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FDA ICH SOP - Agilent Technologies

1. 5 Developers ManufacturersandVendors 97 Agilent Technologies Commitment to Compliance 58 References C m 59 BOSS era a WR ERE kr e RUE a pi ar eM E dE 61 B Dpo 0L Preface 300d to know Qualification of analytical instruments Is required by regulations and quality standards Qualification of analytical instruments and validation of systems is required by many national and international regulations quality standards such as SO 17025 and company policies f executed correctly it also helps to improve instrument uptime and to avoid out of specification situations 005 in laboratories This Analytical Instrument Qualification primer guides analysts laboratory managers quality assurance managers and validation professionals through instrument and system validation at minimal extra cost The concept examples templates and recommended procedures are based on my more than 20 years of multinational experience and incor porate knowledge from validation and qualification practices applied at Agilent Technologies and Labcompliance Readers of this book will learn how to speed up their validation and qualification process thereby avoiding troublesome reworking and gaining confidence for audits and inspections Due to limited space could not include all the information that is available and of interest to readers For additional information can refer
2. A Primer uj jeonAjeuy np yuaLun zs uonep ea Wajsks pue uonedy Analytical Instrument Qualification and system Validation Copyright 2009 Agilent Technologies Printed in Germany January 1 2009 Publication Number 5990 3288EN Agilent Technologies ey 8 Agilent Technologies ae Analytical Instrument Qualification and System Validation Ludwig Huber EM M Table of Content digrrg e ee III 1 introduction cos eoco rre a e ie ees 1 1 1 Literature Overview 3 1 2 Terminology Validation vs Qualification D 1 3 ComponentsofAnalyticaDataOualiy 6 2 Regulations and Quality Standards 9 2 1 Good Laboratory Pract ceRegulations 10 2 2 Current Good Manufacturing Practice Regulations 11 2 3 nternational Conference for Harmonization ES 2 4 Pharmaceutical Inspection Convention Scheme PIC S 14 MEUS Em 15 2 6 21 CFR Part 11 FDAs Regulation on Electronic Records and Signatures 19 2 Learning from Regulations and Quality Standards 16 3 Qualification of Analytical Instruments 17 3 1 OualificationPlann ng 19 3 2 Design GUR GAL essersi eme iy sekileri 22 DER GE M es nr r do yel e m fe 23 Vendor Assessment 25
3. D Test of operational functions T e Sa Test of security functions 5 e e Test for specified application Performance Qualification O Preventive maintenance On going performance tests Figure 2 Qualification phases 40 model In the DO phase user requirements are compared with the vendor s specification In addition users conduct an assessment of the vendor In the installation qualification the selected user s environment is checked whether it meets the vendor s environmental specifications The instrument 18 3 1 Qualification Planning is installed according to vendor s recommendations and correct installation is verified and documented Operational qualification checks if the instrument conforms to the functional specifications as defined in the DO phase Performance qualification verifies that the complete system works for selected applications Preventive maintenance activities and controlled changes also are part of this phase All activities are defined in a validation or qualification plan and results are documented in a summary report Figure 3 illustrates the timeline for the four qualifications Design Installation Operational Performance Qualification Qualification Qualification Qualification pe M me n Before At gt After Whenever the Purchasing installation installation instrument After major is used e g changes daily e g repair
4. updates Atregular intervals risk based Figure 3 Qualification time line Qualification activities should be described in a master plan The plan documents a company s approach for specific activities for example how to qualify analytical instruments how to assess vendors or what to test for commercial computer systems A master plan serves two purposes when implemented right it ensures consistent and efficient implementation of equipment qualifications and it answers an inspector s question for a company s approach for instrument qualification and system validation A validation master plan is also officially required by Annex 157 to the 19 Good to know A validation master plan is officially required by Annex 15 to the European GMP directive 20 European GMP directive All validation activities should be planned The key elements of a validation program should be clearly defined and documented in a Validation Master Plan VMP or equivalent documents FDA regulations and guidelines do not specifically require a validation master plan However inspectors want to know what the company s approach towards validation is The qualification master plan is an ideal tool to communicate this approach both internally and to inspectors In case there are any questions as to why things have been done or not done the master plan should provide the answers Within an organization a validation master plan can be develop
5. Manufacturers should allow user audits and share validation processes test procedures and test results with regulated users Manufacturers and vendors should also notify all users about hardware and software defects discovered after a product s release Furthermore manufacturers or vendors should provide user training installation and qualification support and repair services 57 EM v o Agilent Technologies Commitment to Compliance Agilent Technologies develops and manufactures hardware and software solutions that offer the most comprehensive built in compliance capabilities You can validate these systems methods and data in the shortest possible time and at very low cost Agilent s five steps to successful validation procedure for LC GC CE separation and detection instrumentation includes Step 1 Design qualification DQ Step 2 Installation qualification IQ and operational gualification perfor mance verification OQ PV Step 3 Method validation Step 4 Performance qualification PQ Step 5 Electronic records protection for compliance with 21 CFR Part 11 More information on www agilent com chem validation Additional resources Regular e seminars provide basic and update information on validation and compliance in laboratories More information on www agilent com chem eseminars To make regulatory compliance even easier Agilent Technologies offer cost effective and proven risk based qualificat
6. e Identify and make a list with a description of all hardware operating system software and application software Identification of software should include the version number e Make system drawings where appropriate e For networked systems check communication with network devices 43 4 5 Operational Oualification 44 As part of the installation process computer systems should be well documented with Computer hardware e g manufacturer model Computer firmware e g revision number Operating system vendor product identifier and version Application software vendor product identifier and version Hardware peripherals e g printers CD ROMs Network hardware firmware software and cables Documentation e g operating manuals and specifications CO _ LUE ii es ai ar ey Figure 21 Computer system documentation for 10 Information should be entered into a data base and should be readily available when contacting vendors to report a problem during operation Figure 21 shows a template with examples of an installation protocol Testing software and computer systems can be a complex task Extent of testing should be based on a justified and documented risk assessment The required effort mainly depends on Good to know opecific user configurations should be documented and tested e the criticality of the system for drug product quality and data integrity e the complexity
