PROPOSAL FOR REVISION OF THE SUPPLEMENTARY GUIDELINES ON GOOD MANUFACTURING PRACTICES: VALIDATION, APPENDIX 7: NON-STERILE PROCESS VALIDATION

Working document QAS/13.527 April 2013 RESTRICTED

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PROPOSAL FOR REVISION OF THE

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SUPPLEMENTARY GUIDELINES ON

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GOOD MANUFACTURING PRACTICES: VALIDATION,

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APPENDIX 7: NON-STERILE PROCESS VALIDATION

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(APRIL 2013)

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DRAFT FOR COMMENT

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© World Health Organization 2013 13

All rights reserved.

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This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this 15

draft. The draft may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or 16

adapted, in part or in whole, in any form or by any means outside these individuals and organizations (including 17

the organizations' concerned staff and member organizations) without the permission of the World Health 18

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

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Please send any request for permission to:

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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].

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The designations employed and the presentation of the material in this draft do not imply the expression of any 24

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The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed 28

or recommended by the World Health Organization in preference to others of a similar nature that are not 29

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All reasonable precautions have been taken by the World Health Organization to verify the information 32

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

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

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Please address any comments on this proposal by 24 May 2013 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

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SCHEDULE FOR THE PROPOSED ADOPTION PROCESS OF DOCUMENT QAS/13.527:

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PROPOSAL FOR REVISION OF THE SUPPLEMENTARY GUIDELINE ON 39

GOOD MANUFACTURING PRACTICES: VALIDATION, APPENDIX 7: NON-STERILE 40

PROCESS VALIDATION 41

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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 …

Working document QAS/13.527 page 3 PROPOSAL FOR REVISION OF THE SUPPLEMENTARY GUIDELINE ON 45

GOOD MANUFACTURING PRACTICES: VALIDATION, APPENDIX 7: NON-STERILE 46

PROCESS VALIDATION 47

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The Appendixes of the Supplementary Guideline on Good Manufacturing Practices:

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Validation are currently as follows:

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Appendix 1- Validation of heating, ventilation and air-conditioning systems 69

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Appendix 2 -Validation of water systems for pharmaceutical use 71

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Appendix 3 - Cleaning validation – need for revision?

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Appendix 4 - Analytical method validation 75

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Appendix 5 - Validation of computerized systems 77

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Appendix 6 - Qualification of systems and equipment 79

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Appendix 7 - Non-sterile process validation – proposed to be revised 81

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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 be

appreciated.

Proposal for revision of the 83

Supplementary Guideline on Good Manufacturing Practices: Validation, 84

Appendix 7: Non-sterile process validation 85

86 87

Contents 88

page 89

1. Background and scope 90

2. Glossary 91

3. Introduction 92

4. Phase I. Process design 93

5. Phase II. Qualification and process verification 94

6. Phase III. Continued process verification 95

7. Change control 96

References 97

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1. BACKGROUND AND SCOPE 99

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Further to the Supplementary Guideline on good manufacturing practices: validation, as 101

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

additional 102

guidelines to support current approaches in GMP are published herewith to further support 103

the scope of process validation (also referred to as process qualification) linked to quality risk 104

management and quality by design principles as described by WHO and the International 105

Conference on Harmonisation (ICH).

106 107

This guideline allows for different approaches in process validation. The principles described 108

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

109

Thorough knowledge of product and process development studies; previous manufacturing 110

experience; and quality risk management (QRM) principles are essential in the all approaches 111

to process validation as the focus is now on the life-cycle approach. The life-cycle approach 112

1

Supplementary 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.

Working document QAS/13.527 page 5 links product and process development, validation of the commercial manufacturing process 113

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 and 116

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

117 118

2. GLOSSARY

119 120

control strategy 121

A planned set of controls, derived from current product and process understanding that assures 122

process performance and product quality. The controls can include parameters and attributes related to 123

drug substance and pharmaceutical product materials and components, facility and equipment 124

operating conditions, in-process controls, finished product specifications, and the associated methods 125

and frequency of monitoring and control.

126 127

continued process verification (CPV) 128

Continued process verification (CPV) can be defined as continuous monitoring of 129

manufacturing performance by using extensive in-line, on-line or at-line monitoring and/or 130

controls to evaluate process performance. It is a science and risk-based real-time approach to 131

verify and demonstrate that a process that operates within the predefined specified parameters 132

consistently produces material which meets all its critical quality attributes (CQAs) and 133

control strategy requirements.

134 135

continuous process verification 136

An alternative approach to process validation in which manufacturing process performance is 137

continuously monitored and evaluated.

138 139

critical process parameter (CPP) 140

A process parameter whose variability has an impact on a critical quality attribute 141

and therefore should be monitored or controlled to ensure the process produces the 142

desired quality.

143

144

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critical quality attribute (CQA) 146

A physical, chemical, biological or microbiological property or characteristic that should be 147

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

148 149

life-cycle 150

All phases in the life of a product from the initial development through marketing until the 151

product’s discontinuation (ICH Q8).

