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February 15, 2016

Notice

Our file number: 16-101401-306 Draft Guidance Document: Master Files (MFs) - Procedures and Administrative Requirements Health Canada is pleased to announce the release of the revised Draft Guidance Document: Master Files (MFs) - Procedures and Administrative Requirements for external consultation only. The 2008 Draft Guidance Document - Drug Master Files (DMFs) is outdated and not in line with international efforts to standardize MF terminology and MF procedures. The revised draft is administrative in nature and was developed to facilitate information sharing initiatives that are ongoing in collaboration with the International Generic Drug Regulators Programme (IGDRP). These initiatives include bringing efficiencies to MF practices. It also introduces process changes that are less cumbersome on industry and Health Canada. Changes to the revised draft include:

Revised terminology such as the use of master file, applicant's part and restricted part, incorporating IGDRP criteria for the issuance of new master files and adopting International Council for Harmonisation (ICH) definitions.

Adding clinical trial specific processes. Clarifying the requirements for Letters of Access that are now specific for the MF or MF

component (rather than for a product line). Clarifying timelines for responding to requests for additional information. Requesting that MFs are filed no more than one year but no less than 2 months prior to

filing of a drug submission or clinical trial application (CTA) making reference to those MFs.

Encouraging filing of Certificates of Suitability (CEP)s. Clarification of the timelines and procedures surrounding changes to the MF. All quality

changes to MFs are now called updates and these are only required when a Supplement to an Abbreviated New Drug Submission [(A)NDS], Notifiable Change (for biologics), CTA-Amendment or CTA-Notification need to be filed with Health Canada.

Adding timelines for closure and disposal of an MFs if it is not assessed after 5 years.

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Clarifying the procedures surrounding closure of an MF and indicating that HealthCanada can close an MF due to lack of reference.

Renaming the Fee Form to "MF Fee Form".

As a consequence of some of these changes, fees charged for the provision of non-regulatory MF services and the corresponding service standards are being reassessed. Any proposed changes to the fees or service standards will be communicated to industry stakeholders.

Questions or comments related to the consultation of this guidance document and to the MF process should be directed to:

Health Canada Health Products and Food Branch, Therapeutic Products Directorate Bureau of Policy, Science and International Programs Address Locator 3102C3 Holland Cross, Tower B 1600 Scott St. Ottawa, Ontario K1A 0K9

Telephone: 613-948-4623Email: [email protected]

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DRAFT GUIDANCE DOCUMENT 12

Master Files (MFs) – Procedures and Administrative 13

Requirements 14

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This guidance document is being distributed for comment purposes only. 17 18 19

Published by authority of the 20

Minister of Health 21

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Draft Date 2016/02/10 25 26 27

Health Products and Food Branch 28 29 30 31 32 33 34 35

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Our mission is to help the people of Canada maintain and improve their health.

Health Canada

The Health Products and Food Branch’s (HPFB) mandate is to take an integrated approach to managing the health-related risks and benefits of health products and food by: $ minimizing health risk factors to Canadians while

maximizing the safety provided by the regulatory system for health products and food; and,

$ promoting conditions that enable Canadians to make healthy choices and providing information so that they can make informed decisions about their health.

Health Products and Food Branch

37 38 © Minister of Public Works and Government Services Canada 2016 39 40 41

Également disponible en français sous le titre : Ébauche de la ligne directrice : Fiches 42 maîtresses (FM) - Procédures et exigences administratives43

Health Canada Master Files (MFs): Draft Guidance Document - For comment purposes only Procedures and Administrative Requirements

Draft Date: 2016/02/10 i

FOREWORD 44 45 Guidance documents are meant to provide assistance to industry and health care professionals on 46 how to comply with governing statutes and regulations. Guidance documents also provide 47 assistance to staff on how Health Canada’s mandates and objectives should be implemented in a 48 manner that is fair, consistent and effective. 49 50 Guidance documents are administrative instruments not having force of law and, as such, allow 51 for flexibility in approach. Alternate approaches to the principles and practices described in this 52 document may be acceptable provided they are supported by adequate justification. Alternate 53 approaches should be discussed in advance with the relevant programme area to avoid the 54 possible finding that applicable statutory or regulatory requirements have not been met. 55 56 As a corollary to the above, it is equally important to note that Health Canada reserves the right 57 to request information or material, or define conditions not specifically described in this 58 document, in order to allow the Department to adequately assess the safety, efficacy or quality of 59 a therapeutic product. Health Canada is committed to ensuring that such requests are justifiable 60 and that decisions are clearly documented. 61 62 This document should be read in conjunction with the accompanying notice and the relevant 63 sections of other applicable guidance documents. 64 65

Master Files (MFs): Health Canada Procedures and Administrative Requirements Draft Guidance Document - For comment purposes only

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Document Change Log 66 67

Version Draft Guidance For Industry Master Files (MFs) – Procedures and Administrative Requirements

Replaces Draft Guidance Document - Drug Master Files (DMFs)

Date February 5, 2016 Date September 5, 2008

Change February 10, 2016 Some revisions throughout the document

Nature of and/or Reason for Change

The revised draft is administrative in nature and was developed to facilitate information sharing initiatives that are ongoing in collaboration with the International Generic Drug Regulators Programme (IGDRP). These initiatives include bringing efficiencies to MF practices. The document also introduces process changes that are less cumbersome on industry and Health Canada.

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Table of Contents 70 71

1. INTRODUCTION ................................................................................................................. 1 72

1.1 Policy Objective ............................................................................................................ 1 73 1.2 Policy Statements .......................................................................................................... 1 74 1.3 Scope and Application .................................................................................................. 2 75 1.4 Definitions..................................................................................................................... 3 76 1.5 Background ................................................................................................................... 4 77

2. GUIDANCE FOR IMPLEMENTATION ............................................................................. 5 78

2.1 Health Canada Master Files (MFs) ............................................................................... 5 79 2.1.1 Confidentiality .............................................................................................................. 5 80 2.1.2 Registration Requirements ............................................................................................ 6 81 2.1.3 Naming an MF .............................................................................................................. 7 82 2.1.4 Format and Structure of the MF .................................................................................... 7 83 2.1.5 Official Language of Correspondence .......................................................................... 8 84 2.1.6 Where to Send MF Registrations .................................................................................. 8 85

2.1.6.1 Shipping/Customs Information ......................................................................... 8 86 2.1.7 Letters of Access (LoA) ................................................................................................ 8 87

2.1.7.1 Information to include in the LoA .................................................................... 9 88 2.1.7.2 LoA Filing ......................................................................................................... 9 89 2.1.7.3 LoAs for Clinical Trials (Pharmaceutical and Biologic) ................................ 10 90

2.1.8 Certificates of Suitability to the Monographs of the European Pharmacopeia 91 (CEPs) ......................................................................................................................... 10 92

2.1.9 Appointment of the Authorized MF Agent ................................................................. 10 93 2.1.10 When to File a New MF Registration ......................................................................... 11 94 2.1.11 MF Fees ...................................................................................................................... 12 95

2.2 Processing of MFs....................................................................................................... 12 96 2.2.1 Administrative Holds .................................................................................................. 13 97 2.2.2 Application and File Maintenance Requirements ....................................................... 14 98 2.2.3 MF Performance Standards ......................................................................................... 14 99

2.3 Assessment of MFs ..................................................................................................... 14 100 2.3.1 Solicited Information .................................................................................................. 15 101 2.3.2 Clarification Requests and Letters of Deficiency during MF Assessment in 102

Support of a Submission ............................................................................................. 16 103 2.3.2.1 Clarifications Requests during MF Assessment in Support of a CTA ........... 16 104

2.3.3 MF Assessment Reports ............................................................................................. 16 105 2.4 Updates to a Registered MF ........................................................................................ 17 106

2.4.2 Administrative Changes .............................................................................................. 18 107 2.4.2.1 Transfer of Ownership and Company Name Changes ................................... 18 108 2.4.2.2 Change of the Authorized MF Agent .............................................................. 19 109