7. 2 9 dustallation QUAlINCAUON 1 uuo oerte tert xe pes 26 Testing for nstallattonOualificaton 29 3 4 Operational Qualification 00 30 3 0 Perflormancelualificaton 02 Preventive MaintenanceandReparr 34 Change Control NE ou beams 39 RE 4 Validation of Software and Computer Systems 37 41 MasterandProjectPlann ng 39 42 ReguirementsSpecificatlons 40 43 VendorAssessment 41 4 4 InstallattonOualificaton 43 45 perationalOudlificaton 44 46 Performancelualificaton 4 4 7 Configuration Management and Change Control 4 48 Validation Report x iade edet puris soe guter ee tack von debes 49 49 Validation of Existing legacy Systems 49 4 10 Validation of Spreadsheet Applications 50 5 Implementing USP Chapter 1058 51 5 1 lt 1068 gt i nstrumentGroups D2 5 2 Allocating Instrument into Instrument Groups 54 5 3 Procedures and Qualification Protocols for Three Groups 54 5 4 Responsibilities Communication and Training 56 Ic e li gra e 06 OualityAssurance
8. 6 shows a template that can be used to document design qualifi cation User requirements for an HPLC system should not only have a section to define chromatographic functions and performance but also for physical requirements construction and vendor requirements to the vendor A physical requirement could be that all modules should have the same dimensions to allow stackability for optimal use of the lab s bench 23 24 Function User Supplier Performance Requirements Specification Pass Fail Physical Requirements Construction Requirements Vendor Requirements Figure 6 Template for design qualification space An example of a construction requirement are accessibility of the detector lamp and flow cell from the front of the instrument for easy maintenance Figure shows an example of selected functional and performance specifications of an HPLC system The user defines his her requirement specifications and compares them with the vendor s specifications To set the functional and performance specifications the vendor s specification sheets can be used as guidelines However it is not recommended to simply copy the vendor s specifications because compliance to the functional and performance specifications must be verified later in the process during operational qualification and also when re gualify ng the instrument at a later time Specifying too many functions and setting the values too stringently will significantly i
9. T11 gt 2 0 Compound A and B Tig far T2 a Precision of Amount T13 D Compound A 6 Replicate Injections Precision of Amount T14 196 Compound B 6 Replicate Injections Figure 14 Documentation of PO tests 33 Preventive Maintenance and Repair Analytical instruments should be well maintained to ensure proper ongoing performance Procedures should be in place for regular preventive maintenance of hardware to detect and fix problems before they can have a negative impact on analytical data The procedure should describe e he maintenance to be done e When it is to be done e What should be re qualified after maintenance is done For example a PO test should always be performed after instrument maintenance e How to document maintenance activities Instruments should be labeled with the dates of the last and next scheduled maintenance Planned maintenance activities should follow a documented instrument maintenance plan Some vendors offer maintenance contracts with services for preventive maintenance at scheduled time intervals A set of diagnostic procedures is performed and critical parts are replaced to ensure ongoing reliable system uptime Unplanned activities that are necessary in addition to the planned activities should be formally requested by the user of the instrument or by the person who is responsible for the instrument An example of a request form is shown in figure
10. The vendor s capability and practice to support the user before and during installation and as long as the software is used should also be checked Assessment Comment 1 Through own experience Experience may come from the product with the vendor under consideration or from other products Criteria are Quality of the products failure rate Responsiveness in case of errors phone call on site visit bug fix 2 Through references outside Useful if there is no experience with the company the vendor within your company Criteria are Position of the vendor in the market place Image of the vendor as software supplier Quality reputation of the product 3 Checklist Mail audit Use checklists available within your company and through public organizations e g PDA and from private authors 4 Assessment through Gives an independent assessment of the 3rd party audits quality system and or product development 5 Vendor audit through Gives a good picture of the vendor s the user firm quality system and on the vendors testing practices Figure 20 Methodologies for vendor assessment Figure 20 lists different assessment methodologies Costs for the assessment increase from 1 to 5 Vendor audits are most expensive but could make sense when a company plans to purchase complex computer systems for multiple laboratories or sites The final decision on the methodology should be based on risk assessment Criteria are vendor risk and product
11. by the FDA that includes Good Laboratory Practice GLP Good Clinical Practice GCP and current Good Manufacturing Practice cGMP Part 11 requires computer systems used in FDA regulated environments to be validated Chapter 10 a states e Computer systems should be validated to ensure accuracy reliability and consistent intended performance There is no further instruction on how computer systems should be validated As we have seen in this chapter all important regulations and ISO 17025 have one or more chapters on equipment and computers The wording and the level of detail is different For example the words calibration and qualification are interchangeably used Despite different terminology the message is always the same instruments and computer systems should be suitable for their intended use his means users should e Define the intended use meaning write specifications e Formally assess the vendor s quality system e Formally document installation ICH Q7A calls this installation qualification e est the instrument in the user s environment for functional specifications ICH and PIC S call this operational qualification e Verify ongoing performance through ongoing preventive maintenance system tests e Keep instruments under change control to ensure that the validated state Is ensured after changes Oualification of Analytical nstruments Qualification of Equipment qualificati
12. generally it is not mandated and alternative approaches are possible Nevertheless we would recommend implementing it for FDA regulated environments because of several reasons e he chapter is mandated if any USP monographs require using qualified instruments for a specific analysis e FDA inspectors expect instruments to be qualified when used for regulated testing e he applied 40 qualification model has been very well established since over 10 years and many laboratories are familiar with it e he model is applicable to all types of instruments ranging from simple devices to complex systems e he model is flexible and allows laboratories to define test procedures and acceptance criteria according to the instrument s intended use Because of the importance of the chapter and its advantages we want to dedicate this last primer chapter to recommendations for implementation of USP lt 1058 gt Analytical laboratories typically include a set of tools ranging from simple nitrogen evaporators to complex automated instruments Depending on the complexity the qualification efforts vary The concept is always the same but the extent of testing and the required amount of documentation will change For example a very simple instrument may only need one or two minutes for physical inspection and making a tick mark in a check list while more complex systems can easily take several days for full validation Because of the large variety
