GenericGuideline-Quality-QAS13-522_01032013.pdf

7/30/2019 GenericGuideline-Quality-QAS13-522_01032013.pdf

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Working document QAS/13.522

February 2013

RESTRICTED

12

3

4

GUIDELINES ON SUBMISSION OF DOCUMENTATION FOR A5

MULTISOURCE (GENERIC) FINISHED PHARMACEUTICAL6

PRODUCT: QUALITY PART7

DRAFT FOR COMMENT8

9

10

11

World Health Organization 201312

All rights reserved.13

This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. The draft14may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole, in15any form or by any means outside these individuals and organizations (including the organizations' concerned staff and16member organizations) without the permission of the World Health Organization. The draft should not be displayed on any17web site.18

Please send any request for permission to:19

Dr Sabine Kopp, Manager, Medicines Quality Assurance Programme, Quality Assurance & Safety: Medicines, Department20of Essential Medicines and Health Products, World Health Organization, CH-1211 Geneva 27, Switzerland; e-mail:[email protected]

The designations employed and the presentation of the material in this draft do not imply the expression of any opinion23whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or24of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate25border lines for which there may not yet be full agreement.26

The mention of specific companies or of certain manufacturers products does not imply that they are endorsed or27recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors28and omissions excepted, the names of proprietary products are distinguished by initial capital letters.29

All reasonable precautions have been taken by the World Health Organization to verify the information contained in this30draft. However, the printed material is being distributed without warranty of any kind, either expressed or implied. The31responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health32Organization be liable for damages arising from its use.33

This draft does not necessarily represent the decisions or the stated policy of the World Health Organization.3435

Should you have any comments on the attached text, please send these toDr Sabine Kopp, Manager, Medicines Quality Assurance Programme, QualityAssurance and Safety: Medicines, World Health Organization, 1211 Geneva 27,

Switzerland; e-mail: [email protected]; fax: (+41 22) 791 4730 ([email protected]) and toMs Marie Gaspard ([email protected]), by 25 April 2013.

Working documents are sent out electronically and they will also be placed on the

Medicines web site for comment. If you do not already receive directly our draft

guidelines please let us have your e-mail address (to [email protected]) and we will

add it to our electronic mailing list.


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SCHEDULE FOR THE PROPOSED ADOPTION PROCESS OF DOCUMENT QAS/13.522:37

GUIDELINES ON SUBMISSION OF DOCUMENTATION FOR A MULTISOURCE38

(GENERIC) FINISHED PHARMACEUTICAL PRODUCT: QUALITY PART39

40

41

42

43

44

Recommended by the 47th WHO Expert Committee on

Specifications for Pharmaceutical PreparationsOctober 2012

Drafting of guidelines by L. Paleshnuik, Canada 25 February 2013

Draft mailed for comments 1 March 2013

Consolidation of comments May 2013

Review of comments in informal consultation on quality

assurance guidelinesJuly 2013

Consolidation of comments following consultation September 2013

Presentation to 48th meeting of the WHO Expert

Committee on Specifications for Pharmaceutical

Preparations

14-18 October 2013

Any further action as required


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4546

CONTENTS47

page48

49

1. Introduction .......................................................................................................... 4501.1 Background51

1.2 Objectives52

1.3 Scope53

1.4 General principles54

1.5 Guidance on format55

56

2. Glossary................................................................................................................. 75758

3. Quality summaries ........... ......... ......... ........... .......... ......... .......... .......... ......... ........ 9593.1 ........... Module 2.3: Quality overall summary product dossiers (QOS-PD)60

61

4. Module 3: Quality ........ .......... .......... ......... .......... ........... ......... ......... ........... ........ 1062 4.1 Table of contents of Module 363

4.2 Body of data64

3.2.S Drug substance (or active pharmaceutical ingredient (API))65

3.2.P Drug product (or finished pharmaceutical product (FPP))66

3.2.A Appendices67

3.2.R Regional information68

4.3 Literature references69

70

5. References ........................................................................................................... 587172

Appendix 1 - Recommendations for conducting and assessing comparative dissolution 6073

profiles7475

76

77

78

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1. INTRODUCTION8081

1.1 Background82

83

Through the International Conference on Harmonisation (ICH) process, considerable84

harmonization has been achieved on the organization for the Quality Module of registration85

documents with the issuance of the Common Technical Document (CTD) - Quality (ICH86

M4Q) guideline. This recommended format in the M4Q guideline for the quality information87

of registration applications has become widely accepted by regulatory authorities both within88

and beyond the ICH Regions.89

90

This document, Guidelines on submission of documentation for a multisource (generic)91

finished pharmaceutical product: quality part, provides recommendations on the quality92

information for active pharmaceutical ingredients (APIs) and finished pharmaceutical93

products (FPPs) that should be submitted to national medicines regulatory authorities94

(NMRAs) to support product dossiers (PDs).95

96

Alternate approaches to the principles and practices described in this document may be97 acceptable provided they are supported by adequate scientific justification. It is also98

important to note that the NMRAs may request information or material, or define conditions99

not specifically described in this guidance, in order to adequately assess the quality of a100

pharmaceutical product.101

102

1.2 Objectives103

104

These guidelines are intended to:105

106

assist applicants on the preparation of the Quality Module of PDs for multisource107products by providing clear general guidance on the format of these dossiers;108

109 adopt the modular format of the Common Technical Document - Quality (M4Q) as110

developed by ICH;111

112

provide guidance on the technical and other general data requirements.113114

These measures are intended to promote effective and efficient processes for the development115

of these PDs by applicants and the subsequent assessment procedures by NMRAs.116

117

1.3 Scope118

119

These guidelines apply to PDs for multisource pharmaceutical products containing existing120

APIs of synthetic or semi-synthetic origin. For the purposes of these guidelines an existing121API is one that has been previously approved through a finished product by a stringent122

regulatory authority1

or WHO. Fermentation, biological, biotechnological and herbal APIs123

are covered by other guidelines.124

1Stringent regulatory authority (SRA): a regulatory authority which is:

a member of the International Conference on Harmonisation (ICH) (as specified on www.ich.org);

or

an ICH observer, being the European Free Trade Association (EFTA), as represented by Swiss

Medic, and Health Canada (as may be updated from time to


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125

1.4 General principles126

127

To facilitate the preparation of the PD these guidelines are organized in accordance with the128

structure of the Common Technical Document Quality (M4Q) guideline, as developed by129

ICH.130

131

The text of the M4Q (CTD-Q) guideline has been restated in these guidelines in bold text,132

verbatim, with minor modifications to accommodate WHO terminology and include certain133

text that would be appropriate for multisource pharmaceutical products, notably:134

135

Drug substance is replaced with active pharmaceutical ingredient or API;136 Drug product is replaced with finished pharmaceutical product or FPP;137 application is replaced with product dossier or PD;138 combination product is replaced with fixed-dose combination or FDC;139 clinical batches is replaced with comparative bioavailability or biowaiver batches.140

141

Following the bold text of the M4Q (CTD-Q) guideline additional guidance is provided in142plain text to easily distinguish from the ICH text and is included to provide further clarity on143

general expectations for the content of PDs. This approach is intended to facilitate the144

identification and origin of the text in the guidelines (i.e. from ICH or additional information).145

146

The content of these guidelines should be read in conjunction with relevant information147

described in other existing NMRA guidelines, WHO guidelines or ICH reference documents148

and guidelines. The quality of existing APIs and corresponding multisource products should149

not be inferior to new APIs and innovator FPPs. Therefore, the principles of the ICH150

guidelines that are referenced throughout these and other guidelines may also equally apply to151

existing APIs and multisource products.152

153

Scientific literature may be appropriate to fulfil the requirements for some of the information154or parameters outlined in these guidelines (e.g. qualification of specified identified155

impurities). Furthermore the requirements outlined in certain sections may not be applicable156

for the proposed API or FPP. In these situations a summary and the full reference to the157

scientific literature should be provided or the non-applicability of the requested information158

should be clearly indicated as such with an accompanying explanatory note.159

160

1.5 Guidance on format161

162

For the format and presentation of the PD recommendations outlined in the WHO general163

filing guidelines: Guidelines on submission of documentation for a multisource (generic)164

finished pharmaceutical product: preparation of product dossiers in common technical165

document format(TRS 961, Annex 15) may be followed, with the understanding that module1661 contains regionally required information and therefore the required contents will vary167

depending on the NMRA to which the PD is filed.168

169

time); or

a regulatory authority associated with an ICH member through a legally-binding, mutual

recognition agreement including Australia, Iceland, Liechtenstein and Norway (as may be

updated from time to time).


