy of question and answer response (see Section 3.4)
  • Signed Application Certification Form

Footnotes

Footnote 1

A discussion of "Restricted Part" and "Sponsor's Part" may be found in Section 2.6, "Type I - Active Pharmaceutical Ingredients."

Return to footnote 1 referrer

Footnote 2

Identical medicinal ingredients are defined in the guidance document Interpretation of Identical Medicinal Ingredients.

Return to footnote 2 referrer

Footnote 3

Amendments to DMFs should be submitted according to applicable guidance documents on post-NOC changes.

Return to footnote 3 referrer

Footnote 4

An Agent Authorization Letter is needed for each DMF.  If the DMF number has not yet been assigned then "To be assigned" can be used in place of the DMF number.

Return to footnote 4 referrer

Footnote 5

Please note: Letters of access are specific to one DMF and give access to one company only for a specific product line. If more than one DMF or company is to be authorized, then a separate letter should be provided for each case. If a letter of access is filed with a new DMF and no DMF number has yet been assigned then "To be assigned" can be used in place of the DMF number. In all other instances the DMF number should appear on the letter.

Return to footnote 5 referrer

Footnote 6

For Type IV DMFs, the specific drug submission name should be listed.

Return to footnote 6 referrer

Footnote 7

If a letter of access is filed with a new DMF and no DMF number has yet been assigned then "To be assigned" can be used in place of the DMF number. In all other instances the DMF number should appear on the letter.

Return to footnote 7 referrer

Footnote 8

This letter of access should only be used for DMFs where authorization is provided for specific parts of the DMF. It should only be used for Type II and III DMFs.

Return to footnote 8 referrer

Footnote 9

If any material of animal origin which may be susceptible to TSE/BSE contamination is used as either a starting material, reagent or processing aid in the manufacture of the product complete data on the risk of transmitting TSE/BSE should be provided in 3.2.S.2.3.

Return to footnote 9 referrer

Footnote 10

The guidance document on Cost Recovery-Veterinary Drug Submission Evaluation Fees should be consulted by DMF Owners intending to file a DMF cross-referenced in a veterinary drug submission only. A confirmation that the component described in the DMF will be used for veterinary drugs only should be included in the cover letter.

Return to footnote 10 referrer