13. on relatively small and less complex software and computer systems As a model we will use a chromatographic data system CDS with no or little customization For more complex systems for systems with high level of customization and for any software development activities we refer to literature references with more detail for example references 12 4 1 Master and Project Planning Good to know Risk categories should have been determined following a documented process and should be justified Software and computer system validation should be well planned A computer system validation master plan should not only describe validation approaches but should also have an appendix with a list of all computer systems used in a laboratory Typically inspectors ask for a list when inspecting data that have been generated by a computer system The list should uniquely identify all computer systems It should include a short description of the system and information on the location the application and whether the system is used in regulated areas Inspectors also will ask for the risk category of the system The risk categories can be for example high medium or low The categories should have been determined following a documented process and should be justified Criteria are complexity and impact of the system on drug product quality Most likely the inspector will focus during the inspection on systems that have been classified as h
14. risk Criteria for product risk are e System complexity 4 4 Installation Oualification Number of systems to be purchased Maturity of the system Influence on other systems Impact on drug product quality Impact on business continuity Level of customization When users purchase software such as CDS they need support from a specific vendor for a lengthy time to ensure retrieval and readability of data for several years Therefore the future outlook of a company and the ability to support data is important The way to make an assessment Is to look for how long older data can be supported by the current system This in combination with the size of the company and the position of the company in the target market are good indications to assess the vendor risk The selection decision for a specific vendor should be justified and documented Key points for IQ of computer systems are to verify correct software installation and to document all computer hardware software and configuration settings as the initial baseline configuration Hecommended steps for installation of computer systems include e nstall software on computer following the manufacturer s recommen dations e Verify correct software installation to make sure that all files are correctly installed Software with MD5 based checksum routines is a good tool for this e Make a back up of the software e Configure peripherals like printers and instrument modules
15. the U S FDA The most relevant PIC S document related to this primer is the Good Practice Guide Using Computers in GxP Environments The guidance document is intended to provide a logical explanation of the basic require ments for the implementation validation and operation of computerized systems Recommendations are documented in chapters 4 6 and 4 8 e Apart from user acceptance testing 00 versus the functional specifi cation the regulated user also has responsibility for the PQ performance qualification of the system e he validation documentation should cover all the steps of the life cycle with appropriate methods for measurement and reporting e g assessment reports and details of quality and test measures as required Oe e Regulated users should be able to justify and defend their standards protocols acceptance criteria procedures and records in the light of their own documented risk and complexity assessment 2 5 ISO IEC 17025 ISO IEC 17025 is the most relevant ISO Standard for chemical laborato ries It specifies the general requirements for the competence to carry out tests and or calibrations The standard is widely used as a quality system in environmental food chemical and clinical testing laboratories It is used to assess laboratories that seek accreditation status The standard has many requirements related to the subject of this primer The most important ones can be found in chapter 5 5 Good
16. these possibilities are expressed in ICH Q7A Deviations from approved standards of calibration on critical instruments should be investigated to determine if these could have had an impact on the quality of the intermediate s or API s manufactured using this equipment since the last successful calibration Vendor Assessment Vendors of analytical instruments should be qualified through a formal process The objective is to ensure that vendors provide high quality products and can give adequate support For basic equipment such as pH meters or a balance this can be a single page statement describing why the vendor XY has been selected Certification for a recognized quality system is sufficient for simple instruments The formal assessment statement should be supported by the quality systems certificate Figure 8 shows a template with examples to document vendor assessment criteria for analytical instruments 25 3 3 Installation Qualification 26 L Requirements A Leader in the Market Place Good Experience with the Vendor Quality Assurance ISO Certification Provide Specifications List T Installation Service 10 00 Services Phone and Onsite Support Documented Software Development yes no Figure 8 Selected criteria for vendor assessment For more complex systems especially for critical computer systems such as chromatographic data systems a more detailed assessment is recommended Depending on t
17. words validation and qualification USP has recognized this and addressed it in a paragraph on the first page of chapter 1058 The word qualification relates to instruments that can be individual modules and also systems for example a complete HPLC system comprised of a sampling system a pump a column compartment and a detector Checking the baseline noise of a detector and comparing the results with previously defined specifications would be an example for qualification Qualification is done independently from a specific appli cation or sample Typically the type of specifications can be found in the vendor s product specification sheet he word validation relates to applications processes and methods For example for method validation we specify the limit of quantitation or limit of detection of our sample compounds Such specifications can only be verified with a complete system and accessories such as the 1 3 Components of Analytical Data Ouality Good to know Whether you validate methods verify the suitability of a system or analyze quality control samples you should always have qualified the instrument first right chromatographic column calibration standards and SOPs for running the test Unfortunately validation and qualification are frequently used inter changeably For example for software and computer systems the term validation is always used even though according to the previous definition qualific
18. 15 Requester Bae ae 0 Eum Dr ul Describe Observation High O Medium O Low O Come S Figure 15 Request form for unplanned maintenance Good to know Defective instruments should be either removed from the laboratory or clearly labeled as being defective The reason for the requested maintenance should be entered as well as a priority All maintenance activities should be documented in the instrument s logbook A template with examples is shown in figure 16 Person Instrument Maintenance Performing Owner Maintenance E g routine Printed Name Printed Name E g non routine recalibrated Signature Signature Printed Name Printed Name Signature Signature Figure 16 Maintenance logs Defective instruments should be either removed trom the laboratory area or clearly labeled as being defective Procedures should be available for most common problems such as defective UV detector lamps Procedures should also include information if and what type of requalification is required Uncommon problems for example if an HPLC pump becomes defect without any obvious reason should be handled through a special procedure that guides users of instruments through the repair process and reinstallation In this case the impact of the failure on previously generated data should be evaluated Change Control Analytical instruments and systems go through many changes during their lifetime New hardware module