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There may be a number of instances where repeated sections can be considered appropriate.170

Whenever a section is repeated it should be made clear what the section refers to by creating a171

distinguishing title in parentheses following the M4Q (CTD-Q) guideline heading, e.g. 3.2.S172

Drug substance (or API) (name, Manufacturer A).173

174

Following are recommendations for the presentation of the information in the Quality Module175

for different scenarios that may be encountered:176

177

the Open part(non-proprietary information) of each DMF should always be included178in its entirety in the PD, as an annex to 3.2.S:179

180

for an FPP containing more than one API: one complete 3.2.S section should be181provided for one API,followed by other complete 3.2.S sections for each other API;182

183

for an API from multiple manufacturers: one complete 3.2.S section should be184provided for the API from one manufacturer,followed by other complete 3.2.S185

sections for each other API manufacturer,186

187 for an FPP with multiple strengths (e.g. 10, 50, 100 mg): one complete 3.2.P section188

should be provided with the information for the different strengths provided within the189

subsections. One complete copy of the PD should be provided for each FPP strength;190

191

for an FPP with multiple container closure systems (e.g. bottles and unit dose blisters):192one complete 3.2.P section should be provided with the information for the different193

presentations provided within the subsections;194

195

for multiple FPPs (e.g. tablets and a parenteral product): a separate dossier is required196for each FPP,197

198

for an FPP supplied with reconstitution diluent(s), one complete 3.2.P section199should be provided for the FPP,followed by the information on the diluent(s) in a200

separate part 3.2.P, as appropriate;201

202

for a co-blistered FPP, one complete 3.2.P section should be provided for each203product.204

205

206


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2. GLOSSARY207208

The definitions provided below apply to the words and phrases used in these guidelines.209

Although an effort has been made to use standard definitions as far as possible, they may210

have different meanings in other contexts and documents. The following definitions are211

provided to facilitate interpretation of the guidelines.212

213

active pharmaceutical ingredient (API)214

Any substance or mixture of substances intended to be used in the manufacture of a215

pharmaceutical dosage form, and that, when so used, becomes an active ingredient of that216

pharmaceutical dosage form. Such substances are intended to furnish pharmacological activity217

or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or218

to affect the structure and function of the body (WHO Technical Report Series, No. 961,219

Annex 10, 2011).220

221

API starting material222

A raw material, intermediate, or an API that is used in the production of an API and that is223

incorporated as a significant structural fragment into the structure of the API. An API starting224 material can be an article of commerce, a material purchased from one or more suppliers225

under contract or commercial agreement, or produced in-house (ICH Q7). See also starting226

materials for synthesis.227

228

applicant229

The person or company who submits an application for marketing authorization of a new230

pharmaceutical product, an update to an existing marketing authorization or a variation to an231

existing market authorization. (WHO Technical Report Series, No. 929, Annex 5, 2005).232

233

BCS highly soluble234

An API for which the highest dose recommended by WHO (if the API appears on the WHO235

Model List of Essential Medicines) or highest dose strength available on the market as an oral236solid dosage form (if the API does not appear on the WHO Model List of Essential237

Medicines) is soluble in 250 ml or less of aqueous media over the pH range of 1.26.8 at238

37C (WHO Technical Report Series, No. 937, Annex 7, 2006).239

240

commitment batches241

Production batches of an API or FPP for which the stability studies are initiated or completed242

post-approval through a commitment made in a regulatory application (WHO Technical243

Report Series, No. 953, Annex 2, 2009).244

245

comparator product (reference product)246

A pharmaceutical product with which the generic product is intended to be interchangeable in247

clinical practice. The comparator or reference product will normally be the innovator product248for which efficacy, safety and quality have been established (WHO Technical Report Series,249

No. 937, Annex 7, 2006).250

251

existing API252

An API that is not considered a new active substance, that has been previously approved253

through a finished product by a stringent regulatory authority or WHO, but requires the filing254

of a dossier. This would include, for example, new PDs and variations to multisource products.255

256finished pharmaceutical product (FPP)257


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A finished dosage form of a pharmaceutical product, which has undergone all stages of258

manufacture, including packaging in its final container and labelling (WHO Technical Report259

Series, No. 961, Annex 10, 2011).260

261

innovator pharmaceutical product262

Generally the pharmaceutical product that was first authorized for marketing (normally as a263

patented product) on the basis of documentation of efficacy, safety and quality (WHO264

Technical Report Series, No. 937, Annex 7, 2006).265

266

manufacturer267

A company that carries out operations such as production, packaging, repackaging, labelling268

and relabelling of pharmaceuticals. (WHO Technical Report Series, No. 961, Annex 3, 2011).269

270

multisource (generic) pharmaceutical products271

Pharmaceutically equivalent or pharmaceutically alternative products that may or may not be272

therapeutically equivalent. Multisource pharmaceutical products that are therapeutically273

equivalent are interchangeable (WHO Technical Report Series, No. 937, Annex 7, 2006).274

275 officially recognized pharmacopoeia (or compendia)276

Those pharmacopoeias whose standards are officially recognized by an NMRA. These may277

be national, regional or international pharmacopoeia, at the discretion of the NMRA.278

279

ongoing stability study280

The study carried out by the manufacturer on production batches according to a281

predetermined schedule in order to monitor, confirm and extend the projected retest period (or282

shelf-life) of the API, or confirm or extend the shelf-life of the FPP (WHO Technical Report283

Series, No. 953, Annex 2, 2009).284

285pilot- scale batch286

A batch of an API or FPP manufactured by a procedure fully representative of and simulating287that to be applied to a full production-scale batch. For example, for solid oral dosage forms, a288

pilot scale is generally, at a minimum, one-tenth that of a full production scale or 100 000289

tablets or capsules, whichever is the larger; unless otherwise adequately justified (WHO290


292

primary batch293

A batch of an API or FPP used in a stability study, from which stability data are submitted in294

a registration application for the purpose of establishing a re-test period or shelf-life (WHO295


297production batch298

A batch of an API or FPP manufactured at production scale by using production equipment in299a production facility as specified in the application (WHO Technical Report Series, No. 953,300

Annex 2, 2009).301

302

starting materials for synthesis303

Materials that mark the beginning of the manufacturing process as described in an application304

or in a DMF. A starting material for a synthetic API is a chemical compound of defined305

molecular structure that contributes to the structure of the API. See alsoAPI starting material.306

307

308


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3. QUALITY SUMMARIES309

3103.1 Module 2.3: Quality overall summary product dossiers (QOS-PD)311

312

The Quality Overall Summary (QOS) is a summary that follows the scope and the313

outline of the Body of Data in Module 3. The QOS should not include information, data314

or justification that was not already included in Module 3 or in other parts of the CTD.315

316

The QOS should include sufficient information from each section to provide the Quality317

assessor with an overview of Module 3. The QOS should also emphasise critical key318

parameters of the product and provide, for instance, justification in cases where319

guidelines were not followed. The QOS should include a discussion of key issues that320

integrates information from sections in the Quality Module and supporting information321

from other Modules (e.g., qualification of impurities via toxicological studies), including322

cross-referencing to volume and page number in other Modules.323324

The WHO Quality overall summary product dossiers (QOS-PD) template or the QOS325

template associated with the intended NMRA, if available, should be completed for326 multisource pharmaceutical products containing APIs of synthetic or semi-synthetic origin327

