SUPPLEMENTARY GUIDELINES ON GOOD MANUFACTURING PRACTICES .
Working document QAS/03.055/Rev.2RESTRICTEDWORLD HEALTH ORGANIZATIONORGANISATION MONDIALE DE LA SANTESUPPLEMENTARY GUIDELINES ONGOOD MANUFACTURING PRACTICES (GMP):VALIDATIONThis document has followed the steps given in the schedule on page 2 herein. It has been very widelydistributed and numerous comments have been incorporated.Please address any comments you may have on this revised document to Dr S. Kopp, Quality Assurance andSafety: Medicines, Medicines Policy and Standards, World Health Organization, 1211 Geneva 27,Switzerland; fax: ( 41 22) 791 4730 or e-mail: kopps@who.int, with a copy to bonnyw@who.int,by 20 October 2005. World Health Organization 2005All rights reserved.This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft.The draft may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in partor in whole, in any form or by any means outside these individuals and organizations (including the organizations’concerned staff and member organizations) without the permission of WHO. The draft should not be displayed on anywebsite.Please send any request for permission to:Dr Sabine Kopp, Quality Assurance & Safety: Medicines (QSM), Department of Medicines Policy and Standards(PSM), World Health Organization, CH-1211 Geneva 27, Switzerland.Fax: (41-22) 791 4730; e-mails: kopps@who.int; bonnyw@who.intThe designations employed and the presentation of the material in this draft do not imply the expression of any opinionwhatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city orarea or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps representapproximate border lines for which there may not yet be full agreement.The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed orrecommended by the World Health Organization in preference to others of a similar nature that are not mentioned.Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters.The World Health Organization does not warrant that the information contained in this draft is complete andcorrect and shall not be liable for any damages incurred as a result of its use.
Working document QAS/03.055/Rev.2page 2SCHEDULE FOR THE ADOPTION PROCESS OF DOCUMENT QAS/03.055/Rev.2:SUPPLEMENTARY GUIDELINES ON GMP: VALIDATIONDeadlineFirst draft prepared and mailed for comments20 January 2003Deadline for receipt of comments28 February 2003Collation of commentsMarch 2003Revision of draft documentJuly-August 2003Mailing of draft for second round ofcommentsSeptember 2003Deadline for receipt of comments15 November 2003Collation of commentsDecember 2003Evaluation of commentsMarch 2004Consultation to discuss commentsMay 2004Presentation to Thirty-ninth WHO Expert Committee onSpecifications for Pharmaceutical PreparationsIncorporation of comments of the meeting of May 2005October 2004Finalization of next revised versionJuly 2005Mailing for third round of commentsSeptember 2005Presentation to Fortieth WHO Expert Committee onSpecifications for Pharmaceutical Preparations24-28 October 2005June 2005
Working document QAS/03.055/Rev.2page 3SUPPLEMENTARY GUIDELINES ON GOOD MANUFACTURING PRACTICES(GMP): Scope of document84.Relationship between validation and qualification85.Validation85.1. Approaches to validation5.2. Scope of validation896.Qualification107.Calibration and verification108.Validation Master Plan (VMP)109.Qualification and Validation Protocols1110.Qualification and Validation Reports1111.Qualification stages1212.Change Control1413.Personnel1514.References15Annex 1. Validation of Heating, Ventilation and Air Conditioning(HVAC) systemsAnnex 2. Validation of Water systems for pharmaceutical useAnnex 3. Cleaning validationAnnex 4. Analytical method validationAnnex 5. Validation of computerized systemsAnnex 6. Qualification of systems and equipmentAnnex 7. Non-sterile process validation16222433384473
Working document QAS/03.055/Rev.2page 41.INTRODUCTIONValidation is an essential part of Good Manufacturing Practices (GMP). It is, therefore, anelement of the quality assurance programme associated with a particular product or process.The basic principles of quality assurance have as their goal the production of products that arefit for their intended use. These principles include:(1)(2)(3)Quality, safety and efficacy must be designed and built into the product.Quality cannot be inspected or tested into the product.Each critical step of the manufacturing process must be validated. Other steps in theprocess must be under control to maximize the probability that the finished productmeets all quality and design specifications.Validation of processes and systems is fundamental to achieving these goals. It is by designand validation that a manufacturer can establish confidence that the manufactured products willconsistently meet their product specifications.Documentation associated with validation includes:-Standard Operating Procedures (SOPs)SpecificationsValidation Master Plan (VMP)Qualification protocols and reportsValidation protocols and reports.The implementation of validation work requires considerable resources such as:-Time: generally validation work is subjected to rigorous time schedules.Financial: validation often requires time of specialized personnel and expensivetechnology.Human: collaboration of experts of various disciplines (e.g. a multidisciplinaryteam, comprising quality assurance, engineering, manufacturing and otherdisciplines, depending on product and process to be validated).This guideline aims to give guidance to inspectors of pharmaceutical manufacturing facilitiesand manufacturers of pharmaceutical products on the requirements for validation. It consistsof a main part reflecting general principles of validation and qualification. In addition to themain part, annexes will be added on validation and qualification (e.g. cleaning, computer andcomputerized systems, equipment, utilities and systems, analytical methods, etc.).