19. 8 Each specification should have a unique D code Criticality of the function can be defined as high medium or low Most important questions to ask are what happens if the function does not work at all or if it produces wrong results In the next column the test priority is documented Criticality plays a major role but also the question as to how the user s environment or the user for example through a wrong user configuration can influence correct functioning Requirement Requirement Critical Test Test ID Priority ID 4 1 A single computer should be able H H 21 to control and acquire data from up to four chromatographs 4 2 Before and during data acquisition H H 22 the status of the instrument should be continually monitored and updated on the display along with elapsed run time of the analysis 4 3 The transactions that occur during M L N A analysis including any errors and the instrument conditions at the start and at the end of the analysis should be recorded in the system s log book Figure 18 Example for requirement specification of a chromatographic data system 4 3 Vendor Assessment Requirements of a CDS should not only be specified on the ability to run a chromatographic analysis but also on other requirements that are mainly related to system and data security and data integrity Requirements are stated in FDA s regulation for electronic records and signatures 21 CFR Part 11 and in Annex 11 to the European
20. A QC analysis with monthly newsletter for regular updates http www labcompliance com A website with regular updates including tutorials and many references related to all compliance issues in laboratories Dr Ludwig Huber Chief advisor for global FDA compliance Labcompliance ludwig huber labcompliance com Chapter 1 Introduction Introduction Good to know Equipment shall be routinely calibrated inspected and checked according to a written program to ensure proper performance U EDAC ECER Z The objective of any chemical analytical measurement is to get consistent reliable and accurate data Proper functioning and performance of analyti cal instruments and computer systems plays a major role in achieving this goal Therefore analytical instrument qualification AIO and computer system validation CSV should be part of any good analytical practice There is a second aspect to why validation and qualification are important and this is equally important for those working in a regulated and in an accredited environment Even though frequently not directly spelled out in regulations and official guidelines such as Good Laboratory Practice GLP Good Clinical Practice GCP and Good Manufacturing Practice GMP or in quality standards such as the International Organization for Standardization ISO Standard 17025 validation and qualification is usually required This is confirmed by typical statements
21. Cs and mass spectrometers 53 5 2 Allocating Instrument into Instrument Groups Good to know Within a company the procedures and qualification tasks for instru ment groups should be developed at the highest possible level 5 3 Procedures and Qualification Protocols for Three Groups 54 USP recommends dividing analytical instruments into groups but does not include a matrix with instruments allocated to groups On the other hand such a matrix is of utmost importance for a company otherwise discussions will start over and over again about the right allocation whenever an instrument has to be qualified Our recommendations are 1 Develop a list with all analytical instruments and allocate all of them into groups A B or C 2 Develop a list of procedures for each group that should be available and used when qualifying instruments 3 Develop a list of tasks for each group that should be executed when qualifying instruments Within a company the lists procedures and tasks for groups A B and C should be developed at the highest possible level and preferably there should only be one set available Having a harmonized approach reduces subjectivity for qualification and it is not only very efficient but also ensures consistency We would suggest putting examples of instrument categories and applications in an equipment validation master plan A harmonized approach is also advantageous for external audits or inspection
22. GMPs Very important is the electronic audit trail function Selected specifications for audit trail functionality are shown in figure 19 Requirement Requirement Critical Test Test ID Priority ID 12 02 Data system should have computer H H 6 1 generated time stamped audit trail to record the date and time of operator entries and actions that create modify or delete electronic record 12 03 The system should record individual H H 6 2 users who are responsible for creating modifying and deleting records 12 03 It should be possible to view and H M N A print audit trail information Figure 19 Selected specifications for electronic audit trail A thorough vendor assessment is even more important for computer systems than it is for instrument hardware When instrument hardware arrives in a laboratory it can be physically inspected for any damage and specifications can be fully tested so users can get a good impression of the quality This is not so easy with software DVD covers always look very nice but they say nothing about the quality of the product Also most likely it is impossible for a user to test all functions of a complex commercial computer system Errors may not even become obvious during initial use but only later when certain functions are executed together 41 42 During vendor assessment the user should verify that the software has been designed developed and validated during and at the end of development
23. Rockville MD Jan 2002 8 GAMP Good Automated Manufacturing Practice Guide for Validation of Automated Systems Version 4 2001 9 GAMP Good Automated Manufacturing Practice A Risk based Approach for Compliant GxP Computerized Systems Version 5 2008 10 GAMP Good Practice Guide for Validation of Laboratory Systems 2005 11 L Huber Validation of Computerized Analytical and Networked oystems Interpharm Englewood CO USA April 2002 12 Parenteral Drug Association PDA Validation and qualification of computerized laboratory data acquisition systems LDAS Technical paper 31 2000 59 NM 13 C C Chan H Lam Y C Lee X M Zhang Analytical Method Validation andInstrument Performance Verification Wiley Interscience Hoboken USA 2004 14 Pharmaceutical Inspection Convention Scheme PIC S Good practices for Computerised Systems in Regulated GxP Environments 2003 15 U S FDA GLP Good laboratory practice regulations for non clinical studies Final rule U S FDA Rockville Md USA Title 21 CFR Part 58 1979 16 Organization of Economic Co operation and Development Good laboratory practice in the testing of chemicals final report of the Group of Experts on Good Laboratory Practice 1982 out of print 1 Organization of Economic Co operation and Development The OECD principles of good laboratory practice Series on principles of good laboratory practice and compliance monitoring number 1 GLP consensus do
24. al instruments should be investigated to determine if these could have had an impact 13 Good to know Installation qualification and operational qualification should demonstrate the suitability of computer hardware and soft ware to perform assigned tasks ICH Q7A 2 4 Pharmaceutical Inspection Convention Scheme PIC S 14 on the quality of the intermediate s or API s manufactured using this equipment since the last successful calibration e GMP related computerized systems should be validated The depth and scope of validation depends on the diversity complexity and criticality of the computerized application e Appropriate installation qualification and operational qualification should demonstrate the suitability of computer hardware and software to perform assigned tasks PIC S mission is to lead the international development implementation and maintenance of harmonized Good Manufacturing Practice GMP standards and quality systems of inspectorates in the field of medicinal products his is to be achieved by developing and promoting harmonized GMP standards and guidance documents training competent authorities in particular inspectors assessing and reassessing inspectorates and facilitating the co operation and networking for competent authorities and international organizations As of October 2008 there are 34 partici pating authorities in PIC S and some more have applied for membership for example