(see 1.3 Scope for further clarification) and their corresponding FPPs. For simplicity, these328

guidelines will refer to the QOS-PD, which can be downloaded from the WHO web site.329

330

All sections and fields in the QOS-PD template that would be applicable should be completed.331

It is understood that certain sections and fields may not apply and should be indicated as such332

by reporting not applicable in the appropriate area with an accompanying explanatory note.333

334

The use of tables to summarize the information is encouraged, where possible. The tables335

included in the template may need to be expanded or duplicated (e.g. for multiple strengths),336

as necessary. These tables are included as illustrative examples of how to summarize337

information. Other approaches to summarize the information can be used if they fulfil the338same purpose.339

340

4. MODULE 3: QUALITY341342

4.1 Table of contents of Module 3343

344

A Table of contents for the filed product dossier should be provided.345

3464.2 Body of data347

348

3.2.S Drug substance (or active pharmaceutical ingredient (API))349

350The NMRA, at its discretion, may accept API information in one or more of the following351

three options:352

353

Option 1: Certificate of suitability of the European Pharmacopoeia (CEP); or354 Option 2: Drug master file (DMF) procedure;355 Option 3: Full details in the PD.356

357

The applicant should clearly indicate at the beginning of the API section (in the PD and in the358

QOS-PD) how the information on the API for each API manufacturer is being submitted. The359


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API information submitted by the applicant/FPP manufacturer should include the following360

for each of the options used.361

362

Option 1: Certificate of Suitability of the European Pharmacopoeia (CEP)363364

A complete copy of the CEP (including any annexes) should be provided inModule 1.365

The declaration of access for the CEP should be duly filled out by the CEP holder on366

behalf of the FPP manufacturer or applicant to the NMRA who refers to the CEP.367

368

In addition, a written commitment should be included that the applicant will inform369

the NMRA in the event that the CEP is withdrawn. It should also be acknowledged by370

the applicant that withdrawal of the CEP would require additional consideration of the371

API data requirements to support the PD. The written commitment should accompany372

the copy of the CEP inModule 1.373

374

Along with the CEP, the applicant should supply the following information in the375

dossier, with data summarized in the QOS-PD.376

377o 3.2.S.1.3 General properties discussions on any additional applicable378

physicochemical and other relevant API properties that are not controlled by379

the CEP and Ph.Eur. monograph, e.g. solubilities and polymorphs as per380

guidance in this section.381

o 3.2.S.3.1 Elucidation of structure and other characteristicsstudies to identify382polymorphs (exception: where the CEP specifies a polymorphic form) and383

particle size distribution, where applicable, as per guidance in this section.384

o 3.2.S.4.1 Specification the specifications of the FPP manufacturer including385all tests and limits of the CEP and Ph.Eur. monograph and any additional tests386

and acceptance criteria that are not controlled in the CEP and Ph.Eur.387

monograph, such as polymorphs and/or particle size distribution.388

o 3.2.S.4.2 / 3.2.S.4.3 Analytical procedures and validation for any methods389 used by the FPP manufacturer in addition to those in the CEP and Ph.Eur.390monograph.391

o 3.2.S.4.4 Batch analysisresults from two batches of at least pilot scale,392demonstrating compliance with the FPP manufacturers API specifications.393

o 3.2.S.5Reference standards or materials information on the FPP394manufacturers reference standards.395

o 3.2.S.6 Container closure systemspecifications including descriptions and396identification of primary packaging components. Exception: where the CEP397

specifies a container closure system and the applicant declares to use the same398

container closure system.399

o 3.2.S.7 Stabilityexception: where the CEP specifies a re-test period that is400the same as or of longer duration, and storage conditions which are the same or401higher temperature and humidity as proposed by the applicant.402

403

In the case of sterile APIs, data on the sterilization process of the API, including404

validation data, should be included in the PD.405

406

Option 2: Drug master file (DMF) procedure407408

Full details of the chemistry, manufacturing process, quality controls during409

manufacturing and process validation for the API may be submitted to the NMRA as a410


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DMF by the API manufacturer, for example as outlined in WHOs Guidelines on411

active pharmaceutical ingredient master file procedure (Technical Report Series, No.412

948, Annex 4, 2008).413

414

In such cases, the Open part(non-proprietary information) needs to be included in its415entirety in the PD as an annex to 3.2.S. In addition, the applicant/FPP manufacturer416

should complete the following sections in the PD and QOS-PD in full according to the417

guidance provided unless otherwise indicated in the respective sections:418

419

General information S.1.1 through S.1.3420

Manufacture S.2421

Manufacturer(s) S.2.1422

Description of manufacturing process and process controls S.2.2423

Controls of critical steps and intermediates S.2.4424

Elucidation of structure and other characteristics S.3.1425

Impurities S.3.2426

Control of the APIS.4.1 through S.4.5427

Reference standards or materials S.5428 Container closure system S.6429

Stability S.7.1 through S.7.3430

431

It is the responsibility of the applicant to ensure that the complete DMF (i.e. both the432

applicants Open partand the API manufacturer'sRestricted part) is supplied to the433

NMRA directly by the API manufacturer and that the applicant has access to the434

relevant information in the DMF concerning the current manufacture of the API.435

436

A copy of the letter of access should be provided in the PDModule 1.437

438

DMF holders can use the guidance provided for the option Full details in the PD for439

preparation of the relevant sections of the Open and Restricted parts of their DMFs.440Reference can also be made to the DMF guidelines in WHO Technical Report Series,441

No. 948, Annex 4.442

443

Option 3: Full details in the PD444445

Information on the 3.2.S Active pharmaceutical ingredientsections, including full446

details of chemistry, manufacturing process, quality controls during manufacturing447

and process validation for the API, should be submitted in the PD as outlined in the448

subsequent sections of these guidelines. The QOS-PD should be completed as per449

Section 3.1 of these guidelines.450

451

3.2.S.1 General Information (name, manufacturer)452453

3.2.S.1.1 Nomenclature (name, manufacturer)454

455

Information on the nomenclature of the API should be provided. For example:456

457

(Recommended) International Non-proprietary Name (INN);458 Compendial name, if relevant;459 Chemical name(s);460


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Company or laboratory code;461 Other non-proprietary name(s) (e.g., national name, United States Adopted462

Name (USAN), British Approved Name (BAN)); and463

Chemical Abstracts Service (CAS) registry number.464465

The listed chemical names should be consistent with those appearing in scientific literature466

and those appearing on the product labelling information (e.g. summary of product467

characteristics, package leaflet (also known as patient information leaflet or PIL), labelling).468

Where several names exist, the preferred name should be indicated.469

470

3.2.S.1.2 Structure (name, manufacturer)471

472

The structural formula, including relative and absolute stereochemistry, the molecular473

formula, and the relative molecular mass should be provided.474475

This information should be consistent with that provided in Section 3.2.S.1.1. For APIs476

existing as salts, the molecular mass of the free base or acid should also be provided.477

4783.2.S.1.3 General properties (name, manufacturer)479

480

A list should be provided of physicochemical and other relevant properties of the API.481482

This information can be used in developing the specifications, in formulating FPPs and in the483

testing for release and stability purposes.484

485

The physical and chemical properties of the API should be discussed including the physical486

description, solubilities in common solvents (e.g. water, alcohols, dichloromethane, acetone),487

quantitative aqueous pH solubility profile (e.g. pH 1.2 to 6.8, dose/solubility volume),488

polymorphism, pH and pKa values, UV absorption maxima and molar absorptivity, melting489

point, refractive index (for a liquid), hygroscopicity, partition coefficient, etc (see table in the490QOS-PD). This list is not intended to be exhaustive, but provides an indication as to the type491

of information that could be included.492

493

Some of the more relevant properties to be considered for APIs are discussed below in greater494

detail.495

496Physical description497

498

The description should include appearance, colour and physical state. Solid forms should be499

identified as being crystalline or amorphous (see 3.2.S.3.1 for further information on API500

solid forms).501

502Solubilities/quantitative aqueous pH solubility profile503

504

The following should be provided for all options for the submission of API data.505