Working document QAS/03.055/Rev.2page 52.GLOSSARYThe definitions given below apply to the terms used in this guideline. They may have differentmeanings in other contexts.Calibration (old)The performance of tests and retests to ensure that measuring equipment (e.g. for temperature,weight, pH) used in a manufacturing process or analytical procedure (in production or qualitycontrol) gives measurements that are correct within established limits.Calibration (new)The set of operations that establish, under specified conditions, the relationship between valuesindicated by an instrument or system for measuring (especially weighing), recording, andcontrolling, or the values represented by a material measure, and the corresponding knownvalues of a reference standard. Limits for acceptance of the results of measuring should beestablished.Computer validationDocumented evidence which provides a high degree of assurance that a computerized systemrecords data correctly and that data processing complies with predetermined specifications.Concurrent validationValidation carried out during routine production of products intended for sale.Cleaning validationDocumented evidence to ensure that cleaning procedures are removing residues topredetermined levels of acceptability, taking into consideration i.e. batch size, dosing,toxicology, equipment size, etc.Design Qualification (DQ)Documented evidence that the premises, supporting utilities, equipment and processes havebeen designed in accordance with the requirements of GMP.Good Engineering PracticesEstablished engineering methods and standards that are applied throughout the project lifecycleto deliver appropriate, cost-effective solutions.Installation Qualification (IQ)(old)IQ is the documentary evidence to verify that the equipment has been built and installed incompliance with design specifications.Installation Qualification (IQ)(new)The performance of tests to ensure that the installations (such as machines, measuring devices,utilities, manufacturing areas) used in a manufacturing process are appropriately selected andcorrectly installed and operate in accordance with established specifications.
Working document QAS/03.055/Rev.2page 6Operational Qualification (OQ)(old)OQ is the documentary evidence to verify that the equipment operates in accordance with itsdesign specifications in its normal operating range and performs as intended throughout allanticipated operating ranges.Operational Qualification (OQ)(new)Documented verification that the system or subsystem performs as intended over allanticipated operating ranges.Performance Qualification (PQ)PQ is the documentary evidence which verifies that the equipment or system operatesconsistently and gives reproducibility within defined specifications and parameters forprolonged periods. (The term “process validation” may also be used.)Process validation (See Validation)Documented evidence which provides a high degree of assurance that a specific process willconsistently produce a product meeting its pre-determined specifications and qualitycharacteristics.Prospective validationValidation carried out during the development stage by means of a risk analysis of theproduction process, which is broken down into individual steps; these are then evaluated on thebasis of past experience to determine whether they may lead to critical situations.Qualification (new)Action of proving and documenting that any premises, systems and equipment are properlyinstalled, and/or work correctly and lead to the expected results. Qualification is often a part(initial stage) of Validation, but the individual qualification steps alone do not constituteprocess validation.Retrospective validationInvolves the examination of past experience of production on the assumption that composition,procedures, and equipment remain unchanged.Revalidation (old)Involves the repeat of the initial process validation to provide assurance that changes in theprocess and/or in the process environment, whether intentional or unintentional, do notadversely affect process characteristics and product quality.Revalidation (new)Repeated validation of an approved process (or a part thereof) to ensure continued compliancewith established requirements.Standard operating procedure (SOP)An authorized written procedure giving instructions for performing operations not necessarilyspecific to a given product or material but of a more general nature [new] (e.g. equipment