25. ation should be used Therefore in the context of software and computer systems this primer will also use the term validation The FDA and other agencies do not really care what users call it validation or qualification The inspector s question will always be how did you make sure that the data are accurate As long as there Is a good answer for example through validation of systems and methods it is of secondary importance how users call it However agreement on terminology is of utmost importance within a company so that everybody has the same understanding of qualification and validation Therefore terminology and the exact meaning should be documented in a glossary There were many discussions about the need for instrument qualification in analytical laboratories before the release of USP 1058 taking into account that there are several other components of data quality for example method validation system suitability testing and the analysis of quality control samples USP started the chapter by giving good reasons why instrument qualification Is important Figure 1 illustrates the different components of data quality with analytical instrument qualification as the foundation at the bottom Whether you validate methods or systems verify the suitability of a system for its intended use or analyze quality control samples you should always quality the instrument first It is the basis of all other components It is the collecti
26. cation OA Quality assurance OC Quality control SOP Standard operating procedure Sol System suitability testing USP United States Pharmacopela 61
27. cification Tester confirm that have all tests executed as described Name Signature Date Tests passed yes no Comment Reviewer confirm that have reviewed test documentation Name JJ Signature Date Figure 23 Template for testing Test results should be formally documented Figure 23 shows a template and examples for a test protocol It consists of three parts The header describes the test system test objective and the specification The step by step test procedure expected results and actual results are documented in the middle The test protocol also has a column to document evidence of testing This can be a print out a screen capture or just handwritten recording of visual observations The lower part documents the names of the test engineer and reviewer and has s signature section 4 6 Performance Qualification Good to know PO tests should be designed to challenge a complete system s performance 4 7 Configuration Management and Change Control PO should be designed to challenge a complete system s performance For a computerized analytical system this can mean for example running system suitability testing where critical key system performance charac teristics are measured and compared with documented preset limits PO activities for CDS can include e A complete system test to prove that the application works as intended his can mean running a s
28. cument environment monograph No 45 Paris 1998 18 Commission of the European Communities The rules governing medi cinal products in the European Union Volume 4 Good manufacturing practices Medicinal products for human and veterinary use 2003 19 ICH Q7A Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients 20 ISO IEC 17025 General requirements for the competence of testing and calibration laboratories 2005 21 U S FDA Title 21 of the U S Code of Federal Regulations 21 CFR 11 Electronic Records Electronic Signatures 22 Qualification and validation Annex 15 to the EU Guide to Good Manufacturing Practice 2001 a Glossary CDS Chromatographic Data System cGMP Current Good Manufacturing Practice CFR US Code of Federal Regulations DO Design Qualification EU European Union FDA Food and Drug Administration GAMP Good Automated Manufacturing Practice GCP Good Clinical Practice GLP Good Laboratory Practice GMP Good Manufacturing Practice HPLC High Performance Liquid Chromatography ICH International Conference for Harmonization lO Installation Qualification ISO International Organization for Standardization LIMS Laboratory Information Management System OECD Organization for Economic Co operation and Development OOS Out of specification 00 Operational Qualification PASG UK Pharmaceutical Analytical Sciences Group PIC S O Pharmaceutical Inspection Cooperation Scheme PO Performance Qualifi
29. e any together with corrective actions and or work around solutions The report should include a statement that the instrument or system is qualified or validated After the statement and the report have been signed by management the product can be released for operation Typically the validation plan and the report are the first documents inspectors want to see when they inspect a validation project f every thing is well organized and documented it may well be that after looking at both documents inspectors get such a good impression about the validation work that they will focus on other inspection areas It frequently happens that existing instruments and systems are not formally validated if they are not used in a regulated environment Sometimes these systems are called legacy systems They should be validated if they will be used in a regulated environment a process called retrospective validation Inspectors expect the same documented evidence that the system is suitable for its intended use as for new systems We recommend following the same 40 model for validation as for new systems The main difference is in the DO phase Most likely there is not much information from the vendor available and vendors cannot be assessed There is also no need to develop requirement specifications from scratch The big advantage of an existing system is that there is a lot of information from past use and the used functions are well known The mo
30. e Verify that the instrument conforms with physical and construction Good to know requirements as specified by the user Agilent Technologies provides e Check documentation for completeness operating manuals maintenance instructions standard operating procedures for testing safety and validation certificates documentation and services for installation qualification e nstall hardware instrument fittings and tubing for fluid connections columns in HPLC and GC power cables data flow and instrument control cables e Switch on the instruments and ensure that all modules power up and perform an electronic self test e List equipment manuals and SOPs e Record firmware revision e Prepare an installation report e Enter instrument data into an inventory data base e Prepare review and sign formal IQ documentation 21 Figure 9 shows a template with selected examples that can be used to document completeness of shipment Figure 10 shows an example of how to check if construction requirements such as stackability and accessibility of flow cells are met Purchase Order Item Complete yes no Comment weww o Complete yes no Comment Operating Manual LAN Cable 2 x Tubings with Fittings Figure 9 Template and examples to document completeness of shipment for 10 Requirement Expected Result Pass Fail Accessibility of Flow cell and lamp Pass flow cell and lamp must be accessible from front from fro