506

The solubilities in a number of common solvents should be provided (e.g. water, alcohols,507

dichloromethane, acetone).508

509


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The solubilities over the physiological pH range (pH 1.2 to 6.8) in several buffered media510

should be provided in mg/ml. If this information is not readily available (e.g. literature511

references), it should be generated in-house.512

513

For solid oral dosage forms, the dose/solubility volume should be provided as determined by:514

515

dose/solubility volume =largest dosage strength (mg)

the minimum concentration of the drug (mg/ml)*

516

* corresponding to the lowest solubility determined over the physiological pH range (pH 1.2517

to 6.8) and temperature (37 0.5C).518

519

As per the Biopharmaceutics Classification System (BCS), highly soluble (or highly water520

soluble) APIs are those with a dose/solubility volume of less than or equal to 250 ml.521

522

For example, compound A has as its lowest solubility at 37 0.5C, 1.0 mg/ml at pH 6.8 and523

is available in 100 mg, 200 mg and 400 mg strengths. This API would not be considered a524

BCShighly soluble API as its dose/solubility volume is greater than 250 ml (400 mg/1.0525 mg/ml = 400 ml).526

527

Polymorphism528

529

As recommended in ICHs CTD-Q Questions and answers/location issues document the530

following refers to where specific data should be located in the PD:531

532

the polymorphic form(s) present in the proposed API should be listed in Section5333.2.S.1.3;534

535

the description of manufacturing process and process controls (3.2.S.2.2) should536indicate which polymorphic form is manufactured, where relevant;537

538

the literature references or studies performed to identify the potential polymorphic539forms of the API, including the study results, should be provided in Section 3.2.S.3.1;540

541

if a polymorphic form is to be defined or limited (e.g. for APIs that are notBCShighly542soluble and/or where polymorphism has been identified as an issue), details should be543

included in 3.2.S.4.1 through 3.2.S.4.5.544

545

Additional information is included in the referenced sections of these guidelines.546

547

Particle size distribution548

549As recommended in ICHs CTD-Q Questions and Answers/Location Issues document, the550

studies performed to identify the particle size distribution of the API should be provided in551

Section 3.2.S.3.1 (refer to this section of these guidelines for additional information).552

553

Information from literature554

555

Supportive data and results from specific studies or published literature can be included556

within or attached to this section.557


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558

Reference documents: ICH Q6A559

560

3.2.S.2 Manufacture (name, manufacturer)561562

3.2.S.2.1 Manufacturer(s) (name, manufacturer)563

564

The name, address, and responsibility of each manufacturer, including contractors, and565

each proposed production site or facility involved in manufacturing and testing should566

be provided.567568

The facilities involved in the manufacturing, packaging, labelling, testing and storage of the569

API should be listed. If certain companies are responsible only for specific steps (e.g. milling570

of the API), this should be clearly indicated.571

572

The list of manufacturers/companies should specify the actual addresses of production or573

manufacturing site(s) involved (including block(s) and units(s)), rather than the administrative574

offices. Telephone number(s), fax number(s) and e-mail address(es) should be provided.575576

A valid manufacturing authorization should be provided for the production of APIs. If577

available, a certificate of GMP compliance should be provided in the PD in Module 1.578

579

3.2.S.2.2 Description of Manufacturing Process and Process Controls (name,580

manufacturer)581

582

The description of the API manufacturing process represents the applicants583

commitment for the manufacture of the API. Information should be provided to584

adequately describe the manufacturing process and process controls. For example:585

586

A flow diagram of the synthetic process(es) should be provided that includes molecular587formulae, weights, yield ranges, chemical structures of starting materials, intermediates,588

reagents and API reflecting stereochemistry, and identifies operating conditions and589

solvents.590

591

A sequential procedural narrative of the manufacturing process should be submitted.592

The narrative should include, for example, quantities of raw materials, solvents,593

catalysts and reagents reflecting the representative batch scale for commercial594

manufacture, identification of critical steps, process controls, equipment and operating595

conditions (e.g., temperature, pressure, pH, time).596

597

Alternate processes should be explained and described with the same level of detail as598

the primary process. Reprocessing steps should be identified and justified. Any data to599support this justification should be either referenced or filed in 3.2.S.2.5.600

601

Where the DMF procedure is used, a cross-reference to the Restricted part of the DMF may602

be indicated for confidential information. In this case, if detailed information is presented in603

the Restricted part, the information to be provided for this section of the PD includes a flow604

chart (including molecular structures and all reagents and solvents) and a brief outline of the605

manufacturing process, with special emphasis on the final steps including purification606

procedures. However, for sterile APIs full validation data on the sterilization process should607


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be provided in the Open part (in cases where there is no further sterilization of the final608

product).609

610

The following requirements apply to the third option for submission of API information,611

where full details are provided in the dossier.612

613

As discussed in ICH Q7 and WHO Technical Report Series, No. 957 Annex 2, the point at614

which theAPI starting material is introduced into the manufacturing process is the starting615

point of the application of GMP requirements. TheAPI starting material itself needs to be616

proposed and its choice justified by the manufacturer and accepted as such by assessors. The617

API starting material should be proposed taking into account the complexity of the molecule,618

the proximity of theAPI starting material to the final API, the availability of theAPI starting619

material as a commercial chemical and the quality controls placed upon theAPI starting620

material. This justification should be documented in the dossier and be available for review621

by WHO GMP inspectors.622

623

In situations where the API starting material is a complex molecule and only a minimal624

number of synthetic steps from the final API, a further molecule called the starting material625 for synthesis should be proposed and its choice justified by the applicant. The starting626

material for synthesis defines the starting point in the manufacturing process for an API to be627

described in an application. The applicant should propose and justify which substances628

should be considered as starting materials for synthesis. See section 3.2.S.2.3 for further629

guidance. In the case where the precursor to the API is obtained from fermentation, or is from630

plant or animal origin, such a molecule can be considered the API starting material regardless631

of complexity.632

633

A one step synthesis may be accepted in exceptional cases, for example where the API634

starting material is covered by a CEP, or where the API starting material is an API accepted635

through the DMF procedure, or when the structure of the API is so simple that a one step636

synthesis can be justified, e.g. ethambutol or ethionamide.637638

In addition to the detailed description of the manufacturing process as per ICH M4Q, the639

recovery of materials, if any, should be described in detail with the step in which they are640

introduced into the process. Recovery operations should be adequately controlled such that641

impurity levels do not increase over time. For recovery of solvents, any processing to642

improve the quality of the recovered solvent should be described. Regarding recycling of643

filtrates (mother liquors) to obtain second crops, information should be available on maximum644

holding times of mother liquors and maximum number of times the material can be recycled.645

Data on impurity levels should be provided to justify recycling of filtrates.646

647

Where there are multiple manufacturing sites for one API manufacturer, a comprehensive list648

in tabular form should be provided comparing the processes at each site and highlighting any649differences.650

651

All solvents used in the manufacture (including purification and/or crystallization step(s))652

should be clearly identified. Solvents used in the final steps should be of high purity. Use of653

recovered solvents in the final steps of purification and/or crystallization is not654

recommended, however their use can be justified on presentation of sufficient data655

demonstrating that recovered solvents meet appropriate standards as outlined in ICH Q7.656

657


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Where polymorphic/amorphous forms have been identified, the form resulting from the658

synthesis should be stated.659

660

Where particle size is considered a critical attribute (see 3.2.S.3.1 for details), the particle size661

reduction method(s) (milling, micronization) should be described.662

663

Justification should be provided for alternate manufacturing processes. Alternate processes664

should be explained with the same level of detail as the primary process. It should be665

demonstrated that batches obtained by the alternate processes have the same impurity profile666

as the principal process. If the obtained impurity profile is different it should be demonstrated667

to be acceptable according to the requirements described under S.3.2.668

669

It is acceptable to provide information on pilot scale manufacture, provided it is representative670

of production scale and scale-up is reported immediately to the NMRA according to the671

requirements of the associated variation guidelines (e.g. WHO Technical Report Series, No.672