Working document QAS/03.055/Rev.2page 7operation, maintenance and cleaning; validation; cleaning of premises and environmentalcontrol; sampling and inspection). Certain SOPs may be used to supplement product-specificmaster and batch production documentation.Validation (new)Action of proving and documenting that any process, procedure or method actually leads to theexpected results (see also Qualification).Validation Protocol (VP)(old)The VP is a written plan stating how validation will be conducted, including test parameters,product characteristics, production equipment and decision points on what constitutesacceptable test results.Validation Protocol (or plan) (VP)(new)A document describing the activities to be performed in a validation, including the acceptancecriteria for the approval of a manufacturing process - or a part thereof - for routine use.Validation Report (VR)(old)The VR is a written report on the validation activities, the validation data and the conclusionsdrawn.Validation Report (VR)(new)A document in which the records, results and evaluation of a completed validation programmeare assembled. It may also contain proposals for the improvement of processes and/orequipment.Validation Master Plan (VMP)VMP is a high level document that establishes an umbrella validation plan for the entire projectand summarizes the manufacturer’s overall philosophy and approach, to be used forestablishing performance adequacy. It provides information on the manufacturer’s validationwork programme and defines details of and time-scales for the validation work to beperformed, including stating the responsibilities relating to the plan.VerificationThe application of methods, procedures, tests and other evaluations, in addition to monitoring,to determine compliance with the GMP principles.Worst caseA condition or set of conditions encompassing upper and lower processing limits andcircumstances, within SOPs, which pose the greatest chance of product or process failure whencompared to ideal conditions. Such conditions do not necessarily include product or processfailure.
Working document QAS/03.055/Rev.2page 83.SCOPE OF DOCUMENT3.1 This guideline focuses mainly on the overall concept of validation and is intended as abasic guide for use by GMP inspectors and manufacturers. It is not the intention to beprescriptive in specific validation requirements. This guide serves as a general guideline only.Validation of specific processes and products such as sterile product manufacture requiresmuch more consideration and a detailed approach beyond the scope of this document.3.2 There are many factors affecting the different types of validation and it is, therefore, notintended to define and address all aspects related to one particular type of validation here.3.3 Manufacturers should appropriately plan validation in a manner that will ensureregulatory compliance and ensuring that product quality, safety and consistency are notcompromised.3.4 The general text in the main part may be applicable to validation and qualification ofpremises, equipment, utilities and systems, and processes and procedures. More specificprinciples on qualification and validation are addressed in the annexes. In addition to theinformation in the annexes, semi-automatic or fully automatic Clean-In-Place (CIP) systemsand other special cases should be treated separately.4.RELATIONSHIP BETWEEN VALIDATION AND QUALIFICATIONValidation and qualification are essentially components of the same concept. The termqualification is normally used for equipment, utilities and systems, and validation forprocesses. In this sense, qualification is part of validation. Validation also refers to the overallconcept of validation5.VALIDATION5.1Approaches to validation5.1.1 There are two basic approaches to validation - one based on evidence obtained throughtesting, and one based on the analysis of accumulated (historical) data (also referred to asretrospective validation). Retrospective validation is no longer encouraged and is, in any case,not applicable to the manufacturing of sterile products.5.1.2 The testing approach, which is applicable to both prospective and concurrent validation,may include:-extensive product testing, which may involve extensive sample testing, with theestimation of confidence limits for individual results and batch homogeneity;simulation process trials;challenge/worst case tests, which determine the robustness of the process; andcontrol of process parameters being monitored during normal production runs toobtain additional information on the reliability of the process.