31. ed for e the entire company at a corporate level e multiple or single sites e departments e system categories The master plan is a framework for individual project plans and should be written at the highest level possible This ensures consistent implementation across an organization Equipment and computer validation master plans should include Introduction with a scope of the plan e g sites systems processes Responsibilities e g user departments QA IT Related documents e g risk master plan Products processes to be validated and or qualified Qualification validation approach Risk assessment a S SI go pe qe ox oteps for equipment qualification and computer system validation with examples on type and extent of testing 8 Vendor assessment 9 Handling existing systems 10 Change Control procedures and templates 11 Instrument obsolescence and removal 12 Training plans system operation GMP 13 Templates and references to SOPs 14 Glossary For each individual project a validation project plan should be developed This plan is derived from the validation master plan Figure 4 shows the link between the master plan and project plan Ideally master plans are developed at a corporate level Project plans are written in departments specifically for an instrument or system Depending on the size structure and geographic distribution there also may be a site or country specific master plan that is derived from
32. en the vendor and the user of an instrument The vendor s responsibilities are to e Design develop and manufacture instruments in a quality control environment e Develop functional and operational product specifications e Provide information on how software and instruments are validated during development and supported during the entire life of the products e Allow user audits if required and share approaches for development and testing The user s responsibilities are to e Describe the analysis problem and selection of the technique e Describe the intended use of the equipment e Describe the intended environment including computer environment e Select and document the functional and performance specifications technical environmental safety e Select and assess the vendor Specifications DO should ensure that instruments have all the necessary functions and performance criteria that will enable them to be successfully implemented for the intended application and to meet business requirements Errors in DO can have a tremendous technical and business impact and therefore a sufficient amount of time and resources should be invested in the DO phase For example setting wrong operational specifications for an HPLC system can substantially increase the workload for 00 testing and selecting a vendor with insufficient support capability can decrease instrument up time with a negative business impact Figure
33. ew product approvals import alerts and denials or product recalls Since March 2003 warning letters are reviewed by higher level FDA officials and reflect the FDAs current thinking Warning letters are published on two FDA websites http www fda gov cder warn index htm and http www fda gov foi warning htm The only problem is that there are thousands of them and they mostly relate to marketing and labeling so it is difficult to find the ones that are of interest to laboratories Interesting sites exist that only publish warning letters related to GxP issues For example http www fdawarningletter com has many quotes related to the qualification of instruments and validation of computer systems Good laboratory practice GLP regulations deal with the organization processes and conditions under which preclinical laboratory studies are planned performed monitored recorded and reported GLP data are intended to promote the quality and validity of study data GLP regula tions were first proposed by the U S FDA in November 1976 and final regulations were coded as Part 58 of Chapter 21 of the Code of Federal Regulations in 1979 The Organization for Economic Cooperation and 2 2 Current Good Manufacturing Practice Regulations Development OECD published the principles of Good Laboratory Practice in the Testing of Chemicals in 198219 which has been since updated and incorporated by OECD member countries In the meantime
34. gencies published guidance documents that helped the industry to better understand regulatory requirements In addition private authors published reference books with practical recommendations for implementation e The Pharmaceutical Analysis Science Group UK developed a position paper on the qualification of analytical equipment This paper was a benchmark because it introduced the 40 model with design qualification DQ installation qualification IQ operational qualification 00 and performance qualification PQ for analytical equipment qualification e he Laboratory of the Government Chemist LGC and Eurachem UK developed a guidance document with definitions and step by step instructions for equipment qualification Good to know Qualification of equipment and validation of computer systems are not one time events They start with the definition of the product or project and end with system retirement e The United States Food and Drug Administration developed principles of software validation e The Good Automated Manufacturing Practices Forum GAMP devel oped guidelines for computer validation in 20019 and in 20089 These guides have been specifically developed for computer systems in general and because of their importance have also been used for validation of laboratory systems e GAMP also published a Good Practice Guide for Validation of Laboratory Systems It recommends validation activities and p
35. he complexity and criticality of the system this can be a mail audit 3 party audit and a direct audit through the user firm The purpose of the vendor assessment is to ensure that products are designed developed and manufactured in a documented quality environment The assessment should also verify that the vendor provides the right services and can maintain the instrument through phone and on site support Installation qualification IQ is the documented collection of activities necessary to establish that an instrument is delivered as designed and specified is properly installed in the selected environment and that this environment is suitable for the instrument 2 Responsibility for IO lies with the user but activities should be supported Good to know and can be carried out by the vendor For example before the instrument Responsibility for 10 lies with arrives the vendor should provide the user with environmental specifications the user but activities should be so that the user can prepare the installation site accordingly supported and can be carried out by the vendor Tasks performed for IO include e Prepare the laboratory facility according to vendor environmental specifications e Control and record environmental conditions if critical For example temperature and humidity e Compare equipment received with the purchase order including accessories and spare parts e Check equipment for any damage
36. hout the company independent from the location This allows comparing instrument performance across the company and facilitates exchange of instruments and analytical methods The frequency of 00 depends on the type of instrument on the stability of the performance characteristics but also on the specified acceptance criteria In general the time intervals should be selected so that the probability is high that all parameters are still within the operational specifications Otherwise analytical results obtained with that particular instrument are questionable Here the importance of proper selection of the procedures and acceptance limits becomes very apparent For exam ple if the baseline noise of a UV Visible detector is set to the lowest possible limit as specified by the vendor the lamp will have to be changed more frequently than when set at a factor of 5 higher Inspectors expect 00 tests to be quantitative This means that the test protocol should include expected results and actual results Figure 13 includes an example for recording of test results of a balance The header includes three control weights and acceptable limits for the weight The daily protocol records actual weights and the name and signature of the test person 31 3 5 Performance Qualification Good to know Important for consistent instrument performance are regular preventive maintenance making changes to a system in a controlled manner and regular