X, Annex Y, 2013).673

674

3.2.S.2.3 Control of Materials (name, manufacturer)675676

Materials used in the manufacture of the API (e.g., raw materials, starting materials,677

solvents, reagents, catalysts) should be listed identifying where each material is used in678

the process. Information on the quality and control of these materials should be679

provided. Information demonstrating that materials meet standards appropriate for680

their intended use should be provided, as appropriate. (Details in 3.2.A.2)681682

Where the DMF procedure is used, a cross-reference to the Restricted part of the DMF is683

considered sufficient for this section.684

685



TheAPI starting material should be fully characterized and suitable specifications proposed689

and justified, including at a minimum control for identity, assay, impurity content and any690

other critical attribute of the material. For eachAPI starting material, the name and691

manufacturing site address of the manufacturer(s) should be indicated. A brief description of692

the preparation of theAPI starting material should be provided for each manufacturer,693

including the solvents, catalysts and reagents used. A single set of specifications should be694

proposed for the starting material that applies to material from all sources. Any future695

changes to the API starting material manufacturers, mode of preparation or specifications696

should be notified.697

698

As indicated in section 3.2.S.2 there are occasions where a starting material for synthesis may699also need to be defined. In general, the starting material for synthesisdescribed in the PD700

should:701

702

be a synthetic precursor of one or more synthesis steps prior to the final API703intermediate. Acids, bases, salts, esters and similar derivatives of the API, as well as704

the racemate of a single enantiomer API, are not considered final intermediates;705

be a well characterized, isolated and purified substance with its structure fully706elucidated including its stereochemistry (when applicable);707


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have well defined specifications that include among others one or more specific708identity tests and tests and limits for assay and specified, unspecified and total709

impurities; and710

be incorporated as a significant structural fragment into the structure of the API.711712

Copies of the specifications for the materials used in the synthesis, extraction, isolation and713

purification steps should be provided in the PD, including starting materials, reagents,714

solvents, catalysts and recovered materials. Confirmation should be provided that the715

specifications apply to materials used at each manufacturing site. A certificate of analysis of716

the starting material for synthesis should be provided. A summary of the information on717

starting materials should be provided in the QOS-PD.718

719

The carry-over of impurities of the starting materials for synthesis into the final API should be720

considered and discussed.721

722

A letter of attestation should be provided confirming that the API and the starting materials723

and reagents used to manufacture the API are withoutrisk of transmitting agents of animal724

spongiform encephalopathies.725726

When available, a CEP demonstrating TSE-compliance should be provided. A complete copy727

of the CEP (including any annexes) should be provided in Module 1.728

729


731

3.2.S.2.4 Controls of Critical Steps and Intermediates (name, manufacturer)732

733

Critical Steps: Tests and acceptance criteria (with justification including experimental734

data) performed at critical steps identified in 3.2.S.2.2 of the manufacturing process to735

ensure that the process is controlled should be provided.736

737Intermediates: Information on the quality and control of intermediates isolated during738

the process should be provided.739740

Where the DMF procedure is used a cross-reference to the Restricted part of the DMF is741

considered sufficient for this section of the PD, with the exception of information that is also742

relevant for the applicant (ref: APIMF guidelines in WHO Technical Report Series, No. 948,743

Annex 4).744

745



748

The critical steps should be identified. These can be among others: steps where significant749impurities are removed or introduced, steps introducing an essential molecular structural750

element such as a chiral centre or resulting in a major chemical transformation, steps having751

an impact on solid-state properties and homogeneity of the API that may be relevant for use in752

solid dosage forms.753

754

Specifications for isolated intermediates should be provided and should include tests and755

acceptance criteria for identity, purity and assay, where applicable.756

757



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759

3.2.S.2.5 Process Validation and/or Evaluation (name, manufacturer)760

761

Process validation and/or evaluation studies for aseptic processing and sterilisation762

should be included.763764


considered sufficient for this section of the PD.766

767



770

It is expected that the manufacturing processes for all APIs are properly controlled. If the API771

is prepared as sterile, a complete description should be provided for aseptic processing and/or772

sterilization methods. The controls used to maintain the sterility of the API during storage and773

transportation should also be provided. Alternate processes should be justified and described774

(see guidance in 3.2.S.2.2 for the level of detail expected).775

776 3.2.S.2.6 Manufacturing Process Development (name, manufacturer)777

778

A description and discussion should be provided of the significant changes made to the779

manufacturing process and/or manufacturing site of the API used in producing780

comparative bioavailability or biowaiver, scale-up, pilot, and, if available, production781

scale batches.782

783

Reference should be made to the API data provided in Section 3.2.S.4.4.784785


considered sufficient for this section of the PD.787

7883.2.S.3 Characterisation (name, manufacturer)789

790

3.2.S.3.1 Elucidation of Structure and other Characteristics (name, manufacturer)791

792

Confirmation of structure based on e.g., synthetic route and spectral analyses should be793

provided. Information such as the potential for isomerism, the identification of794

stereochemistry, or the potential for forming polymorphs should also be included.795796

Elucidation of structure797

798

The PD should include quality assurance (QA) certified copies of the spectra, peak799

assignments and a detailed interpretation of the data of the studies performed to elucidate800and/or confirm the structure of the API. The QOS-PD should include a list of the studies801

performed and a conclusion from the studies (e.g. if the results support the proposed802

structure).803

804

For APIs that are not described in an officially recognized pharmacopoeia, the studies carried805

out to elucidate and/or confirm the chemical structure normally include elemental analysis,806

infrared (IR), ultraviolet (UV), nuclear magnetic resonance (NMR) and mass spectra (MS)807

studies. Other tests could include X-ray powder diffraction (XRPD) and differential scanning808

calorimetry (DSC).809


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810

For APIs that are described in an officially recognized pharmacopoeia, it is generally811

sufficient to provide copies of the IR spectrum of the API from each of the proposed812

manufacturer(s) run concomitantly with an officially recognized pharmacopoeial reference813

standard. See Section 3.2.S.5 for details on acceptable reference standards or materials.814

815

Isomerism/Stereochemistry816

817

When an API is chiral, it should be specified whether specific stereoisomers or a mixture818

of stereoisomers have been used in the comparative biostudies, and information should819

be given as to the stereoisomer of the API that is to be used in the FPP.820

821Where the potential for stereoisomerism exists, a discussion should be included of the822

possible isomers that can result from the manufacturing process and the steps where chirality823

was introduced. The identicality of the isomeric composition of the API to that of the API in824

the comparator product should be established. Information on the physical and chemical825

properties of the isomeric mixture or single enantiomer should be provided, as appropriate.826

The API specification should include a test to ensure isomeric identity and purity.827828

The potential for interconversion of the isomers in the isomeric mixture, or racemisation of829

the single enantiomer should be discussed.830

831

When a single enantiomer of the API is claimed for non-pharmacopoeial APIs, unequivocal832

proof of absolute configuration of asymmetric centres should be provided such as determined833

by X-ray of a single crystal.834

835

If, based on the structure of the API, there is not a potential for stereoisomerism, it is836

sufficient to include a statement to this effect.837

838

Polymorphism839840

Many APIs can exist in different physical forms in the solid state. Polymorphism is841

characterized as the ability of an API to exist as two or more crystalline phases that have842

different arrangements and/or conformations of the molecules in the crystal lattice.843

Amorphous solids consist of disordered arrangements of molecules and do not possess a844

distinguishable crystal lattice. Solvates are crystal forms containing either stoichiometric or845

nonstoichiometric amounts of a solvent. If the incorporated solvent is water, the solvates are846

also commonly known as hydrates.847

848

Polymorphic forms of the same chemical compound differ in internal solid-state structure849

and, therefore, may possess different chemical and physical properties, including packing,850

thermodynamic, spectroscopic, kinetic, interfacial and mechanical properties. These851properties can have a direct impact on API processability, pharmaceutical product852

manufacturability and product quality/performance, including stability, dissolution and853

bioavailability. Unexpected appearance or disappearance of a polymorphic form may lead to854

serious pharmaceutical consequences.855

856

Applicants and API manufacturers are expected to have adequate knowledge about the857

polymorphism of the APIs used and/or produced. Information on polymorphism can come858

from the scientific literature, patents, compendia or other references to determine if859

polymorphism is a concern, e.g. for APIs that are notBCS highly soluble. In the absence of860