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2.5 Withdrawal of Letters of Access ................................................................................. 19 110 2.6 MF Closures ................................................................................................................ 20 111

3. CONTACT INFORMATION .............................................................................................. 20 112

4. REFERENCES .................................................................................................................... 21 113

4.1 Health Canada Documents .......................................................................................... 21 114 4.2 ICH Guidelines ........................................................................................................... 23 115 4.3 VICH Documents........................................................................................................ 24 116


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1. INTRODUCTION 117 118 A Master File (MF) is a reference that provides information about specific processes or 119 components used in the manufacturing, processing, or packaging of a drug. The MF is a useful 120 vehicle for providing information to Health Canada, where that information is of a proprietary 121 nature [that is (i.e.), confidential business information] and is not available to the manufacturer 122 of the dosage form or to the sponsors of a drug submission or clinical trial application (hereafter 123 referred to as the applicants). 124 125 The federal government is required by law to assure that confidential business information (CBI) 126 is not given to unauthorized recipients. As a result, Health Canada’s policy, outside the Access to 127 Information Act, prevents it from providing CBI contained in an MF to anyone other than the 128 MF Holder or Authorized MF Agent. Information in the Applicant’s part of an MF (formerly the 129 Open Part) can only be discussed with applicants to whom access has been provided in writing. 130 131 This guidance provides MF related-definitions, information on filing requirements, processing 132 and assessment procedures related to Type I to IV MFs and outlines the registration requirements 133 for MF applications including closures, withdrawals, updates, and administrative changes. 134 135

1.1 Policy Objective 136 137 To provide guidance and direction on the procedures that allows MF Holders to file CBI directly 138 with Health Canada that may be referenced to support an applicant’s drug submission or clinical 139 trial application (CTA) with respect to Quality information. 140 141

1.2 Policy Statements 142 143 For the purpose of this guidance document and in accordance with the Guidance Document: 144 Preparation of Drug Regulatory Activities in the Electronic Common Technical Document 145 Format, MFs are categorized as regulatory transactions (Refer to section 1.4 for definition). 146 147 They are voluntary registrations filed with Health Canada that can be referenced by applicants 148 seeking drug marketing authorizations or clinical trial authorizations involving pharmaceuticals 149 and biologics. 150 151 It is the responsibility of the applicants to submit the relevant non-proprietary information 152 provided by the MF Holder, obtained in the public domain, and/or developed by the applicant in 153 the drug submission or clinical trial application (CTA). 154 155 The applicants should ensure that the information included in the MF is up to date and that the 156 MF has been received by Health Canada. 157 158


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The MF will be held in strict confidence and will be used in support of the drug submission or 159 CTA only upon receipt of a written letter of access from the MF Holder. 160 161

1.3 Scope and Application 162 163 This guidance document applies to all MF Holders, applicants using an MF to support drug 164 submissions for human use or CTAs and Health Canada employees involved in MF processes. 165 Submissions and applications include New Drug Submissions (NDSs), Abbreviated New Drug 166 Submissions (ANDSs), Supplements to New Drug Submissions (SNDS) or Supplemental 167 Abbreviated New Drug Submissions (SANDS), Applications for Drug Identification Numbers 168 (DINAs and DINBs-(B)), Notifiable Changes (NC) (in the case of biologics), Post-Authorization 169 Division 1 Changes for biologics (PDC-B), Post-DIN Changes for pharmaceuticals, early 170 Biologic Product Reports (YBPR), CTAs and CTA-Amendments (CTA-A). MFs may be 171 referenced by more than one applicant. 172 173 The guidance also applies to MF Holders intending to file MFs that are cross-referenced in drug 174 submissions for both human and veterinary use or CTAs. For information on the requirements 175 for MFs related to veterinary drug products and substances, refer to the Guidance for Industry 176 Preparation of Veterinary New Drug submissions. 177 178 The guidance does not apply to MFs used in support of natural health products (NHPs) subject to 179 the Natural Health Products Regulations. For NHP Master Files, refer to the Product Licence 180 Application form or contact the Natural and Non-prescription Health Products Directorate 181 (NNHPD). 182 183 MFs are classified according to the following types: 184 185 Type I Active Substance Master Files (ASMFs)

Type II Container Closure System Master Files (CCS MFs)

Type III Excipient Master Files (Excipient MFs)

Type IV Dosage Form Master Files

For pharmaceuticals Drug substance or intermediate in the manufacture of a drug substance. This can include Active Pharmaceutical Ingredients (API). For biologics Drug substance can include bulk process intermediates, vaccine antigens, excipients of biological origin (with the exception of gelatin),

Container closure systems (CCS) or CCS components.

Excipients, capsule shells, coating ingredients, colourants, flavours, and other additives, including alum and growth media.

Dosage forms and drug product intermediates.


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adjuvants (except for alum), albumin, critical raw materials for radiopharmaceuticals or vectors for gene therapy. 186

1.4 Definitions1 187 188 Applicant - The company submitting an NDS, ANDS, SNDS, SANDS, DINA or DINB, NC, 189 PDC-B, YBPR, CTA or CTA-A. This may or may not be the dosage form manufacturer (also 190 referred to as the Sponsor). 191 192 Applicant’s Part - The non-confidential business information contained in a MF, formerly called 193 the Open Part (see Section 2.1). 194 195 Authorized MF Agent - Any person appointed by the MF Holder to file an MF or serve on behalf 196 of the MF Holder. 197 198 Confidential Business Information in respect of a person to whose business or affairs the 199 information relates, means - subject to the regulations - business information 200

201 (a) that is not publicly available, 202 203 (b) in respect of which the person has taken measures that are reasonable in the 204

circumstances to ensure that it remains not publicly available, and 205 206 (c) that has actual or potential economic value to the person or their competitors because it is 207

not publicly available and its disclosure would result in a material financial loss to the 208 person or a material financial gain to their competitors; [Food and Drugs Act] 209

210 Cover Letter - The letter accompanying the MF which explains the content of the package 211 provided to Health Canada. 212 213 Dosage Form - A pharmaceutical product type [for example (e.g.), tablet, capsule, solution, 214 cream] that contains a drug substance generally, but not necessarily, in association with 215 excipients. 216 217 Dosage Form Manufacturer - The company which manufactures the finished dosage form. 218 219 Drug Product - The dosage form in the final immediate packaging intended for marketing. 220 221

1 The terminology used in this guidance document is the same as used in the ICH guidelines. Where

terminology is not defined in this section, the reader is referred to these guidelines.


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Drug Substance - Any substance or mixture of substances intended to be used in the manufacture 222 of a drug product and that, when used in the production of a drug, becomes an active ingredient 223 of the drug product. 224 225 Letter of Access (LoA) - A letter written and signed by the MF Holder or Authorized MF Agent 226 permitting Health Canada to access the information contained in the MF on behalf of the 227 applicant. 228 229 Manufacturer - The company that manufactures the product covered by the MF. This may be a 230 manufacturer of a drug substance, container closure system (CCS) or CCS component, an 231 excipient, or a finished dosage form. 232 233 MF Holder - The company who owns the MF. This may be the manufacturer of the product 234 described in the MF and/or the owner of the confidential business information. 235 236 MF Update - An update is a revision or change to any information provided in an existing MF 237 and replacement for an existing MF. 238 239 Person(s) - Individuals, partnerships, corporations or associations. 240 241 Regulatory Activity - a collection of all regulatory transactions throughout the process of a 242 specific activity which includes, but is not limited to, NDS, ANDS, DIN Application, CTAs, 243 YBPR. 244 245 Regulatory Transaction (Sequence) - any information package sent by the sponsor as part of a 246 regulatory activity such as initial data, unsolicited and solicited information. 247 248 Restricted Part - The confidential business information contained in a MF. Formerly called the 249 Closed Part (see Section 2.1). 250 251 Statement of Commitment - A declaration from the MF Holder that the information provided in 252 the MF is true and accurate. 253 254