152 153

pharmaceutical quality system (PQS) 154

Management system to direct and control a pharmaceutical company with regard to 155

quality.

156 157

process validation 158

Documented evidence which provides a high degree of assurance that a specific process will 159

consistently result in a product that meets its predetermined specifications and quality 160

characteristics.

161 162

3. INTRODUCTION 163

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Process validation data should be generated for all products to demonstrate the adequacy of 165

the manufacturing process at each site of manufacture. The validation should be carried out in 166

accordance with good manufacturing practices (GMP) and data should be held at the 167

manufacturing location and made available for inspection. Manufacturers should confirm that 168

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 process 171

design stage through commercial production, which provides scientific evidence that a 172

process is capable of consistently delivering a quality product. Process validation provides 173

documented evidence that a process is capable of reliably and repeatedly rendering a product 174

of the required quality.

175 176

A risk assessment approach should be used to determine the scope and extent to which 177

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

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Working document QAS/13.527 page 7 parameters (e.g. those that may have an impact on the quality of the product) in the process of 179

manufacturing a pharmaceutical product and other relevant studies demonstrating that the 180

process is capable of delivering the desired product, quality should be identified and 181

documented and be based on knowledge of the product or processes concerned, according to 182

the stage of the product life-cycle. Process validation should cover at least these critical steps 183

and parameters.

184 185

Where necessary, a flow diagram may be helpful, covering all operations and controls in the 186

process to be validated. When applying QRM to a given operation, the steps preceding and 187

following that operation should also be considered. Amendments to the flow diagram may be 188

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

189 190

Different approaches can be followed when validating a process.

191 192

Manufacturers should ensure that the principles of process validation described in this 193

guideline are implemented. These include and cover phases of validation during process 194

design, scale up, qualification of premises, utilities and equipment, process performance 195

verification and ongoing monitoring of batches manufactured for commercial supply to 196

ensure that the process remains in a state of control.

197 198

The objectives of process validation include ensuring that:

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— 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.

203 204

The validation should cover all manufactured strengths and all manufacturing sites used for 205

production of the marketed product. A matrix approach may be acceptable based on 206

appropriate risk assessment.

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There are different approaches to process validation which include traditional process 209

validation with prospective and concurrent validation, continuous process performance 210

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

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substantial amount of product and process knowledge and understanding has been gained 212

through historical data and manufacturing experience) and a combination of traditional 213

process validation and continuous process verification.

214 215

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

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Manufacturers should plan towards implementing the new approach in process validation that 218

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

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Phase I. Process design 221

Phase II. Qualification and process verification 222

Phase IIA. Qualification 223

Phase IIB. Continuous process performance verification 224

Phase III. Continued process verification 225

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4. PHASE I. PROCESS DESIGN 227

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As part of the process validation life-cycle some process validation studies may be conducted 229

on pilot-scale batches (corresponding to at least 10% or 100 000 units whichever is the 230

greater) of the production scale.

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

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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.

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The number of batches produced in this validation exercise should be sufficient to allow the 237

normal extent of variation and trends to be established and to provide sufficient data for 238

evaluation. Extensive testing should be performed on the product at various stages during the 239

manufacturing process of the batches.

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Manufacturers should define the stage at which the product is considered to be validated and 242

the basis on which that decision was made. It should include a justification for the number of 243

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

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Working document QAS/13.527 page 9

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Validation should be done in accordance with process validation protocols. Data should be 246

collected and reviewed against predetermined acceptance criteria, and reflected in process 247

validation reports.

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The protocol should include:

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— a description of the process;

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— a description of the experiment;

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— details of the equipment and/or facilities to be used (including measuring or recording 253

equipment) together with its calibration status;

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— the variables to be monitored;

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

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— the product performance characteristics/attributes to be monitored, together with the test 257

methods;

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— the acceptable limits;

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— time schedules;

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— personnel responsibilities;

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

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The results should be documented in the validation report which reflects the validation 264

protocol.

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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.

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The planned commercial production and control records, which contain the operational limits 270

and overall strategy for process control, should be carried forward to the next phase for 271

confirmation.

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5. PHASE II. QUALIFICATION AND PROCESS VERIFICATION 274

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Process verification is divided into two phases. These phases include qualification of 276

premises, utilities and equipment where commercial scale batches will be manufactured and 277

continuous process performance verification.

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Phase IIA. Qualification 280

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Premises, utilities, support systems and equipment should be appropriately qualified before 282

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

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In a traditional approach, stages of qualification may include design, installation, operational 285

and performance qualification.

286 287

In some cases process validation may be conducted concurrently with performance 288

qualification.

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Phase IIB. Continuous process performance verification 291

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After completion of qualification, commercial batches should be subjected to continuous 293

process performance verification as part of process validation. It should confirm that scale up 294

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

295 296

CPV demonstrates that a process that operates within the predefined specified parameters 297

consistently produces a product which meets all its critical quality attributes (CQAs) and 298

control strategy requirements.