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published data for APIs that are notBSC highly soluble, polymorphic screening will be861

necessary to determine if the API can exist in more than one crystalline form. Polymorphic862

screening is generally accomplished via crystallization studies using different solvents and863

conditions.864

865

There are a number of methods that can be used to characterize the polymorphic forms of an866

API. Demonstration of a nonequivalent structure by single crystal X-ray diffraction is867

currently regarded as the definitive evidence of polymorphism. XRPD can also be used to868

provide unequivocal proof of polymorphism. Other methods, including microscopy, thermal869

analysis (e.g. DSC, thermal gravimetric analysis and hot-stage microscopy) and spectroscopy870

(e.g. IR, Raman, solid-state nuclear magnetic resonance (ssNMR)) are helpful to further871

characterize polymorphic forms. Where polymorphism is a concern, the872

applicants/manufacturers of APIs should demonstrate that a suitable method, capable of873

distinguishing different polymorphs, is available to them.874

875

Decision tree 4(1) of ICH Q6A can be used where screening is necessary and 4(2) can be used876

to investigate if different polymorphic forms have different properties that may affect877

performance, bioavailability and stability of the FPP and to decide whether a preferred878 polymorph should be monitored at release and on storage of the API. Where there is a879

preferred polymorph, acceptance criteria should be incorporated into the API specification to880

ensure polymorphic equivalence of the commercial material and that of the API batches used881

in the comparative bioavailability or biowaiver studies. The polymorphic characterization of882

the API batches used in comparative bioavailability or biowaiver studies by the above883

mentioned methods should be provided. The method used to control polymorphic form884

should be demonstrated to be specific for the preferred form.885

886

Polymorphism can also include solvation or hydration products (also known as887

pseudopolymorphs). If the API is used in a solvated form, the following information should888

be provided:889

890 specifications for the solvent-free API in 3.2.S.2.4, if that compound is a synthetic891

precursor;892

specifications for the solvated API including appropriate limits on the weight ratio of893API to solvent (with data to support the proposed limits);894

a description of the method used to prepare the solvate in 3.2.S.2.2.895896

Particle size distribution897

898

For APIs that are notBCShighly soluble contained in solid FPPs, or liquid FPPs containing899

undissolved API, the particle size distribution of the material can have an effect on the in vitro900

and/or in vivo behaviour of the FPP. Particle size distribution can also be important in dosage901

form performance (e.g. delivery of inhalation products), achieving uniformity of content in902low-dose tablets (e.g. 2 mg or less), desired smoothness in ophthalmic preparations and903

stability of suspensions.904

905

If particle size distribution is an important parameter (e.g. as in the above cases), results from906

an investigation of several batches of the API should be provided, including characterization907

of the batch(es) used in the comparative bioavailability or biowaiver studies. API908

specifications should include controls on the particle size distribution to ensure consistency909

with the material in the batch(es) used in the comparative bioavailability and biowaiver910

studies (e.g. limits for d10, d50 and d90). The criteria should be established statistically based911


21/61


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on the standard deviation of the test results from the previously mentioned studies. The912

following is provided for illustrative purposes as possible acceptance criteria for particle size913

distribution limits:914

915

d10 not more than (NMT) 10% of total volume less than X m916 d50 XX m XXX m917 d90 not less than (NLT) 90% of total volume less than XXXX m.918

919

Other controls on particle size distribution can be considered acceptable, if scientifically920

justified.921

922


924

3.2.S.3.2 Impurities (name, manufacturer)925

926

Information on impurities should be provided.927928

Details on the principles for the control of impurities (e.g. reporting, identification and929qualification) are outlined in the ICH Q3A, Q3B and Q3C impurity guidelines. Additional930

information to provide further guidance on some of the elements discussed in the ICH931

guidelines is outlined below.932

933

Regardless of whether a pharmacopoeial standard is claimed, a discussion should be provided934

of the potential and actual impurities arising from the synthesis, manufacture, or degradation935

of the API. This should cover starting materials, by-products, intermediates, chiral impurities936

and degradation products and should include the chemical names, structures and origins. The937

discussion of pharmacopoeial APIs should not be limited to the impurities specified in the938

API monograph.939

940

The tables in the QOS-PD template should be used to summarize the information on the API-941related and process-related impurities. In the QOS-PD, the term origin refers to how and942

where the impurity was introduced (e.g. Synthetic intermediate from Step 4 of the943

synthesis, Potential by-product due to rearrangement from Step 6 of the synthesis). It944

should also be indicated if the impurity is a metabolite of the API.945

946

The ICH thresholds for reporting, identification (used to set the limit for individual unknown947

impurities) and qualification are determined on the basis of potential exposure to the impurity,948

e.g. by the maximum daily dose (MDD) of the API. For APIs available in multiple dosage949

forms and strengths having different MDD values, it is imperative that the thresholds and950

corresponding controls for each of the presentations be considered to ensure that the risks951

posed by impurities have been addressed. This is normally achieved by using the highest952

potential daily MDD, rather than the maintenance dose. For parenteral products, the953maximum hourly dose of the API should also be included.954

955

It is acknowledged that APIs of semi-synthetic origin do not fall within the scope of the ICH956

impurity guidelines. However, depending on the nature of the API and the extent of the957

chemical modification steps, theprinciples on the control of impurities (e.g. reporting,958

identification and qualification) could also be extended to APIs of semi-synthetic origin. As959

an illustrative example, an API whose precursor molecule was derived from a fermentation960

process, or a natural product of plant or animal origin that has subsequently undergone several961

chemical modification reactions generally would fall within this scope, whereas an API whose962


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sole chemical step was the formation of a salt from a fermentation product generally would963

not fall within this scope. It is understood that there is some latitude for these types of APIs.964

965

Identification of impurities966

967

It is recognized by the pharmacopoeias that APIs can be obtained from various sources and968

thus can contain impurities not considered during the development of the monograph.969

Furthermore, a change in the production or source may give rise to additional impurities that970

are not adequately controlled by the official compendial monograph. As a result, each PD is971

assessed independently to consider the potential impurities that may arise from the proposed972

route(s) of synthesis. For these reasons, the ICH limits for unspecified impurities (e.g. NMT973

0.10% or 1.0 mg per day intake (whichever is lower) for APIs having a maximum daily dose9742 g/day) are generally recommended, rather than the general limits for unspecified impurities975

that may appear in the official compendial monograph that could potentially be higher than976

the applicable ICH limit.977

978

Qualification of impurities979

980 The ICH impurity guidelines should be consulted for options on the qualification of981

impurities. The limit specified for an identified impurity in an officially recognized982

pharmacopoeia is generally considered to be qualified. The following is an additional option983

for qualification of impurities in existing APIs:984

985

The limit for an impurity present in an existing API can be accepted by comparing the986

impurity results found in the existing API with those observed in an innovator product987

using the same validated, stability-indicating analytical procedure (e.g. comparative988

HPLC studies). If samples of the innovator product are not available, the impurity989

profile may also be compared to a different approved FPP with the same route of990

administration and similar characteristics (e.g. tablet versus capsule). It is991

recommended that the studies be conducted on comparable samples (e.g. age of992samples) to obtain a meaningful comparison of the impurity profiles.993

994

Levels of impurities generated from studies under accelerated or stressed storage995

conditions of the innovator or approved FPPare not considered acceptable/qualified.996