1.5 Background 255 256 Health Canada is the Federal department responsible for helping Canadians maintain and 257 improve their health. Health Canada plays an active role in ensuring the access to safe, effective, 258 and high quality drugs and health products. 259 260 The principles outlined in this guidance document are intended to create greater alignment with 261 the procedures used internationally for the management of Master Files (MFs). Extensive 262 knowledge has been gained through international regulatory initiatives such as the International 263


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Generic Drug Regulators Programme (IGDRP) which was created to promote collaboration and 264 convergence in generic drug regulatory programs. The guidance document also incorporates 265 procedures and terminology resulting from the adoption of International Council for 266 Harmonisation (ICH) guidelines and the use of Certificates of Suitability to the monographs of 267 the European Pharmacopeia (CEPs). For the purpose of this document, and in keeping with 268 international best practices, the term Master Files is used. 269 270

2. GUIDANCE FOR IMPLEMENTATION 271 272

2.1 Health Canada Master Files (MFs) 273 274 Type I ASMFs and Type IV Dosage Form Master Files are divided in two parts: the “Restricted 275 Part” and the “Applicant’s Part” which is provided to the Applicant and is usually included as 276 part of the applicants drug submission or clinical trial application (CTA), with the accompanying 277 Letter of Access (LoA). 278 279 For Type I ASMFs, the Applicant’s Part contains the information that the ASMF Holder regards 280 as non-confidential to the applicant, whereas the Restricted Part contains the information that the 281 ASMF Holder regards as confidential. An MF will not be considered complete if both parts have 282 not been provided to Health Canada. 283 284 The LoA is signed by the MF Holder and grants Health Canada permission to assess the 285 information provided in the MF during the assessment of the applicant’s drug submission or 286 CTA. The Restricted Parts are filed by the MF Holder to Health Canada directly. An MF is 287 submitted by the MF Holder only in cases where the company does not wish to disclose 288 confidential business information (CBI) to the applicant of the drug submission or CTA. 289 290

2.1.1 Confidentiality 291 292 Within Health Canada, MFs are kept confidential and only officials of Health Canada 293 have permission to access these records. Therefore, data and other scientific or technical 294 information are assessed and filed in strict confidence. In legal terms, this CBI belongs to 295 the suppliers that generate it and has traditionally been protected by intellectual property 296 law. In Canada, intellectual property includes, in part, patents, trademarks, copyright and 297 trade secrets. 298 299 However, submitted information which objectively qualifies as CBI is subject to the 300 federal Access to Information Act [http://laws-lois.justice.gc.ca/eng/acts/a-1/] when there 301 is a formal request made under that Act. Section 20 of the Act protects information that 302 qualifies as third party commercial, scientific or technical information and is a mandatory 303 exemption, which means that government institutions must not disclose certain third 304 party information. This is true whether the circumstance is the provision of information 305


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for the public, such as adverse drug reaction or for a regulatory decision document, or 306 when the drug product information is subject to an access to information request. 307 308 Section 20 of the Access to Information Act gives the government the authority to refuse 309 to disclose information that meets the requirements in this section as is often the case for 310 applicants and/or MF Holders information. It effectively defines the scope of “third party 311 confidential information” that accords persons certain rights and protections with respect 312 to information under the control of a government institution. 313 314

2.1.2 Registration Requirements 315 316 It is recommended that MFs are filed no more than one year but no less than 2 months 317 prior to the filing of a drug submission or clinical trial application making reference to 318 those MFs. All MFs are expected to include at least one letter of access when filed. 319 320 For New MF Registrations the following electronic documents are required: 321 322 • One signed cover letter, including the MF name 323 • MF Agent Authorization Letter from MF Holder, if applicable 324 • MF Application Form 325 • Master File Fee Form and appropriate fees 326 • Certificate of Suitability (CEP) and Attestations (for Type I MFs only), if applicable 327 • Letter(s) of Access (see section 2.3.2) 328 329 For Type I ASMFs and Type IV Dosage Form Master Files, the following additional 330 electronic documents are required: 331 332 • The MF must include the Applicant and the Restricted Parts 333 • A Copy of Quality Overall Summary (QOS) in Word format 334 • The Certified Product Information Document (CPID) in Word format, if applicable. 335 336 For Type II CCS MFs and Type III Excipient MFs, multiple components may be 337 included in a single MF provided that the components are similar (e.g., a complete 338 container closure system, different stopper formulations, multiple flavours). A limit of 50 339 components will be enforced per MF. Additional components should be filed in a new 340 MF. 341 342 An MF filed in support of a CTA may include a QOS in lieu of the Applicant and the 343 Restricted Parts. 344 345 Of note, Health Canada does not approve MF registrations. As such, Health Canada does 346 not have a database that is accessible to the public listing all MFs registered in Canada. 347


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2.1.3 Naming an MF 348 349 For Type I ASMFs, the preferred name of the MF should be the generic name (e.g., the 350 International Nonproprietary Name (INN) for an active pharmaceutical ingredient) 351 followed by any manufacturer’s internal API brand names or codes to identify a 352 particular product. If applicable, any counter ions, solvated states of the API should be 353 clearly identified. 354 355 A single MF may contain information on different products in accordance with section 356 2.1.10 for Type I MF or within a product family (e.g., for stoppers of the same 357 formulation). A Type IV Dosage Form Master File may have more than one product 358 strength with the same formulation except for changes necessary to accommodate the 359 different strengths. However in such cases, the information in the MFs for each product 360 should be clearly differentiated within the Dosage Form Master Files. 361 362 If the MF Holder has more than one MF for a similar product, the cover letter should 363 state this explicitly and provide information to distinguish the different products. The MF 364 Holder should provide an MF name that distinguishes the MF from any previously 365 registered MFs. 366 367

2.1.4 Format and Structure of the MF 368 369 As of January 1st 2016, Health Canada no longer accepts paper copies of MFs. MFs must 370 follow the filing and formatting requirements outlined in the Guidance Document 371 Preparation of Drug Regulatory Activities in the “Non-eCTD Electronic-Only” Format 372 which includes guidance on MF structure and content as well as the breakdown of the 373 Applicant and the Restricted Parts. Also refer to the 2015 Notice - Re: Preparation of 374 Drug Master File (DMF) in "Non-eCTD Electronic-Only" Format. 375 376 MF Holders may also file their MFs in eCTD format and should consult the Guidance 377 Document: Preparation of Drug Regulatory Activities in the Electronic Common 378 Technical Document Format. Prior to filing an eCTD MF, MF Holders should contact 379 Health Canada via email to [email protected]. 380 381 All documents should be provided in Portable Document Format (PDF) or Microsoft 382 Word. Documents may also be provided in Microsoft Excel where applicable. 383 384 By March 2016, all MFs previously registered with Health Canada must have filed a 385 complete conversion to replace their paper MF with a non-eCTD or eCTD electronic 386 version. Failure to comply and provide the electronic copy to Office of Submissions and 387 Intellectual Property (OSIP) will result in the MF being suspended (no further access for 388 assessment will be granted and no updates will be accepted). Once a MF is suspended 389


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and if the MF Holder wishes to reactivate the MF, a letter should be sent to Health 390 Canada with the converted MF in electronic format as above. Applicable fees for 391 updating will be applied. 392

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2.1.5 Official Language of Correspondence 394 395 The MF can be filed in either of Canada’s official languages (English or French). 396 397

2.1.6 Where to Send MF Registrations 398 399 An MF should be filed to the MF Administration Unit’s forwarding address: 400 Health Canada 401 Health Products and Food Branch 402 Therapeutic Products Directorate 403 Master File Administration Unit 404 Address Locator 0201D 405 101 promenade Tunney's Pasture Driveway 406 Ottawa Ontario 407 K1A 0K9 408 Canada 409 410 Email: [email protected] 411 Fax number: 613-941-0825 412 413 A completed and signed MF Application Form must accompany the MF. 414 415 2.1.6.1 Shipping/Customs Information 416 417 MF Holders are responsible for all costs associated with shipping documents and 418 electronic information to Health Canada, including any applicable customs and/or 419 brokerage fees. Packages must indicate "Terms DDP (Delivered Duty Paid)". Any 420 packages filed to Health Canada with a request for additional charges by a shipper or 421 brokerage firm will be returned to the sender at their expense. 422 423

