WHO Non Sterile Process Validation

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Working document QAS/13.527

April 2013

RESTRICTED

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PROPOSAL FOR REVISION OF THE2

SUPPLEMENTARY GUIDELINES ON3

GOOD MANUFACTURING PRACTICES: VALIDATION,4

APPENDIX 7: NON-STERILE PROCESS VALIDATION5

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(APRIL 2013)78

DRAFT FOR COMMENT910

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World Health Organization 201313

All rights reserved.14

This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this15

draft. The draft may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or16adapted, in part or in whole, in any form or by any means outside these individuals and organizations (including17

the organizations' concerned staff and member organizations) without the permission of the World Health18

Organization. The draft should not be displayed on any web site.19

Please send any request for permission to:20

Dr Sabine Kopp, Medicines Quality Assurance Programme, Quality Assurance and Safety: Medicines,21

Department of Essential Medicines and Health Products, World Health Organization, CH-1211 Geneva 27,22

Switzerland. Fax: (41-22) 791 4730; e-mail: [email protected]

The designations employed and the presentation of the material in this draft do not imply the expression of any24

opinion whatsoever on the part of the World Health Organization concerning the legal status of any country,25

territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted26

lines on maps represent approximate border lines for which there may not yet be full agreement.27

The mention of specific companies or of certain manufacturers products does not imply that they are endorsed28

or recommended by the World Health Organization in preference to others of a similar nature that are not29

mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital30

letters.31

All reasonable precautions have been taken by the World Health Organization to verify the information32

contained in this draft. However, the printed material is being distributed without warranty of any kind, either33

expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no34

event shall the World Health Organization be liable for damages arising from its use.35

This draft does not necessarily represent the decisions or the stated policy of the World Health Organization.36

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Please address any comments on this proposal by 24 May2013 to Dr S. Kopp, Medicines Quality

Assurance Programme, World Health Organization, 1211 Geneva 27, Switzerland, fax: (+41 22) 791 4730

or e-mail: [email protected] with a copy to [email protected].

We are sending out our working documents electronically only and they are also placed on the

Medicines web site for comment. If you do not already receive our documents please let us have youre-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/13.527:38

PROPOSAL FOR REVISION OF THE SUPPLEMENTARY GUIDELINE ON39

GOOD MANUFACTURING PRACTICES: VALIDATION, APPENDIX 7: NON-STERILE40

PROCESS VALIDATION41

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43

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Need for revision of published good manufacturing

practices: validation identified by Prequalification of

Medicines Programme

March 2013

Wide circulation of draft document for comment April 2013

Compilation of feedback received June 2013

Discussion of feedback during informal consultation on

quality assurance guidelines

July 2013

Mailing of revision for comment August 2013

Presentation to forty-eighth meeting of the WHO Expert

Committee on Specifications for Pharmaceutical

Preparations

October 2013

Any further action as necessary


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PROPOSAL FOR REVISION OF THE SUPPLEMENTARY GUIDELINE ON45

GOOD MANUFACTURING PRACTICES: VALIDATION, APPENDIX 7: NON-STERILE46

PROCESS VALIDATION47

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The Appendixes of the Supplementary Guideline on Good Manufacturing Practices:66

Validation are currently as follows:67

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Appendix 1- Validation of heating, ventilation and air-conditioning systems69

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Appendix 2 -Validation of water systems for pharmaceutical use71

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Appendix 3 - Cleaning validation need for revision?73

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Appendix 4 - Analytical method validation75

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Appendix 5 - Validation of computerized systems77

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Appendix 6 - Qualification of systems and equipment79

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Appendix 7 - Non-sterile process validation proposed to be revised81

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Note from Secretariat:

The current text of the Supplementary Guideline on Good Manufacturing Practices:

Validation (Ref: World Health Organization, WHO Technical Report Series, No. 937,

2006, Annex 4) is available on the following web site:http://www.who.int/medicines/areas/quality_safety/quality_assurance/production/en/index.html

Moreover, comments are being sought at the same time, if the Appendix 3 on Cleaning

validation be revised in line with the current developments on setting health based

exposure limits for use in risk identification in the manufacture of different medicinal

products in shared facilities; if yes concrete proposals for revision would beappreciated.