Working document QAS/03.055/Rev.2page 95.2Scope of validation5.2.1 There should be an appropriate and sufficient system including organizational structureand documentation infrastructure, sufficient personnel and financial resources to performvalidation tasks in timely manner. Management and persons responsible for Quality Assuranceshould be involved.5.2.2 Personnel with appropriate qualifications and experience should be responsible forperforming validation. They should represent different departments depending on thevalidation work to be performed.5.2.3 There should be proper preparation and planning before validation is performed. Thereshould be a specific programme for validation activities.5.2.4 Validation should be performed in a structured way according to the documentedprocedures and protocols.5.2.5 Validation should be performed for (1) new premises, equipment, utilities and systems,and processes and procedures, (2) at periodic intervals, and (3) when major changes have beenmade.5.2.6 Validation should be performed in accordance with written protocols. The outcome ofthe validation should be reflected in written reports.5.2.7 Validation can be prospective, concurrent, or retrospective, depending on whenvalidation is performed.5.2.8 Validation should be done over a period of time, e.g. at least three consecutive batches(full production scale) should be validated, to show consistency. Worst case situations shouldbe considered.5.2.9 There should be a clear distinction between in-process controls and validation. Inprocess tests are performed during the manufacture of each batch using specifications andmethods devised during the development phase. The objective is to monitor the processcontinuously.5.2.10 When a new manufacturing formula or method is adopted, steps should be taken todemonstrate its suitability for routine processing. The defined process, using the materials andequipment specified, should be shown to yield a product consistently of the required quality.5.2.11 Manufacturers should identify what validation work is needed to prove control of thecritical aspects of their operations. Significant changes to the facilities, the equipment andprocesses which may affect the quality of the product should be validated. A risk assessmentapproach should be used to determine the scope and extent of validation.
Working document QAS/03.055/Rev.2page 106.QUALIFICATION (See Glossary)6.1 Qualification should be completed before process validation is performed. The processof qualification should be a logical, systematic process and should start from the design phaseof the premises, equipment, utilities and equipment.6.2 Depending on the function and operation of equipment, utility or system, only installationqualification (IQ) and operational qualification (OQ) may be required, as the correct operationof the equipment, utility or system could be considered to be a sufficient indicator of itsfunction (refer to Section 12 for IQ, OQ and PQ). (The equipment, utility and system shouldthen be maintained, monitored and calibrated according to a regular schedule.)6.3Major equipment and critical utilities and systems, however, require IQ, OQ and PQ.7.CALIBRATION AND VERIFICATION7.1 Calibration and verification of equipment, instruments and other devices as applicable,used in production and quality control, should be performed at regular intervals.7.2 Calibration should normally be performed by officially recognized bodies. Personnel whoprovide calibration and preventative maintenance should have appropriate qualifications andtraining.7.3 A calibration programme should be available and indicate information such as calibrationstandards and limits, responsible persons, calibration intervals, records and actions to be takenwhen problems are identified.7.4 There should be traceability to standards (e.g. national, regional or internationalstandards) used in the calibration.7.5 Calibrated equipment, instruments and other devices should be labelled, coded orotherwise identified to indicate the status of calibration and the date when recalibration is due.7.6 When the equipment, instruments and other devices have not been used for a certainperiod of time, their function and calibration status should be verified and shown to besatisfactory before use.8.VALIDATION MASTER PLAN (VMP)The VMP should reflect the key elements of the validation programme. It should be conciseand clear and contain at least: A validation policyOrganizational structure of validation activitiesSummary of facilities, systems, equipment and processes validated and to be validate
The VR is a written report on the validation activities, the validation data and the conclusions drawn. Validation Report (VR)(new) A document in which the records, results and evaluation of a completed validation programme are assembled. It may also contain proposals for the improvement of processes and/or equipment. Validation Master Plan (VMP)
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Working document QAS/15.639/Rev.1 May 2016 Draft document for comment Draft document for comment 1 SUPPLEMENTARY GUIDELINES ON 2 GOOD MANUFACTURING PRACTICES FOR HEATING, 3 VENTILATION AND AIR-CONDITIONING SYSTEMS FOR 4 NON-STERILE PHARMACEUTICAL DOSAGE FORMS (May5 2016) 6 REVISED DRAFT FOR COMMENT 7 Should you have any comments on the attached text, please send these to Dr S. Kopp, Group
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of compliance of OTC drug products to 21 CFR Part 210 Current Good Manufacturing Practice in Manufacturing, Processing, Packing, or Holding of Drugs; General and 21 CFR Part 211 Current Good Manufacturing Practice for Finished Pharmaceuticals, a