2.1.7 Letters of Access (LoA) 424 425 MF Holders file confidential business information (CBI) directly with Health Canada that 426 may be referenced to support an applicant’s drug submission or CTA with respect to 427 Quality information. The information in the MF will only be used if the MF Holder 428 provides Health Canada with a signed original LoA to the MF Applicant. The LoA grants 429 Health Canada permission to access the information contained in the MF. 430 431


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2.1.7.1 Information to include in the LoA 432 433 The following information should be included in the LoA: 434 435 • MF number, if assigned by Health Canada, if not yet assigned state “to be assigned” 436 • Name of MF 437 • Manufacturer’s Internal Code, if applicable 438 • Applicant’s Name being granted access to the MF 439 • The appropriate Master File Fee Form and Fees 440

441 2.1.7.2 LoA Filing 442 443 A separate LoA is required for each applicant who cross-references the MF in their drug 444 submission or CTA and each letter is subject to the applicable fees. A LoA needs to be 445 signed by the MF Holder. A copy of the LoA should be sent to the applicant prior to 446 filing their drug submission or CTA. 447 448 For Type I and IV, a LoA is for an MF in its entirety and is valid for all products from the 449 applicant cross-referencing the MF. 450 451 For Type II or III, a LoA can be filed to grant access for an entire MF or specific 452 components within a MF. Only one LoA is required, per applicant, if granting access to 453 the entire MF or for multiple components within a MF. When granting access for an 454 additional component, not included in the first LoA, a new LoA is required with the 455 applicable fee. 456 457 When a MF Holder is filing a Type IV Dosage Form Master File that references a Type I 458 ASMF, the MF Holder for the Type I ASMF must file a LoA granting access to the MF 459 Holder of the Type IV Dosage Form Master File. Separate LoAs must be filed granting 460 the applicant access to the Type I ASMF and to the Type IV Dosage Form Master File as 461 well. 462 463 As stated under section 2.1.11, the fee for the registration for a LoA is applicable to each 464 time a LoA is filed, including when a LoA is refiled (e.g., LoAs should be refiled if the 465 applicant’s name is changed). LoAs should not be refiled if they are already on file. In 466 these cases, MF Holders will be charged the applicable LoA fee. 467 468 Please contact OSIP prior to refiling a LoA to confirm requirements. 469 470 Note: The declaration of access section in a CEP is not equivalent to a LoA. Furthermore, 471 a copy or the CEP should not be submitted with each LoA. See section 2.1.8 for 472 information on submitting CEPs. 473


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2.1.7.3 LoAs for Clinical Trials (Pharmaceutical and Biologic) 474 475 LoAs can be filed in support of all phases of a CTA or for only specified phases, this is at 476 the discretion of the MF Holder. 477 478 The LoA should name the sponsor of the CTA and the Name of the Clinical Trial. 479 Additional information such as hospital information, principal investigator and protocol 480 number can be provided. 481 482 The LoA should be filed directly to the MF Administration Unit with accompanying 483 Master File Fee Form and fee. A copy should be included in the CTA or CTA-484 Amendment. No additional copy should be provided outside of the Applications. 485 486

2.1.8 Certificates of Suitability to the Monographs of the European Pharmacopeia 487 (CEPs) 488

489 MF Holders are encouraged to include the CEP when filing their MF with Health Canada 490 as applicable. MF Holders are requested to confirm at the time of filing if no CEP is 491 available. 492 493 If one is not available at the time of filing it should be provided as the CEP becomes 494 available. Furthermore, when an updated CEP is issued it should be sent to the MF 495 Administration Unit. All CEPs should be accompanied with the relevant attestations 496 outlined in the notice posted on the Health Canada website (http://www.hc-sc.gc.ca/dhp-497 mps/prodpharma/activit/int/edqm_2007-eng.php). When providing an updated CEP, new 498 attestations should be provided. 499 500 Stakeholders are requested to consult the Health Canada website at the above link for 501 current information on the acceptance of CEPs. 502

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2.1.9 Appointment of the Authorized MF Agent 504 505 When an Agent is appointed they are responsible for all correspondence on the MF, 506 including but not limited to the following: 507 508

issuing Letters of Access 509

handling deficiencies 510

handling the payment of fees 511

handling associated correspondence and, 512

filing updates and administrative changes. 513 514 515


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When the MF Holder is not based in North America, it is recommended that a North 516 American MF Agent be used in order to expedite communications. An Authorized MF 517 Agent may perform all functions listed in this guidance document on behalf of the MF 518 Holder after they have been appointed by the MF Holder. 519

520

2.1.10 When to File a New MF Registration 521 522 The examples below indicate the criteria representing when a New Type I (ASMF) MF 523 registration is required: 524 525

Different active substance 526

Different salt of an active substance 527

Different complex of an active substance 528

Different co-crystal of an active substance 529

Different solvate or hydrate form of an active substance 530

Different isomer or mixture of isomers of an active substance 531

Racemate of an optically pure active substance 532

Optically pure enantiomer of a racemic active substance 533

Enantiomer of an active substance 534

Introduction of a new substantially different route of synthesis (i.e. resulting in a 535 different specification for the active substance) 536

Different polymorphic forms (resulting in substantially different physicochemical 537 and/or pharmacokinetic properties) 538

Any other change to the active substance that results in substantially different 539 physicochemical and/or pharmacokinetic properties) 540

Sterile grade of a non-sterile active substance 541

Non-sterile grade of a sterile active substance 542

Change/addition of raw materials of different animal origin (only where there is a 543 substantial change in the safety of the active substance) 544

545 When two (or more) MFs are being filed for similar Active Substances and differ only 546 due to additional processing steps or minor variations, cross-references to the other 547 related MFs can be included in the cover letters to expedite the assessment of the 548 common information. 549 550 The following examples will not necessarily be considered to represent a new ASMF and 551 in most cases could be incorporated in a single ASMF with the same MF number. 552 553

Slightly different routes of synthesis which do not result in substantially different 554 physicochemical and/or pharmacokinetic properties 555

Different manufacturing sites using the same or similar routes of synthesis (i.e. same 556


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specification for the active substance) 557

Different particle size grades (this should be controlled in the drug product 558 manufacturer’s active substance specification) 559

Different container closure system resulting in a different re-test and storage 560 conditions 561

Other changes which do not result in substantially different physicochemical and/or 562 pharmacokinetic properties) 563

564 MF Holders should consult the relevant programme area before submitting the MF if they 565 are unsure of whether a separate master MF should be submitted. 566 567

2.1.11 MF Fees 568 569 The administration of MFs is a non-regulatory voluntary service provided to the fee 570 payers. Fees are collected for the registration and processing of each New MF, Letter of 571 Access (LoA) and Update. If a LoA is refiled then the fee is applicable each time it is 572 refiled. 573 574 Refer to the Master File Fee Form regarding fees for the processing of a New MF, LoA 575 and Update. 576 577 Fees are increased annually by 2% on the first of April. 578 579 For further information on how to pay fees for MFs, refer to the Guidance Document: 580 How to Pay Fees to Health Products and Food Branch (HPFB) (http://www.hc-581 sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/costs-couts/crpay_rcfrais_for-582 eng.php). 583 584 MFs are not eligible for fee mitigation. 585

586

2.2 Processing of MFs 587 588 MFs are processed in sequence according to the date of receipt. When a MF registration package 589 is received the following activities are performed: 590 591

Assigning an MF number and a dossier ID to the MF (only for New MF registration 592 submissions) 593