997

A specified impurity present in the existing API is considered qualified if the amount998

of the impurity in the existing API reflects the levels observed in the innovator or999

approved FPP.1000

1001

Basis for setting the acceptance criteria1002

1003

The basis for setting the acceptance criteria for the impurities should be provided. This is1004established by considering the identification and qualification thresholds for API-related1005

impurities (e.g. starting materials, by-products, intermediates, chiral impurities or degradation1006

products) and the concentration limits for process-related impurities (e.g. residual solvents) as1007

per the applicable ICH guidelines (e.g. Q3A, Q3C).1008

1009

The qualified level should be considered as the maximum allowable limit. However, limits1010

which are considerably wider than the actual manufacturing process capability are1011

generally discouraged. For this reason, the acceptance criteria are also set taking into1012

consideration the actual levels of impurities found in several batches of the API from each1013


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manufacturer, including the levels found in the batches used for the comparative1014

bioavailability or biowaiver studies. When reporting the results of quantitative tests, the actual1015

numerical results should be provided rather than vague statements such as within limits or1016

conforms. In the cases where a large number of batches have been tested it is acceptable to1017

summarize the results of the total number of batches tested with a range of analytical results.1018

1019

If there are identified impurities specified in an official compendial monograph that are not1020

controlled by the proposed routine in-house analytical procedure, a justification for their1021

exclusion from routine analyses should be provided (e.g. Impurities D, E and F listed in the1022

Ph.Int. monograph are not potential impurities from the proposed route of synthesis used by1023

manufacturer X). If acceptable justification cannot be provided it should be demonstrated1024

that the routine in-house method is capable of separating and detecting the impurities1025

specified in the official compendial monograph at an acceptable level (e.g. 0.10%). If such a1026

demonstration cannot be performed, a one-time study should be conducted applying the1027

pharmacopoeial method to several recent batches to demonstrate the absence of the1028

pharmacopoeial listed impurities.1029

1030

ICH class II solvent(s) used prior to the last step of the manufacturing process may be1031 exempted from routine control in API specifications if suitable justification is provided.1032

Submission of results demonstrating less than 10% of the ICH Q3C limit (option I) of the1033

solvent(s) in three consecutive production-scale batches or six consecutive pilot-scale batches1034

of the API or a suitable intermediate would be considered acceptable justification. The last1035

step solvents used in the process should always be routinely controlled in the final API.1036

1037

For guidance on acceptable residual solvent limits, refer to ICH Q3C. The limit for residues1038

of triethylamine (TEA) is either 320 ppm on the basis of ICH Q3C option I or 3.2 mg/day on1039

the basis of permitted daily exposure (PDE).1040

1041

The absence of known established highly toxic impurities (genotoxic) used in the process or1042

formed as a by-product should be discussed and suitable limits should be proposed. The limits1043should be justified by appropriate reference to available guidances (e.g.1044

EMEA/CHMP/QWP/251344/2006 or USFDA Guidance for Industry: Genotoxic and1045

carcinogenic impurities in drug substances and products, recommended approaches,1046

December 2008) or by providing experimental safety data or published data in peer-reviewed1047

journals.1048

1049

Residues of metal catalysts used in the manufacturing process and determined to be present in1050

batches of API are to be controlled in specifications. This requirement does not apply to1051

metals that are deliberate components of the pharmaceutical substance (such as a counter ion1052

of a salt) or metals that are used as a pharmaceutical excipient in the FPP (e.g. an iron oxide1053

pigment). The guidelines on the specification limits for residues of metal catalysts or metal1054

reagents EMEA/CHMP/SWP/4446/2000 or any equivalent approaches can be used to address1055this issue. The requirement normally does not apply to extraneous metal contaminants that are1056

more appropriately addressed by GMP, GDP or any other relevant quality provision such as1057

the heavy metal test in monographs of recognized pharmacopoeias that cover metal1058

contamination originating from manufacturing equipment and the environment.1059

1060

Reference documents: ICH Q3A, Q3C, Q6A1061

1062

3.2.S.4 Control of the API (name, manufacturer)1063

1064


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page 24

3.2.S.4.1 Specification (name, manufacturer)1065

1066

The specification for the API should be provided.10671068

As defined in ICHs Q6A guideline, a specification is:1069

1070

a list of tests, references to analytical procedures and appropriate acceptance1071

criteria, which are numerical limits, ranges, or other criteria for the tests described. It1072

establishes the set of criteria to which an API or FPP should conform to be1073

considered acceptable for its intended use. Conformance to specifications means1074

that the API and / or FPP, when tested according to the listed analytical procedures,1075

will meet the listed acceptance criteria. Specifications are critical quality standards1076

that are proposed and justified by the manufacturer and approved by regulatory1077

authorities.1078

1079

Copies of the API specifications, dated and signed by authorized personnel (e.g. the person in1080

charge of the quality control or quality assurance department) should be provided in the PD,1081

including specifications from each API manufacturer as well as those of the FPP1082 manufacturer.1083

1084

The FPP manufacturers API specification should be summarized according to the table in the1085

QOS-PD template under the headings tests, acceptance criteria and analytical procedures1086

(including types, sources and versions for the methods).1087

1088

The standarddeclared by the applicant could be an officially recognized compendial1089standard (e.g. Ph.Int., Ph.Eur., BP, USP, JP) or an in-house (manufacturers) standard.1090

The specification reference number and version (e.g. revision number and/or date)1091should be provided for version control purposes.1092

For the analytical procedures, the type should indicate the kind of analytical procedure1093used (e.g. visual, IR, UV, HPLC, laser diffraction), the source refers to the origin of1094the analytical procedure (e.g. Ph.Int., Ph.Eur., BP, USP, JP, in-house) and the version1095

(e.g. code number/version/date) should be provided for version control purposes.1096

1097

In cases where there is more than one API manufacturer, the FPP manufacturers API1098

specifications should be one single compiled set of specifications that is identical for each1099

manufacturer. It is acceptable to lay down in the specification more than one acceptance1100

criterion and/or analytical method for a single parameter with the statement for API from1101

manufacturer A (e.g. in the case of residual solvents).1102

1103

Any non routine testing should be clearly identified as such and justified along with the1104

proposal on the frequency of non routine testing.1105

1106The ICH Q6A guideline outlines recommendations for a number ofuniversal and specific1107

tests and criteria for APIs.1108

1109

Reference documents: ICH Q3A, Q3C, Q6A, officially recognized pharmacopoeia1110

1111

3.2.S.4.2 Analytical Procedures (name, manufacturer)1112

1113

The analytical procedures used for testing the API should be provided.11141115


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Copies of the in-house analytical procedures used to generate testing results provided in the1116

PD, as well as those proposed for routine testing of the API by the FPP manufacturer, should1117

be provided. Unless modified, it is not necessary to provide copies of officially recognized1118

compendial analytical procedures.1119

1120

Tables for summarizing a number of the different analytical procedures and validation1121

information (e.g. HPLC assay/impurity methods, GC methods) can be found in the 2.3.R1122

Regional information section of the QOS-PD (i.e. 2.3.R.2). These tables may be used to1123

summarize the in-house analytical procedures of the FPP manufacturerfor determination of1124

the residual solvents, assay and purity of the API, in section 2.3.S.4.2 of the QOS-PD. Other1125

methods used to generate assay and purity data in the PD can be summarized in 2.3.S.4.4 (c)1126

or 2.3.S.7.3 (b) of the QOS-PD. Officially recognized compendial methods need not be1127

summarized unless modifications have been made.1128

1129

Although HPLC is normally considered the method of choice for determining API-related1130

impurities, other chromatographic methods such as GC and TLC can also be used, if1131

appropriately validated. For determination of related substances, reference standards should1132

normally be available for each of the identified impurities, particularly those known to be1133 toxic and the concentration of the impurities should be quantitated against their own reference1134

standards. Impurity standards may be obtained from pharmacopoeias (individual impurities1135

or resolution mixtures), from commercial sources or prepared in-house. It is considered1136

acceptable to use the API as an external standard to estimate the levels of impurities, provided1137

the response factors of those impurities are sufficiently close to that of the API, i.e. between1138