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Proposal for revision of the83

Supplementary Guideline on Good Manufacturing Practices: Validation,84

Appendix 7: Non-sterile process validation85

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Contents88

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1. Background and scope902. Glossary913. Introduction924. Phase I. Process design935. Phase II. Qualification and process verification946. Phase III. Continued process verification957. Change control96References97

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1. BACKGROUND AND SCOPE99100

Further to the Supplementary Guideline on good manufacturing practices: validation, as101

published in the World Health Organization (WHO) Technical Report, No. 937,1

additional102

guidelines to support current approaches in GMP are published herewith to further support103

the scope of process validation (also referred to as process qualification) linked to quality risk104

management and quality by design principles as described by WHO and the International105

Conference on Harmonisation (ICH).106

107

This guideline allows for different approaches in process validation. The principles described108

in this guideline are applicable to non-sterile finished pharmaceutical dosage forms.109

Thorough knowledge of product and process development studies; previous manufacturing110

experience; and quality risk management (QRM) principles are essential in the all approaches111

to process validation as the focus is now on the life-cycle approach. The life-cycle approach112

1Supplementary guidelines on good manufacturing practices: validation. In: WHO Expert Committee on

Specifications for Pharmaceutical Preparations. Fortieth report. Geneva, World Health Organization. WHO

Technical Report Series, No. 937 (Annex 5), 2006.


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links product and process development, validation of the commercial manufacturing process113

and maintenance of the process during routine commercial production.114

115

A risk based approach to validation is recommended, linked to in-line or on-line controls and116

monitoring to ensure that a process is in a state of control during routine manufacture.117

118

2. GLOSSARY119120

control strategy121

A planned set of controls, derived from current product and process understanding that assures122

process performance and product quality. The controls can include parameters and attributes related to123

drug substance and pharmaceutical product materials and components, facility and equipment124

operating conditions, in-process controls, finished product specifications, and the associated methods125

and frequency of monitoring and control.126

127

continued process verification (CPV)128

Continued process verification (CPV) can be defined as continuous monitoring of129

manufacturing performance by using extensive in-line, on-line or at-line monitoring and/or130

controls to evaluate process performance. It is a science and risk-based real-time approach to131

verify and demonstrate that a process that operates within the predefined specified parameters132

consistently produces material which meets all its critical quality attributes (CQAs) and133

control strategy requirements.134

135

continuous process verification136

An alternative approach to process validation in which manufacturing process performance is137

continuously monitored and evaluated.138

139

critical process parameter (CPP)140

A process parameter whose variability has an impact on a critical quality attribute141

and therefore should be monitored or controlled to ensure the process produces the142

desired quality.143

144

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critical quality attribute (CQA)146

A physical, chemical, biological or microbiological property or characteristic that should be147

within an appropriate limit, range or distribution to ensure the desired product quality.148

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life-cycle150

All phases in the life of a product from the initial development through marketing until the151

products discontinuation (ICH Q8).152

153

pharmaceutical quality system (PQS)154

Management system to direct and control a pharmaceutical company with regard to155

quality.156

157

process validation158

Documented evidence which provides a high degree of assurance that a specific process will159

consistently result in a product that meets its predetermined specifications and quality160

characteristics.161

162

3. INTRODUCTION163164

Process validation data should be generated for all products to demonstrate the adequacy of165

the manufacturing process at each site of manufacture. The validation should be carried out in166

accordance with good manufacturing practices (GMP) and data should be held at the167

manufacturing location and made available for inspection. Manufacturers should confirm that168

a manufacturing process is under control before a product is placed on the market.169

170

Process validation is associated with the collection and evaluation of data, from the process171

design stage through commercial production, which provides scientific evidence that a172

process is capable of consistently delivering a quality product. Process validation provides173

documented evidence that a process is capable of reliably and repeatedly rendering a product174

of the required quality.175

176

A risk assessment approach should be used to determine the scope and extent to which177

process(es) and starting material variability may affect product quality. The critical steps and178


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parameters (e.g. those that may have an impact on the quality of the product) in the process of179

manufacturing a pharmaceutical product and other relevant studies demonstrating that the180

process is capable of delivering the desired product, quality should be identified and181

documented and be based on knowledge of the product or processes concerned, according to182

the stage of the product life-cycle. Process validation should cover at least these critical steps183

and parameters.184

185

Where necessary, a flow diagram may be helpful, covering all operations and controls in the186

process to be validated.When applying QRM to a given operation, the steps preceding and187

following that operation should also be considered.Amendments to the flow diagram may be188

made where appropriate and should be documented as part of the validation documentation.189

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Different approaches can be followed when validating a process.191

192

Manufacturers should ensure that the principles of process validation described in this193

guideline are implemented. These include and cover phases of validation during process194

design, scale up, qualification of premises, utilities and equipment, process performance195

verification and ongoing monitoring of batches manufactured for commercial supply to196

ensure that the process remains in a state of control.197

198

The objectives of process validation include ensuring that:199

200

the process design is evaluated to show that it is reproducible,201

the commercial manufacturing process is defined and controlled,202

ongoing assurance is gained to show that the process remains in a state of control.203