Verifying that the correct information, documents and forms have been filed and that all 594 submitted information, documents and forms are complete for administrative purposes 595 (including those related to cost-recovery). 596

597 598


Draft Date: 2016/02/10 13

Once the MF registration package is administratively complete: 599 600

a filing date is assigned (which is the date when the MF is considered administratively 601 complete), and 602

an acknowledgement letter is sent to the designated MF contact as listed on the MF 603 Application Form 604

605 If required information, forms or fees are missing or incomplete, the MF will be placed on 606 Administrative Hold, in which case the Office of Submissions and Intellectual Property (OSIP) 607 will issue an MF transaction rejection letter to the MF contact requesting the missing 608 information. 609 610

2.2.1 Administrative Holds 611 612 At different stages during the administrative processing of MFs it may be necessary to 613 place the MF transaction on Administrative Hold when the MF package is incomplete 614 (i.e. missing required information and material). This hold will remain in place until the 615 required information is submitted. 616 617 There are two categories of administrative holds: 618

619 A. Process Hold 620

OSIP will place the MF on Process Hold when the MF is considered incomplete, or 621 when the information is filed as the wrong transaction type (i.e., New MF should 622 have been filed as an Update). When the reason for the Process Hold is addressed, the 623 MF transaction is considered administratively complete and a filing date will be 624 applied. 625 626

B. Cost Recovery Hold 627 In the event that the Master File Fee Form or applicable fee is not provided or the 628 applicable fee is insufficient, OSIP will request the fee form and payment from the 629 MF contact. Pending receipt of the fee form or payment, the transaction will be 630 placed on a Cost Recovery Hold. If the fee form or payment is not received in the 631 timeframe indicated in the letter issued by cost recovery, the transaction will not be 632 accepted. When the reason for the Cost Recovery Hold is addressed, the submission 633 is considered administratively complete and a filing date will be applied. 634

635 Failure to respond to a request for additional or corrected information in the prescribed 636 time will result in the MF being shredded and/or closed. 637 638 639


14 Draft Date: 2016/02/10

2.2.2 Application and File Maintenance Requirements 640 641 All correspondence (e.g., cover letters or letters of access to an MF) should come from 642 the MF Holder, where applicable. Any information filed by a third party will be returned 643 to the sender at their expense. 644 645 All information that is included in the Applicant’s Part of the MF must be provided to the 646 applicant of the drug submission or clinical trial application referencing the MF, and is to 647 be included in their submission/application to Health Canada. 648

649

2.2.3 MF Performance Standards 650 651 All information and material filed in the MF registration will be processed by the MF 652 Administration Unit within 30 calendar days of receiving a complete package. 653

654

2.3 Assessment of MFs 655 656 MFs are always assessed in the context of a drug submission or clinical trial application and 657 therefore, decisions rendered on the Quality-related data in a MF pertain to the drug seeking 658 market authorization or clinical trial authorization. 659 660 For specific information on the technical requirements of an MF, the following guidance 661 documents should be consulted: 662 663 For pharmaceuticals 664

Draft Guidance Document - Quality (Chemistry and Manufacturing) Guidance: New 665 Drug Submissions (NDSs) and Abbreviated New Drug Submissions (ANDSs) 666 (http://www.hc-sc.gc.ca/dhp-mps/consultation/drug-medic/consult_qual-eng.php) 667

Guidance Document - Quality (Chemistry and Manufacturing) Guidance: Clinical Trial 668 Applications (CTAs) for Pharmaceuticals (http://www.hc-sc.gc.ca/dhp-669 mps/prodpharma/applic-demande/guide-ld/clini/qual_cta_dec-eng.php) 670

Certified Product Information Document - Chemical Entities CPID-CE (http://hc-671 sc.gc.ca/dhp-mps/prodpharma/applic-demande/templates-modeles/cpidce_dcipec-672 eng.php) 673 674

For biologics 675

Preparation of the Quality Information for Drug Submissions in the CTD Format: 676 Biotechnological/ Biological (Biotech) Products (http://www.hc-sc.gc.ca/dhp-677 mps/brgtherap/applic-demande/guides/qualit/prod/tech-doc-biologic/ctd_biotech-678 eng.php) 679

Preparation of the Quality Information for Drug Submissions in the CTD Format: Blood 680


Draft Date: 2016/02/10 15

Products (http://www.hc-sc.gc.ca/dhp-mps/brgtherap/applic-681 demande/guides/qualit/prod/tech-doc-biologic/ctd_blood-sang_prods-eng.php) 682

Preparation of the Quality Information for Drug Submissions in the CTD Format: 683 Conventional Biotherapeutic Products (http://www.hc-sc.gc.ca/dhp-684 mps/brgtherap/applic-demande/guides/qualit/prod/tech-doc-biologic/ctd_convbio-685 eng.php) 686

Preparation of the Quality Information for Drug Submissions in the CTD Format: 687 Vaccines (http://www.hc-sc.gc.ca/dhp-mps/brgtherap/applic-688 demande/guides/qualit/prod/tech-doc-biologic/ctd_vacc-eng.php) 689

Blank Certified Product Information Document (Schedule D Drugs) (CPID (Schedule D 690 Drugs)) Template in the CTD Format (http://www.hc-sc.gc.ca/dhp-mps/brgtherap/applic-691 demande/guides/qualit/prod/tech-doc-biologic/ctd_cpid-dcip_schd-ann-eng.php) 692

Draft Guidance for Industry, Preparation of the Quality Information for 693 Radiopharmaceuticals (Schedule C Drugs) using the Quality Information Summary-694 Radiopharmaceuticals (QIS-R) and Certified Product Information Document- 695 Radiopharmceuticals (CPID-R) Templates (http://www.hc-sc.gc.ca/dhp-696 mps/brgtherap/applic-demande/guides/radiopharm/qisr-sdqr_guide-eng.php) 697

698 For specific information on the content of Type II CCS MFs and Type III Excipient MFs not 699 covered in the above guidance documents, the relevant Assessment Bureau should be contacted. 700 701

2.3.1 Solicited Information 702 703 For Type I ASMFs, all non-confidential business information on the drug substance 704 should be included in the drug submission/application. The Applicant’s Part of the MF 705 may, therefore, be subject to discussions between Health Canada and the applicant that 706 has been granted access to reference the MF. 707 708 Outside of the Access to Information (ATI) regime, all communications with respect to 709 the Restricted Part of the MF will be kept exclusively between the MF Holder and Health 710 Canada officials. If any comments are considered necessary concerning the Restricted 711 Part of the MF they will be forwarded directly to the MF Holder in the form of an MF 712 Letter of Deficiency or clarification request. Comments pertaining to the Applicant’s Part 713 of the MF (e.g., analytical methods, stability data) may also be forwarded to the MF 714 Holder. 715 716 When deficiencies are noted within the MF’s Restricted Part, the Applicant will be 717 notified that there are outstanding issues that need to be addressed before the MF can be 718 considered acceptable to support their submission/application. Other applicants cross-719 referencing the deficient MF (for which a response to the MF Letter of Deficiency or 720 clarification request has yet to be received) will receive the same notice. No new Letter of 721


16 Draft Date: 2016/02/10

Deficiency will be issued to the MF Holder unless new comments need to be forwarded 722 (e.g., different requirements for API used in a different dosage form). 723 724

2.3.2 Clarification Requests and Letters of Deficiency during MF Assessment in 725 Support of a Submission 726

727 During the assessment of Types I, II, III MFs, if further clarification of information is 728 required, a 5 day clarification request will be issued to the MF Holder. If the MF Holder 729 does not respond to a clarification request within the given timeframe, or if the MF has a 730 significant number of deficiencies, then a Letter of Deficiency will be issued. The MF 731 Holder will have 45 calendar days to respond to the Letter of Deficiency. If additional 732 time is required, the MF Holder should contact the relevant Assessment Bureau Director 733 to request an extension. 734