37. igh risk Figure 1 shows a template with examples on how to document a computer system inventory The list should also include information on the state of validation Non validated systems should have a timeframe for system validation Now the importance of the risk category becomes obvious Non validated systems classified as high risk must not be used for any regulated work Time Frame for Validation h high risk m medium risk low risk Figure 17 Template for computer system inventory The content items of project plans for computer systems are similar to equipment hardware However because of a higher complexity and higher validation effort the document is longer For practical reasons table 39 4 2 Reguirement Specifications 40 Good to know Requirement specifications should be linked to test cases in a traceability matrix templates will not work well Longer project plans are written in text form and a hyperlinked table of contents will help to find individual sections Project plans should have a section on risk assessment It should describe how risk assessment is planned and documented and what risk levels mean for the extent of validation Requirement specifications of software and computer systems should be linked to test cases in some kind of traceability matrix This can be a table on its own or the link can be built into the requirements table A template with examples is shown in figure 1
38. initial operation ongoing use and change control Good to know The 40 model is recommended for users of commercial instruments without significant customization by the user 1 2 Terminology Validation vs Qualification e All publications refer to some kind of life cycle model with a formal change control procedure being an important part of the whole process Different models have been suggested for different kinds of instruments For example the 40 model as described by Freeman and Bedson has been recommended for users of commercial instruments without significant customization by the user The V model as recommended by GAMP4 is suitable for software development as well as for users of commercial Instruments with customization by the user A major breakthrough came when USP released its general chapter on analytical instrument qualification The major benefit of the chapter was that it formalized the 40 model and clarified some issues that have been frequently discussed before for example that an instrument s firmware does not need separate qualification but should be qualified as part of the instrument hardware An agreement on terminology is of utmost importance for a common understanding of validation and qualification The author has frequently noted at validation symposia that different speakers used different terms for the same thing and the same terms for different things Most frequent question arose about the
39. ion services that meet evolving business needs The company has been ranked several times by lab professionals in independent surveys as the preferred supplier for validation More information on www agilent com chem compliance e Regular QA OC newsletter with FDA and other compliance updates More information on www agilent com chem pharmaqaqc More information on Agilent products www agilent com chem 58 _ e References 1 U S FDA Title 21 of the U S Code of Federal Regulations 21 CFR 211 Current good manufacturing practice for finished pharmaceuticals 2 Unites States Pharmacopeia Chapter 1058 Analytical Instrument Qualification Rockville USA 2008 3 P Bedson and M Sargent The development and application of guidance on equipment qualification of analytical instruments Accreditation and Quality Assurance 1 6 265 274 1996 4 P Coombes Laboratory Systems Validation Testing and Practice DHI Publishing LTD Raleigh USA 2002 5 L Huber Validation and Qualification in Analytical Laboratories Interpharm Informa Healthcare New York USA 1998 Second revision 2007 6 M Freeman M Leng D Morrison and R P Munden from the UK Pharmaceutical Analytical Sciences Group PASG Position Paper on the qualification of analytical equipment Pharm Techn Europe 40 46 November 1995 7 United States Food and Drug Administration FDA General Principal of Software Validation Final Guidance for Industry and FDA Staff
40. is placed on getting a good understanding of and implement ing USP chapter 1058 After an introduction to the chapter s approach for instrument qualification this primer will lead you through individual qualification phases and give recommendations for implementation The primer will not only help readers understand the instrument qualification process but also offers templates and examples to easily implement qualification Because of the nature and size of this primer all the details of operational qualification and system validation cannot be given For more details please refer to reference articles and text books Exact procedures and test parameters very much depend on the type of instrument and applications Details on recommendations and services can be obtained from instrument vendors Although the primer has recommendations for validation of standard commercial computerized analytical systems without the need for major customization it does not give details on validation of complex systems such as Laboratory Information Management Systems LIMS or on validation activities during software development but refers to further literature Due to their importance equipment qualification issues have been addressed by several organizations Before 1990 the regulatory focus of instrument and computer validation was primarily on manufacturing equipment which changed after 1990 In response to industry task forces regulatory a
41. most industrial countries and some developing countries have their own GLPs All GLP regulations include chapters on equipment design calibration and maintenance for example U S GLP regulations Sections 58 61 and 58 63 e Automatic mechanical or electronic equipment used in the generation measurement or assessment of data shall be of appropriate design and adequate capacity to function according to the protocol and shall be suitably located for operation inspection cleaning and maintenance e Equipment used for generation measurement or assessment of data shall be adequately tested calibrated and or standardized e Written standard operating procedures shall set forth in sufficient detail the methods materials and schedules to be used in routine inspection cleaning maintenance testing calibration and or standardization of equipment and shall specify remedial action to be taken in the event of failure or malfunction of equipment e Written records shall be maintained on all inspection operations The GLP principles of the OECD include similar but shorter sections on equipment e The apparatus used for the generation of data and for controlling environmental factors relevant to the study should be suitably located and of appropriate design and adequate capacity e Apparatus and materials used in a study should be periodically inspected cleaned maintained and calibrated according to Standard Operating Proced
42. ncrease the workload for 00 For example if a company has a need for an isocratic HPLC system but plans to purchase a gradient system for future use only an isocratic sys tem should be formally specified for regulatory purposes This means as long as the instrument is not used for gradient runs no gradient test need to be conducted Later on when the system is used for gradient analysis the specifications should be changed through a change control procedure The specifications should be set so that there is a high likelihood that the instrument conforms to them not only during initial OO but also during requalification for example a year later Otherwise users may be expected Good to know Vendors of critical analytical instruments should be qualified through a formal process Function User Vendor Performance Requirement Specification Pass Fail Autosampler gt 90 x 2 mL vials 100 x 2 mL vials passed capacity Injection volume lt 1 with 10 uL 0 5 96 with passed precision injection volume 10 uL injection volume Flow rate range 1 5 mL min 0 1 10 mL min passed Baseline noise lt 2x10 AU lt 4 x 106 passed Keyboard Control through Control through passed control local user local user interface interface Figure 7 Selected HPLC specifications for design qualification to initiate an investigation to determine if the non qualified instrument could have had a negative impact on the quality of the product For example