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The validation should cover all manufactured strengths and all manufacturing sites used for205

production of the marketed product. A matrix approach may be acceptable based on206

appropriate risk assessment.207

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There are different approaches to process validation which include traditional process209

validation with prospective and concurrent validation, continuous process performance210

verification (where an enhanced approach to development has been employed or where a211


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substantial amount of product and process knowledge and understanding has been gained212

through historical data and manufacturing experience) and a combination of traditional213

process validation and continuous process verification.214

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Continued process verification is considered as a third phase in process validation.216

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Manufacturers should plan towards implementing the new approach in process validation that218

should consist of three phases in the product life-cycle.219

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Phase I. Process design221

Phase II. Qualification and process verification222

Phase IIA. Qualification223

Phase IIB. Continuous process performance verification224

Phase III. Continued process verification225

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4. PHASE I. PROCESS DESIGN227228

As part of the process validation life-cycle some process validation studies may be conducted229

on pilot-scale batches (corresponding to at least 10% or 100 000 units whichever is the230

greater) of the production scale.231

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In certain cases, however, it may be necessary to provide production-scale validation data.233

The number of batches (minimum of three) should be based on the variability of the process,234

the complexity of the process/product and the experience of the manufacturer.235

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The number of batches produced in this validation exercise should be sufficient to allow the237

normal extent of variation and trends to be established and to provide sufficient data for238

evaluation. Extensive testing should be performed on the product at various stages during the239

manufacturing process of the batches.240

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Manufacturers should define the stage at which the product is considered to be validated and242

the basis on which that decision was made. It should include a justification for the number of243

batches used based on the complexity and expected variability of the process.244


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Validation should be done in accordance with process validation protocols. Data should be246

collected and reviewed against predetermined acceptance criteria, and reflected in process247

validation reports.248

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The protocol should include:250

a description of the process;251

a description of the experiment;252

details of the equipment and/or facilities to be used (including measuring or recording253

equipment) together with its calibration status;254

the variables to be monitored;255

the samples to be taken where, when, how, how many and how much (sample size);256

the product performance characteristics/attributes to be monitored, together with the test257

methods;258

the acceptable limits;259

time schedules;260

personnel responsibilities;261

details of methods for recording and evaluating results, including statistical analysis.262

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The results should be documented in the validation report which reflects the validation264

protocol.265

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A conclusion and recommendation should be made on the extent of monitoring and the in-267

process controls necessary for routine production, on the basis of the results obtained.268

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The planned commercial production and control records, which contain the operational limits270

and overall strategy for process control, should be carried forward to the next phase for271

confirmation.272

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5. PHASE II. QUALIFICATION AND PROCESS VERIFICATION274275

Process verification is divided into two phases. These phases include qualification of276

premises, utilities and equipment where commercial scale batches will be manufactured and277

continuous process performance verification.278

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Phase IIA. Qualification280

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Premises, utilities, support systems and equipment should be appropriately qualified before282

process performance verification (as part of validation) is started.283

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In a traditional approach, stages of qualification may include design, installation, operational285

and performance qualification.286

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In some cases process validation may be conducted concurrently with performance288

qualification.289

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Phase IIB. Continuous process performance verification291

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After completion of qualification, commercial batches should be subjected to continuous293

process performance verification as part of process validation. It should confirm that scale up294

in batch size did not adversely affect the characteristics of a product.295

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CPV demonstrates that a process that operates within the predefined specified parameters297

consistently produces a product which meets all its critical quality attributes (CQAs) and298

control strategy requirements.299

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The process should be verified on commercial-scale batches prior to marketing of the product.301

Extensive in-line or at-line controls should be used to monitor process performance and302

product quality in a timely manner. Relevant process quality attributes of incoming materials303

or components, in-process material and finished products should be collected. This should304

include the verification of attributes, parameters and end points, and assessment of CQA and305


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critical process parameter (CPP) trends. Process analytical technology applications and306

multivariate statistical process control (MSPC) can be used.307

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The scope and extent of continuous process verification will be influenced by a number of309

factors including:310

prior development and manufacturing knowledge from similar products and/or processes;311

the extent of process understanding gained from development studies and commercial312

manufacturing experience;313

the complexity of the product and/or manufacturing process;314

the level of process automation and analytical technologies used;315

process robustness and manufacturing history since point of commercialization as316

appropriate.317

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Manufacturers should describe the appropriateness and feasibility of the CPV strategy319

including the process parameters and material attributes that will be monitored as well as the320

analytical methods that will be employed.321

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Continuous process verification can be introduced at any time of the life-cycle of the product:323

it can be used to design process validation protocols for the initial commercial production;324

to revalidate commercialized products as part of process changes;325

to support continual improvement throughout the remainder of the life-cycle.326

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It is expected that additional monitoring for the first commercial batches should be done328

where continuous process verification is implemented.329

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Manufacturers should define:331

the number of batches for which additional monitoring is proposed;332

the type of testing/monitoring to be performed;333

the acceptance criteria to be applied;334

how the data will be evaluated.335

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Statistical models or tools used should be described.337