735 For Type IV Dosage Form Master Files, communications with the MF Holder will be in 736 accordance with the Guidance for Industry: Management of Drug Submissions. 737 738 If the response to a Letter of Deficiency has yet to be received or is not satisfactory at the 739 time the decision is being taken on the applicant’s drug submission, then a Notice of 740 Non-Compliance (NON) will be issued to the applicant. No additional correspondence 741 will be sent to the MF Holder however, they are expected to respond in the timeframe 742 given to the applicant to respond to the NON. 743 744 If at the time a decision is being rendered on the applicant’s submission the MF is found 745 to be deficient, then an NON will be sent to the applicant and a Letter of Deficiency will 746 be issued to the MF Holder (unless a letter was previously issued as outlined above). 747

748 2.3.2.1 Clarifications Requests during MF Assessment in Support of a CTA 749

750 If further information is required during the assessment of an MF in support of a CTA, a 751 2 calendar day clarification request will be issued to the MF Holder, and the sponsor will 752 be notified in writing. The sponsor should ensure a timely response is sent by the MF 753 Holder. Failure to provide a satisfactory response within the specified time frame could 754 result in withdrawal of the CTA or issuance of Not Satisfactory Notice as per the 755 Guidance Document: For Clinical Trial Sponsor: Clinical Trial Applications. 756 757

2.3.3 MF Assessment Reports 758 759

Upon completion of the MF assessment, reports may be sent to MF Holders as per Health 760 Canada’s Guidance for Industry: Management of Drug Submissions (refer to section 6.1 761 Reviewer Reports). 762

763


Draft Date: 2016/02/10 17

2.4 Updates to a Registered MF 764 765 Updates are to be filed by the MF Holder and should be addressed to the MF Administration 766 Unit (see section 2.1.6). 767 768 Updates to the MF are not required on a timed basis, but are required when changes are in 769 accordance with the reporting categories outlined in Health Canada’s Post-Notice of Compliance 770 (NOC) Changes - Quality Guidance Document or Guidance Document: For Clinical Trial 771 Sponsor: Clinical Trial Applications . 772 773 A single electronic copy of the Update should be filed with a signed cover letter. The cover letter 774 should clearly indicate: 775 776 • MF number 777 • Dossier ID/HC file number 778 • Type of MF (I, II, III or IV) 779 780 Additional administrative documents: 781 782 • A side by side comparison of the affected sections of the MF listing the level of the change 783

and the impact of that change 784 • An up-to-date list of all applicants authorized to access the MF 785 • A revised MF Application Form 786 • Master File Fee Form and fees 787 788 When filing an Update to a MF for an additional formulation or component, a limit of 50 789 components/formulations per MF will be enforced. Additional components or formulations 790 should be filed in a new MF. The MF Holder should file a current index listing all 791 components/formulations when filing the update for the MF. 792 793 An entire MF should not be filed with an Update unless it is a conversion as outlined in the 794 Guidance Document Preparation of Drug Regulatory Activities in the “Non-eCTD Electronic-795 Only” Format. 796 797 For drug submissions: 798 799 Updates to MFs should be filed when the applicant for an associated submission is required to 800 submit a Level I - Supplement (i.e., a major Quality change) or a Level II - Notifiable Change (in 801 the case of Biologics). At the time of filing, the Update should also include any changes made in 802 the interim period which are considered Level III - Annual Notifications in the Post-Notice of 803 Compliance (NOC) Changes - Quality Guidance Document. This does not exempt applicants 804 from reporting level III changes in their annual report to Health Canada and as such, these 805


18 Draft Date: 2016/02/10

changes should be communicated directly to each applicant referencing the MF in a timely 806 manner. 807 808 All changes to an MF should be accompanied with a side-by-side table listing the changes in 809 comparison to the previous MF and each change should be clearly noted as being a change that 810 falls either under Level I, II, III or IV as described by the Post-NOC Changes: Quality Guidance 811 Document - Appendices 1-3. 812 813 In addition, the MF Holder should notify each applicant that has been granted access to the MF 814 in advance of implementing the change(s) so that applicants can update their records and file the 815 appropriate submission to Health Canada as per the conditions of the Post-NOC Changes Quality 816 Guidance Document. The MF Update should be filed and an acknowledgement letter received in 817 advance of Health Canada receiving the applicant’s submission for the post-NOC change (e.g., 818 Supplement, Notifiable Change). 819 820 For Clinical Trial Applications: 821 822 MF Holders should update MFs if the previously filed information is not current. Furthermore, 823 the MF Holder should notify each clinical trial sponsor that has been granted access to the MF, 824 of the changes so that sponsors can update their records and file either a CTA-Amendment 825 (CTA-A) or a CTA-Notification (CTA-N)to Health Canada as per the Guidance Document: For 826 Clinical Trial Sponsor: Clinical Trial Applications. The Acknowledgement Letter for the update 827 of the MF should be received in advance of filing the CTA-A or CTA-N by clinical trial 828 sponsors. 829 830

2.4.2 Administrative Changes 831 832

2.4.2.1 Transfer of Ownership and Company Name Changes 833 834 For a Transfer in Ownership and a Company Name Change of an MF, the original MF 835 Holder should advise Health Canada in writing if ownership or the name of the MF has 836 changed due to the following reasons: 837 838

Buy-Out 839

Merger 840

Corporate restructuring 841

Company Name Change 842

Any other reason for a Transfer of Ownership 843 844

845


Draft Date: 2016/02/10 19

The following documentation should be provided electronically: 846 847

Cover letter from current MF Holder (or Authorized MF Agent, if applicable) with 848 name and address of the new MF Holder 849

New MF Holder should concurrently provide a letter accepting transfer of ownership 850 (not applicable for a company name change) 851

Proof of company name change (i.e., proof of incorporation or certificate of 852 continuance) 853

Confirmation that all Letters of Access remain valid 854

An up-to-date list of all applicants authorized to access the MF 855

Confirmation that all manufacturing sites and processing remain the same 856

Confirmation that the previous Authorized MF Agent is still valid, if applicable 857

Revised MF Application Form 858 859 All transfers of ownerships should include confirmation from both the current MF Holder 860 and the new MF Holder. It is not acceptable for Health Canada to receive notice of the 861 transaction from only the new MF Holder. 862 863 2.4.2.2 Change of the Authorized MF Agent 864 865 If a company wishes to change the currently Authorized MF Agent, a notification must 866 be provided in writing from the MF Holder to Health Canada’s Administration Unit. It is 867 the responsibility of the MF Holder to ensure that the new appointee has all the 868 information required (e.g., historical records). It is not the responsibility of Health 869 Canada to provide duplicate information to a new appointee. 870

871

2.5 Withdrawal of Letters of Access 872 873 MF Holders who wish to withdraw a Letter of Access (LoA) for a particular applicant to 874 reference a MF should advise Health Canada in writing of the reasons for withdrawal of access 875 and provide a list of applicants who still have access to their MF. 876 877 The applicant whose LoA to the MF is being withdrawn should be informed of the withdrawal of 878 the LoA by the MF Holder. The letter should clearly state the date after which the material will 879 no longer be supplied to the applicant. Substances supplied prior to the date where the LoA was 880 withdrawn due to a supply agreement termination may still be used in authorized products 881 according to the conditions of authorization, but the MF may no longer be referenced in 882 subsequent applications. 883 884 Health Canada will retain the withdrawn LoA or will dispose of it according to appropriate 885 procedures established for record retention and disposal in accordance with the Library and 886 887


20 Draft Date: 2016/02/10

Archives of Canada Act. It is understood that when a LoA is withdrawn, the previously 888 manufactured drug substance/material will no longer be supplied to the applicant. 889 890