80 and 120%. In cases where the response factor is outside this range, it may still be1139

acceptable to use the API, provided a correction factor is applied. Data to support calculation1140

of the correction factor should be provided for an in-house method. Unspecified impurities1141

may be quantitated using a solution of the API as the reference standard at a concentration1142

corresponding to the limit established for individual unspecified impurities (e.g. 0.10%). The1143

test for related substances in the Ph.Int. monograph for lamivudine serves as a typical1144

example.11451146

The system suitability tests (SSTs) represent an integral part of the method and are used to1147

ensure the adequate performance of the chosen chromatographic system. As a minimum,1148

HPLC and GC purity methods should include SSTs for resolution and repeatability. For1149

HPLC methods to control API-related impurities, this is typically done using a solution of the1150

API with a concentration corresponding to the limit for unspecified impurities. Resolution of1151

the two closest eluting peaks is generally recommended. However, the choice of alternate1152

peaks can be used if justified (e.g. choice of a toxic impurity). In accordance with the Ph.Int.1153

section onMethods of Analysis, the repeatability test should include an acceptable number of1154

replicate injections. HPLC assay methods should include SSTs for repeatability and in1155

addition either peak asymmetry, theoretical plates or resolution. For TLC methods, the SSTs1156

should verify the ability of the system to separate and detect the analyte(s) (e.g. by applying a1157spot corresponding to the API at a concentration corresponding to the limit of unspecified1158

impurities).1159

1160

Reference documents: ICH Q2, WHO Technical Report Series, No. 943, Annex 31161

1162

3.2.S.4.3 Validation of Analytical Procedures (name, manufacturer)1163

1164Analytical validation information, including experimental data for the analytical1165

procedures used for testing the API, should be provided.1166


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page 26

1167

Copies of the validation reports for the analytical procedures used to generate testing results1168

provided in the PD, as well as those proposed for routine testing of the API by the FPP1169

manufacturer, should be provided.1170

1171

Tables for summarizing a number of the different analytical procedures and validation1172

information (e.g. HPLC assay/impurity methods, GC methods) can be found in the 2.3.R1173

Regional information section of the QOS-PD (i.e. 2.3.R.2). These tables may be used to1174

summarize the validation information of the analytical procedures ofthe FPP manufacturer1175

for determination of residual solvents, assay and purity of the API, in section 2.3.S.4.3 of the1176

QOS-PD. The validation data for other methods used to generate assay and purity data in the1177

PD can be summarized in 2.3.S.4.4 (c) or 2.3.S.7.3 (b) of the QOS-PD.1178

1179

As recognized by regulatory authorities and pharmacopoeias themselves, verification of1180

compendial methods can be necessary. The compendial methods as published are typically1181

validated based on an API or an FPP originating from a specific manufacturer. Different1182

sources of the same API or FPP can contain impurities and/or degradation products that were1183

not considered during the development of the monograph. Therefore the monograph and1184 compendial method should be demonstrated suitable to control the impurity profile of the API1185

from the intended source(s).1186

1187

In general verification is not necessary for compendial API assay methods. However,1188

specificity of a specific compendial assay method should be demonstrated if there are any1189

potential impurities that are not specified in the compendial monograph. If an officially1190

recognized compendial method is used to control API-related impurities that are not specified1191

in the monograph, full validation of the method is expected with respect to those impurities.1192

1193

If an officially recognized compendial standard is claimed and an in-house method is used in1194

lieu of the compendial method (e.g. for assay or for specified impurities), equivalency of the1195

in-house and compendial methods should be demonstrated. This could be accomplished by1196performing duplicate analyses of one sample by both methods and providing the results from1197

the study. For impurity methods, the sample analyzed should be the API spiked with1198

impurities at concentrations equivalent to their specification limits.1199

1200

Reference documents: ICH Q21201

1202

3.2.S.4.4 Batch Analyses (name, manufacturer)1203

1204

Description of batches and results of batch analyses should be provided.12051206

The information provided should include batch number, batch size, date and production site of1207

relevant API batches used in comparative bioavailability or biowaiver studies, preclinical and1208clinical data (if relevant), stability, pilot, scale-up and, if available, production-scale batches.1209

This data is used to establish the specifications and evaluate consistency in API quality.1210

1211

Analytical results should be provided from at least two batches of at least pilot scale from1212

each proposed manufacturing site of the API and should include the batch(es) used in the1213

comparative bioavailability or biowaiver studies. A pilot-scale batch should be manufactured1214

by a procedure fully representative of and simulating that to be applied to a full production-1215

scale batch.1216

1217


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page 27

Copies of the certificates of analysis, both from the API manufacturer(s) and the FPP1218

manufacturer, should be provided for the profiled batches and any company responsible for1219

generating the test results should be identified. The FPP manufacturers test results should be1220

summarized in the QOS-PD.1221

1222

The discussion of results should focus on observations noted for the various tests, rather than1223

reporting comments such as all tests meet specifications. For quantitative tests (e.g.1224

individual and total impurity tests and assay tests), it should be ensured that actual numerical1225

results are provided rather than vague statements such as within limits or conforms.1226

1227

A discussion and justification should be provided for any incomplete analyses (e.g. results not1228

tested according to the proposed specification).1229

1230

Reference documents: ICH Q3A, Q3C, Q6A1231

1232

3.2.S.4.5 Justification of Specification (name, manufacturer)1233

1234

Justification for the API specification should be provided.12351236

A discussion should be provided on the inclusion of certain tests, evolution of tests, analytical1237

procedures and acceptance criteria, differences from the officially recognized compendial1238

standard(s), etc. If the officially recognized compendial methods have been modified or1239

replaced, a discussion should be included.1240

1241

The justification for certain tests, analytical procedures and acceptance criteria may have been1242

discussed in other sections of the PD (e.g. impurities, particle size distribution) and does not1243

need to be repeated here, although a cross-reference to their location should be provided.1244

1245

Reference documents: ICH Q3A, Q3C, Q6A, officially recognized pharmacopoeia1246

12473.2.S.5 Reference Standards or Materials (name, manufacturer)1248

1249

Information on the reference standards or reference materials used for testing of the1250

API should be provided.12511252

Information should be provided on the reference standard(s) used to generate data in the PD,1253

as well as those to be used by the FPP manufacturer in routine API and FPP testing.1254

1255

The source(s) of the reference standards or materials used in the testing of the API should be1256

provided (e.g. those used for the identification, purity, assay tests). These could be classified1257

asprimary or secondary reference standards.1258

1259A suitable primary reference standard should be obtained from an officially recognized1260

pharmacopoeial source (e.g. Ph.Int., Ph.Eur., BP, USP, JP) where one exists and the lot1261

number should be provided. Where a pharmacopoeial standard is claimed for the API and/or1262

the FPP, the primary reference standard should be obtained from that pharmacopoeia when1263

available. Primary reference standards from officially recognized pharmacopoeial sources do1264

not need further structural elucidation.1265

1266

Otherwise, a primary standard may be a batch of the API that has been fully characterized1267

(e.g. by IR, UV, NMR, MS analyses). Further purification techniques may be needed to1268


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page 28

render the material acceptable for use as a chemical reference standard. The purity1269

requirements for a chemical reference substance depend upon its intended use. A chemical1270

reference substance proposed for an identification test does not require meticulous1271

purification, since the presence of a small percentage of impurities in the substance often has1272

no noticeable effect on the test. On the other hand, chemical reference substances that are to1273

be used in assays should possess a high degree of purity (such as 99.5% on the dried or1274

water/solvent free basis). Absolute content of the primary reference standard must be declared1275

and should follow the scheme: 100% minus organic impurities (quantitated by an assay1276

procedure, e.g. HPLC, DSC, etc.) minus inorganic impurities minus volatile impurities by loss1277

on drying (or water content minus residual solvents).1278

1279

A secondary (or in-house) reference standard can be used by establishing it against a suitable1280

primary reference standard, e.g. by providing legible copies of the IR of the primary and1281

secondary reference standards run concomitantly and by providing its certificate of analysis,1282

including assay determined against

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