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6. PHASE III. CONTINUED PROCESS VERIFICATION339340

Manufacturers should monitor product quality of commercial batches after completion of341

Phase I and Phase II of process validation. This will provide evidence that a state of control is342

maintained throughout the product life-cycle.343

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Periods of enhanced sampling and monitoring may help to increase process understanding as345

part of continuous improvement.346

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Process trends such as the quality of incoming materials or components, in-process and348

finished product results and non-conformances should be collected and assessed in order to349

verify the validity of the original process validation or to identify required changes to the350

control strategy.351

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The extent and frequency of ongoing process validation should be reviewed periodically and353

modified if appropriate throughout the product life-cycle.354

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Continued process validation (CdPV) should not be confused with product quality review.356

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Table 2 provides a summary of the new approach to process validation.358

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Table 2. New approach to process validation360

Product life-cycle

Process validation

Phase I Phase II Phase III

Process design Qualification Continuous process

verification

Continued process

verification

- Pilot scale (andscale-up batches

where appropriate)

- Risk assessment to

identify critical

quality attributes and

process control

parameters

- Premises- Utilities

- Equipment

- Commercial-scalebatches

- In-line or on-line

monitoring (e.g. PAT)

- Defined number of

batches

- Periodic review oftrends

- May include

sampling and testing


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- Protocols and

reports

- Validate process

- Define CQA and

CPPs to be

monitored in Phase II

Change control

GMP

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7. CHANGE CONTROL362363

Changes during the life-cycle of a product should be managed through a change control364

procedure. Sufficient data should be generated to demonstrate that the revised process will365

result in a product of the desired quality, consistent with the approved specification.366

367

The change control procedure and records should ensure that all aspects are thoroughly368

documented and approved including regulatory approval where appropriate (variation).369

Manufacturers should follow change control procedures when changes are planned to370

existing systems or processes.371

372

Validation should be considered when changes are planned to production and/or control373

procedures.374

375

Changes that are likely to require revalidation may include:376

changes in the manufacturing process (e.g. mixing times, drying temperatures);377

changes in the equipment (e.g. addition of automatic detection systems);378

production area and support system changes (e.g. rearrangement of areas or a new water379

treatment method);380

transfer of processes to another site;381

unexpected changes (e.g. those observed during self-inspection or during routine analysis382

of process trend data).383

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Based on risk assessment, revalidation should be considered in the case of:385

changes in the master formula, methods, starting material manufacturer, equipment and/or386

instruments;387


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equipment calibrations and preventive maintenance carried out;388

changes to standard operating procedures (SOPs);389

changes to cleaning and hygiene programmes.390

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REFERENCES392

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1. Guideline on Process Validation, 29 March 2012394

EMA/CHMP/CVMP/QWP/70278/2012-Rev1 , Committee for Medicinal Products for395

Human Use (CHMP), Committee for Medicinal Products for Veterinary Use (CVMP)396

www.ema.europa.eu/uideline/2012/04/WC500125399.pdf.397

398

2. Guidance for Industry, Process Validation: General Principles and Practices, U.S.399

Department of Health and Human Services, Food and Drug Administration,400

Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation401

and Research (CBER), Center for Veterinary Medicine (CVM), January 2011,402

Current Good Manufacturing Practices (CGMP) Revision 1.403

404

3. ICH Harmonised Tripartite Guideline, Pharmaceutical Development Q8(R2), Current405

Step 4 version, dated August 2009.406

407

4. ICH Harmonised Tripartite Guideline, Quality Risk Management, Q9, Current Step 4408

version, dated 9 November 2005.409

410

5. ICH Harmonised Tripartite Guideline, Pharmaceutical Quality System, Q10, Current411

Step 4 version, dated 4 June 2008412

http://www.ich.org/products/guidelines/quality/article/quality-guidelines.html413

414

6. Quality Assurance of pharmaceuticals. WHO guidelines, related guidance and415

GXP training materials. Geneva, World Health Organization,2013 (CD-ROM).416

417

418


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7. WHO good manufacturing practices: main principles for pharmaceutical products. In:419

WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-420

fifth report. Geneva, World Health Organization. WHO Technical Report Series, No.421

961 (Annex 3), 2011 (WHO good manufacturing practices: main principles for422

pharmaceutical products).423

424

8. WHO guidelines on quality risk management. In: WHO Expert Committee on425

Specifications for Pharmaceutical Preparations. Forty-seventh report. Geneva, World426

Health Organization. WHO Technical Report Series, No. 981 (Annex 2), 2013 (in427

press).428

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WHO Non Sterile Process Validation

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