2.6 MF Closures 891 892 MF Holders who wish to close a MF should notify Health Canada in writing of the reason for the 893 closure, including a statement that their obligations have been fulfilled (i.e. synthesis, 894 manufacturing process and quality controls have been kept up-to-date and any changes that 895 affected applicants have been communicated to each of them and to Health Canada). On closure, 896 MF holders should provide Health Canada with a list of all applicants using the MF. It is 897 understood that when an MF is closed, the drug substance can no longer be manufactured at that 898 site. Health Canada will assess the reasons for the closure and initiate post-market activities if 899 necessary. If the reasons for closure of the MF are related to safety, the applicant should be 900 informed of the reasons and should contact Health Canada regarding the Health Risk Assessment 901 and any recall actions. The MF will be retained by Health Canada according to appropriate 902 procedures established for record retention and disposal in accordance with the Library and 903 Archives of Canada Act. The MF may be accessed by Health Canada after closure in accordance 904 with the law. 905 906 Health Canada will close and dispose of a MF that has not been assessed within 5 years of 907 registration. If the MF Holder wishes to register the MF again with Health Canada, a new MF 908 should be filed, with all applicable data, and a new MF number will be assigned. Applicable fees 909 will be applied. 910 911 3. CONTACT INFORMATION 912 913 Questions or comments related to this guidance document and to the MF process should be 914 directed to: 915 916 Health Canada 917 Health Products and Food Branch 918 Therapeutic Products Directorate 919 Master File Administration Unit 920 Address Locator 0201D 921 101 promenade Tunney's Pasture Driveway 922 Ottawa Ontario 923 K1A 0K9 924 Canada 925 926 Email: [email protected] 927 Fax number: 613-941-0825 928 929


Draft Date: 2016/02/10 21

4. REFERENCES 930 931

4.1 Health Canada Documents 932 933 Health Canada documents can be found on the website http://www.hc-sc.gc.ca. 934 935 Legislation: 936

Food and Drugs Act (http://laws-lois.justice.gc.ca/eng/acts/f-27/) 937

Food and Drug Regulations (http://laws-938 lois.justice.gc.ca/eng/regulations/c.r.c.,_c._870/index.html) 939

Medical Devices Regulations (http://laws-lois.justice.gc.ca/eng/regulations/sor-98-940 282/FullText.html) 941

Access to Information Act (http://laws-lois.justice.gc.ca/eng/acts/a-1/) 942

Library and Archives of Canada Act (http://laws-lois.justice.gc.ca/eng/acts/L-7.7/) 943 944 Related Guidances: 945

Master File Application Form (http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-946 demande/form/dmfapp_fmmdem_2012-eng.php) 947

Guidance for Industry: Management of Drug Submissions (http://www.hc-sc.gc.ca/dhp-948 mps/prodpharma/applic-demande/guide-ld/mgmt-gest/mands_gespd-eng.php) 949

Guidance Document: Preparation of Drug Regulatory Activities in the Common 950 Technical Document (CTD) Format (http://www.hc-sc.gc.ca/dhp-951 mps/prodpharma/applic-demande/guide-ld/ctd/ctd_prep_nds-eng.php) 952

Guidance Document Preparation of Drug Regulatory Activities in the “Non-eCTD 953 Electronic-Only” Format (http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-954 demande/guide-ld/ctd/gd_prep_non_ectd_ld-eng.php) 955

Guidance Document: Preparation of Drug Regulatory Activities in the Electronic 956 Common Technical Document Format (http://www.hc-sc.gc.ca/dhp-957 mps/prodpharma/applic-demande/guide-ld/ectd/prep_ectd_format-eng.php) 958

Product Licence Application form (http://www.hc-sc.gc.ca/dhp-959 mps/prodnatur/applications/licen-prod/form/form_pl-dlmm-eng.php) 960

Guidance for Industry Preparation of Veterinary New Drug submissions (http://www.hc-961 sc.gc.ca/dhp-mps/vet/legislation/guide-ld/vdd_nds_guide-eng.php) 962

Draft Guidance Document - Quality (Chemistry and Manufacturing) Guidance: New 963 Drug Submissions (NDSs) and Abbreviated New Drug Submissions (ANDSs) 964 (http://www.hc-sc.gc.ca/dhp-mps/consultation/drug-965 medic/qual_ndsands_draft_pdnpadn_ebauche-eng.php) 966

Evidence for Quality of Finished Natural Health Products 967 (http://publications.gc.ca/collections/collection_2007/hc-sc/H164-40-2007E.pdf) 968

Guidance for Industry Preparation of Veterinary New Drug submissions (http://www.hc-969 sc.gc.ca/dhp-mps/vet/legislation/guide-ld/vdd_nds_guide-eng.php) 970


22 Draft Date: 2016/02/10

Post-Notice of Compliance (NOC) Changes: Quality Document (http://www.hc-971 sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-972 ld/postnoc_change_apresac/noc_pn_quality_ac_sa_qualite-eng.php) 973

Notice: Guidance for Industry: Pharmaceutical Quality of Aqueous Solutions 974 (http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-975 ld/chem/aqueous_aqueuses-eng.php) 976

Guidance for Industry - Pharmaceutical Quality of Inhalation and Nasal Products 977 (http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-978 ld/chem/inhalationnas-eng.php) 979

Guidance Document - Quality (Chemistry and Manufacturing) Guidance: Clinical Trial 980 Applications (CTAs) for Pharmaceuticals (http://www.hc-sc.gc.ca/dhp-981 mps/prodpharma/applic-demande/guide-ld/clini/qual_cta_dec-eng.php) 982

Guidance Document: For Clinical Trial Sponsor: Clinical Trial Applications 983 (http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-984 ld/clini/ctdcta_ctddec-eng.php) 985

Guidance for Industry: Stereochemical Issues in Chiral Drug Development 986 (http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/chem/stereo-987 eng.php) 988

Guidance for Industry: Preparation of Quality Information for Drug Submissions in the 989 CTD Format: Biotechnological/ Biological (Biotech) Products (http://www.hc-990 sc.gc.ca/dhp-mps/brgtherap/applic-demande/guides/qualit/prod/tech-doc-991 biologic/ctd_biotech-eng.php) 992

Guidance Document: Submission and Information Requirements for Extraordinary Use 993 New Drugs (EUNDs) (http://www.hc-sc.gc.ca/dhp-mps/brgtherap/applic-994 demande/guides/eund-dnue-eng.php) 995

Health Canada Good Manufacturing Practices (GMP) Guidelines (http://www.hc-996 sc.gc.ca/dhp-mps/compli-conform/gmp-bpf/docs/gui-0001-eng.php) 997

Health Canada Annex to the Good Manufacturing Practices Guidelines and Good 998 Manufacturing Practices (GMP) for Positron Emitting Radiopharmaceuticals (PERs) 999 (http://www.hc-sc.gc.ca/dhp-mps/compli-conform/gmp-bpf/docs/gui_0071_tc-tm-1000 eng.php) 1001

Cleaning Validation Guidances (http://www.hc-sc.gc.ca/dhp-mps/compli-conform/gmp-1002 bpf/validation/gui_0028_tc-tm-eng.php) 1003

Process Validation: Aseptic Processes for Pharmaceuticals (http://www.hc-sc.gc.ca/dhp-1004 mps/compli-conform/gmp-bpf/validation/app-papp-eng.php) 1005

Guidance for Industry: Product – Specific Facility Information (http://www.hc-1006 sc.gc.ca/dhp-mps/brgtherap/applic-demande/guides/info/index-eng.php) 1007

PIC/S Annex 1: Explanatory Notes for Industry on the Preparation of a Site Master File 1008 (http://www.hc-sc.gc.ca/dhp-mps/compli-conform/licences/directives/gui_0005_tc-tm-1009 eng.php) 1010

Validation Documentation Requirements and Responsibilities for Drug Fabricators, 1011


Draft Date: 2016/02/10 23

Packagers/Labellers, Distributors and Importers (http://www.hc-sc.gc.ca/dhp-1012 mps/compli-conform/gmp-bpf/validation/req_resp-exig_resp_tc-tm-eng.php) 1013