299 300

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

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Extensive in-line or at-line controls should be used to monitor process performance and 302

product quality in a timely manner. Relevant process quality attributes of incoming materials 303

or components, in-process material and finished products should be collected. This should 304

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

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Working document QAS/13.527 page 11 critical process parameter (CPP) trends. Process analytical technology applications and 306

multivariate statistical process control (MSPC) can be used.

307 308

The scope and extent of continuous process verification will be influenced by a number of 309

factors including:

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

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— the extent of process understanding gained from development studies and commercial 312

manufacturing experience;

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

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— the level of process automation and analytical technologies used;

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— process robustness and manufacturing history since point of commercialization as 316

appropriate.

317 318

Manufacturers should describe the appropriateness and feasibility of the CPV strategy 319

including the process parameters and material attributes that will be monitored as well as the 320

analytical methods that will be employed.

321 322

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

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

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— to revalidate commercialized products as part of process changes;

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

326 327

It is expected that additional monitoring for the first commercial batches should be done 328

where continuous process verification is implemented.

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Manufacturers should define:

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

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— the type of testing/monitoring to be performed;

333

— the acceptance criteria to be applied;

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— how the data will be evaluated.

335 336

Statistical models or tools used should be described.

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6. PHASE III. CONTINUED PROCESS VERIFICATION 339

340

Manufacturers should monitor product quality of commercial batches after completion of 341

Phase I and Phase II of process validation. This will provide evidence that a state of control is 342

maintained throughout the product life-cycle.

343 344

Periods of enhanced sampling and monitoring may help to increase process understanding as 345

part of continuous improvement.

346 347

Process trends such as the quality of incoming materials or components, in-process and 348

finished product results and non-conformances should be collected and assessed in order to 349

verify the validity of the original process validation or to identify required changes to the 350

control strategy.

351 352

The extent and frequency of ongoing process validation should be reviewed periodically and 353

modified if appropriate throughout the product life-cycle.

354 355

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

356 357

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

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Table 2. New approach to process validation 360

Product life-cycle Process validation

Phase I Phase II Phase III

Process design Qualification Continuous process verification

Continued process verification - Pilot scale (and

scale-up batches where appropriate) - Risk assessment to identify critical quality attributes and process control parameters

- Premises - Utilities - Equipment

- Commercial-scale batches

- In-line or on-line monitoring (e.g. PAT) - Defined number of batches

- Periodic review of trends

- May include

sampling and testing

Working document QAS/13.527 page 13 - Protocols and

reports

- Validate process - Define CQA and CPPs to be

monitored in Phase II

Change control GMP 361

7. CHANGE CONTROL

362 363

Changes during the life-cycle of a product should be managed through a change control 364

procedure. Sufficient data should be generated to demonstrate that the revised process will 365

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 thoroughly 368

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

369

Manufacturers should follow change control procedures when changes are planned to 370

existing systems or processes.

371 372

Validation should be considered when changes are planned to production and/or control 373

procedures.

374 375

Changes that are likely to require revalidation may include:

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

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

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— production area and support system changes (e.g. rearrangement of areas or a new water 379

treatment method);

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— transfer of processes to another site;

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— unexpected changes (e.g. those observed during self-inspection or during routine analysis 382

of process trend data).

383 384

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

385

— changes in the master formula, methods, starting material manufacturer, equipment and/or 386

instruments;

387

— equipment calibrations and preventive maintenance carried out;

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— changes to standard operating procedures (SOPs);

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— changes to cleaning and hygiene programmes.

390 391

REFERENCES 392

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1. Guideline on Process Validation, 29 March 2012 394

EMA/CHMP/CVMP/QWP/70278/2012-Rev1 , Committee for Medicinal Products for 395

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 Evaluation 401

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), Current 405

Step 4 version, dated August 2009.

406 407

4. ICH Harmonised Tripartite Guideline, Quality Risk Management, Q9, Current Step 4 408

version, dated 9 November 2005.

409 410

5. ICH Harmonised Tripartite Guideline, Pharmaceutical Quality System, Q10, Current 411

Step 4 version, dated 4 June 2008 412

http://www.ich.org/products/guidelines/quality/article/quality-guidelines.html 413

414

6. Quality Assurance of pharmaceuticals. WHO guidelines, related guidance and 415

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

416

417

418

Working document QAS/13.527 page 15 7. WHO good manufacturing practices: main principles for pharmaceutical products. In:

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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 for 422

pharmaceutical products).

423 424

8. WHO guidelines on quality risk management. In: WHO Expert Committee on 425

Specifications for Pharmaceutical Preparations. Forty-seventh report. Geneva, World 426

Health Organization. WHO Technical Report Series, No. 981 (Annex 2), 2013 (in 427

press).

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