Validation Guidelines for Pharmaceutical Dosage Forms (http://www.hc-sc.gc.ca/dhp-1014 mps/compli-conform/gmp-bpf/validation/gui_29-eng.php) 1015

Guidance - Regulatory Requirements to Minimize the Risk of Transmission of 1016 Transmissible Spongiform Encephalopathies (TSEs) via Animal-Sourced Materials used 1017 in the Manufacture of Schedule D (Biologic) Drugs 1018

Guidance Document: Preparation of Clinical Trial Applications for use of Cell Therapy 1019 Products in Humans (08/15) (http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-1020 demande/guide-ld/clini/cell-therapy-therapie-cellulaire-eng.php) 1021

Guidance Document: Plant Molecular Farming (PMF) Applications: Plant -Derived 1022 Biologic Drugs for Human Use (05/14) (http://www.hc-sc.gc.ca/dhp-1023 mps/brgtherap/applic-demande/guides/pmf-mcv-eng.php) 1024

Guidance for Industry: Stereochemical Issues in Chiral Drug Development (02/00) 1025 (http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/chem/stereo-1026 eng.php) 1027

1028

4.2 ICH Guidelines 1029 1030

Q1A(R2): Stability Testing of New Drug Substances and Products (http://www.hc-1031 sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/ich/qual/q1a(r2)-eng.php) 1032

Q1B: Stability Testing: Photostability Testing of New Drug Substances and Products 1033 (http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/ich/qual/q1b-1034 eng.php) 1035

Q1C: Stability Testing Requirements for New Dosage Forms (http://www.hc-1036 sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/ich/qual/q1c-eng.php) 1037

Q1D: Bracketing and Matrixing Designs for Stability Testing of Drug Substances and 1038 Drug Products (http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-1039 ld/ich/qual/q1d-eng.php) 1040

Q1E: Evaluation of Stability Data (http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-1041 demande/guide-ld/ich/qual/q1e-eng.php) 1042

Q2(R1): Validation of Analytical Procedures: Text and Methodology (http://www.hc-1043 sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/ich/qual/q2r1-eng.php) 1044

Q3A(R): Impurities in New Drug Substances (http://www.hc-sc.gc.ca/dhp-1045 mps/prodpharma/applic-demande/guide-ld/ich/qual/q3a(r)-eng.php) 1046

Q3B(R): Impurities in New Drug Products (http://www.hc-sc.gc.ca/dhp-1047 mps/prodpharma/applic-demande/guide-ld/ich/qual/q3b(r)-eng.php) 1048

Q3C: Impurities: Guideline for Residual Solvents (http://www.hc-sc.gc.ca/dhp-1049 mps/prodpharma/applic-demande/guide-ld/ich/qual/q3cr5-step4etape-eng.php) 1050

Q3D: Guideline for Elemental Impurities (http://www.hc-sc.gc.ca/dhp-1051 mps/prodpharma/applic-demande/guide-ld/ich/qual/q3d-step4etape -eng.php) 1052


24 Draft Date: 2016/02/10

Q5A(R1): Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of 1053 Human or Animal Origin (http://www.ich.org/) 1054

Q5B: Analysis of the Expression Construct in Cells Used for Production of r-DNA 1055 Derived Protein Products (http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-1056 demande/guide-ld/ich/qual/q5b-eng.php) 1057

Q5C: Stability Testing of Biotechnological/ Biological Products (http://www.hc-1058 sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/ich/qual/q5c-eng.php) 1059

Q5D: Derivation and Characterisation of Cell Substrates Used for Production of 1060 Biotechnological/ Biological Products (http://www.hc-sc.gc.ca/dhp-1061 mps/prodpharma/applic-demande/guide-ld/ich/qual/q5d-eng.php) 1062

Q5E: Comparability of Biotechnological/ Biological Products Subject to Changes in 1063 their Manufacturing Process (http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-1064 demande/guide-ld/ich/qual/q5e_step4_etape4-eng.php) 1065

Q6A: Specifications: Test Procedures and Acceptance Criteria for New Drug Substances 1066 and New Drug Products: Chemical Substances (http://www.hc-sc.gc.ca/dhp-1067 mps/prodpharma/applic-demande/guide-ld/ich/qual/q6a-step4etape-eng.php) 1068

Q6B: Specifications: Test Procedures and Acceptance Criteria for Biotechnological/ 1069 Biological Products (http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-1070 demande/guide-ld/ich/qual/q6b-eng.php) 1071

Q7: Good Manufacturing Practices Guide for Active Pharmaceutical Ingredients 1072 (http://www.hc-sc.gc.ca/dhp-mps/consultation/compli-conform/2012-gui-0104-eng.php) 1073

Q7 Q&As: Questions and Answers: Good Manufacturing Practice Guide for Active 1074 Pharmaceutical Ingredients (http://www.ich.org/) 1075

Q8(R2): Pharmaceutical Development (http://www.ich.org/) 1076

Q9: Quality Risk Management (http://www.ich.org/) 1077

Q10: Pharmaceutical Quality System (http://www.ich.org/) 1078

Q11: Development and Manufacture of Drug Substances (Chemical Entities and 1079 Biotechnological/ Biological Entities) (http://www.ich.org/) 1080

Questions and Answers on Q11 [to be added when posted] 1081

M4(R3): Organisation of the Common Technical Document for the Registration of 1082 Pharmaceuticals for Human Use (http://www.ich.org/) 1083

M4Q(R1): The Common Technical Document for the Registration of Pharmaceuticals 1084 for Human Use: Quality 1085

M8: Electronic Common Technical Document (eCTD) 1086 1087

4.3 VICH Documents 1088 1089

GL3(R): Stability Testing of New Veterinary Drug Substances and Medicinal Products 1090 (http://www.vichsec.org/guidelines/pharmaceuticals/pharma-quality/pharma-1091 stability.html) 1092

1093


Draft Date: 2016/02/10 25

GL4: Stability Testing: Requirements for New Dosage Forms 1094 (http://www.vichsec.org/guidelines/pharmaceuticals/pharma-quality/pharma-1095 stability.html) 1096

GL5: Stability Testing: Photostability Testing of New Drug Substances and Products 1097 (http://www.vichsec.org/guidelines/pharmaceuticals/pharma-quality/pharma-1098 stability.html) 1099

GL8: Stability Testing for Medicated Premixes 1100 (http://www.vichsec.org/guidelines/pharmaceuticals/pharma-quality/pharma-1101 stability.html) 1102

GL10(R): Impurities in New Veterinary Drug Substances 1103 (http://www.vichsec.org/guidelines/pharmaceuticals/pharma-quality/impurities.html) 1104

GL11(R): Impurities in New Veterinary Medicinal Products 1105 (http://www.vichsec.org/guidelines/pharmaceuticals/pharma-quality/impurities.html) 1106

GL17: Stability Testing of New Biotechnological / Biological Veterinary Medicinal 1107 Products (http://www.vichsec.org/guidelines/biologicals/bio-quality/stability.html) 1108

GL18: Impurities: Residual Solvents in New Veterinary Medicinal Products, Active 1109 Substances and Excipients (http://www.vichsec.org/guidelines/pharmaceuticals/pharma-1110 quality/impurities.html) 1111

GL39: Test Procedures and Acceptance Criteria for New Veterinary Drug Substances 1112 and New Medicinal Products: Chemical Substances 1113 (http://www.vichsec.org/guidelines/pharmaceuticals/pharma-quality/pharma-1114 specifications.html) 1115

GL40:Test Procedures and Acceptance Criteria for New Biotechnological / Biological 1116 Veterinary Medicinal Products (http://www.vichsec.org/guidelines/biologicals/bio-1117 quality/specifications.html) 1118

GL45: Bracketing and Matrixing Designs for Stability Testing of New Veterinary Drug 1119 Substances and Medicinal Products (Step 4) 1120 (http://www.vichsec.org/guidelines/pharmaceuticals/pharma-quality/pharma-1121 stability.html) 1122