43. nt Detector must be All modules have the Pass stackable with other same width and depth 1200 Series HPLC modules Figure 10 Verification of construction requirements for 10 28 All instruments should be entered into the IQ protocol and or into a data base An example of this documentation is shown in figure 11 The IQ documents should be updated whenever there is a change made to any entry in the IQ documents Examples of changes are a firmware revision and the location of the instrument within a building or site Identification Manufacturer Best HPLC Model D4424A Firmware revision 1 00 Serial Number E4431A Internal ID Asset number D33243 Current location Glab4 Size w x b x h cm 30x22x7 Condition when installed New Supplier contact phone for services 14541 64532 Figure 11 Equipment documentation for IQ Testing for Installation Qualification Installation should verify that the instrument hardware and software are properly installed It does not verify that the instrument conforms to the functional and performance specification This is done later in the 00 phase For individual modules testing is limited to perform and document the instruments self diagnostics when it is switched on For systems comprised of multiple modules correct connection between the modules should be verified For a modular analytical system this can be easily achieved by running a test sample and comparing the output with a reference pl
44. of instruments with different qualification and documentation requirements it can be very complicated if each type of instrument is handled differently To simplify the process USP recommends dividing all instruments into three groups A B and C and to define for each group a specific set of qualification tasks The standard lists examples for each group but at the same time makes it clear that the categories are not only instrument but also applications specific Examples for all three groups are shown in figure 25 Three instrument categories A B C Level of qualification depends of the type of instrument and on application User defines category and level of qualification Magnetic Stirrers Balances HPLC systems Vortex mixers pH meters Mass spectrometers Visual inspection Verification with Full qualification May not require specifications formal qualification Figure 25 Instrument groups A B and C Group A includes standard equipment with no measurement capability Examples are nitrogen evaporators magnetic stirrers vortex mixers and centrifuges Group B includes standard equipment and instruments providing measure values for example a balance This group also includes equipment controlling physical parameters such temperature pressure or flow Examples are water baths and ovens Group C includes instruments and computerized analytical systems Examples are computerized IR spectrometers HPL
45. of the system e information on what has been tested by the vendor and the related test environment e the level of customization and configuration Most extensive tests are necessary if the system has been developed for a specific user In this case the user should test all functions For commercial off the shelf systems that come with a validation certificate only tests should be done of functions that are highly critical for the operation or that can be influenced by the environment Examples are data acquisition over relatively long distances from analytical instruments at high acquisition rates Specific user configurations should be documented and tested for example correct settings of network IP addresses should be verified through connectivity testing Specification computer can control and acquire data from 4 HPLCs All instruments connected Data acquisition from all HPLCs High data acquisition rate Figure 22 Example for high load testing 45 46 When computer systems can control and obtain data from multiple analytical instruments tests should be conducted with a high number of instruments transmitting data The example in figure 22 illustrates that according to specifications 4 instruments can be controlled Correct functioning of the system should be verified with all four instruments connected and delivering data at high acquisition rates TestID lFestSystem ID Test Objective Spe
46. on and validation of computerized systems cover the Analytical entire life of a product It starts when somebody has a need for a specific product and ends when the equipment is retired For computer systems Instruments validation ends when all records on the computer system have been migrated and validated for accuracy and completeness on a new one Because of the length of time and complexity the process has been broken down into shorter phases so called lifecycle phases Several lifecycle models have been described for qualification and validation Most common ones are the V and 40 model The V model includes code development and code testing for software which is important when validation also covers software development For the purpose of this primer where we deal with commercially available instruments and systems we have selected the 40 model with phases such as design qualification DO installation qualification IQ operational qualification OQ performance qualification PQ The process is illustrated in figure 2 Good to know NN Compare user requirements Design Qualification with supplier specifications All activities are defined in a Supplier assessment validation or qualification plan e Verify environment and results are documented in NET rack e Installation Qualification e Verify arrival as purchased e a summary report i i e a Check proper installation of o hardware and software e o 3
47. on of documented evidence to demonstrate that an instrument suitably performs for its intended purpose and that it is properly maintained and calibrated If the instrument is not well qualified weeks can be spent to validate an HPLC method without success until a determination is made that the HPLC detector did not meet specifications for linearity or base line noise Ouality control checks Verifies that the system performs System according to analysts expectations suitability tests Verifies accuracy of sample analysis Proof that analytical procedure Analytical methods does what it purports to do validation Analytical instrument Proof suitability of the Moe qualification instrument for intended use Figure 1 Components of analytical data quality After you have qualified the instrument you validate analytical methods on qualified instruments This should prove that the method works as intended We do this independently of any specific instrument If you want to use the method on instruments from different vendors you also should validate the method on those instruments Then you can combine any specific instrument with a specific method and run system suitability tests This ensures that the complete system meets the analyst s expectations under the specific conditions of the tests The highest level of testing is the analysis of quality control samples You analyze standards or samples with known am
48. ot An example of test specifications and results are shown in figure 12 29 3 4 Operational Qualification 00 Good to know Users or their qualified designees should perform 00 tests to verify that the instrument meets manu facturer or users specification in the user s environment USE 1050 1 30 Actions Expected Result Pass Fail A chromatogram similar as in the installation manual is obtained 1 Set instrument conditions according to the installation manual for analyzing the installation verification sample 2 Inject the installation 1 Chromatogram must include 1 pass verification sample four peaks 2 First two peaks are higher than 2 pass the last two a peaks 3 Retention time of 3 peak should 3 pass be between 2 5 and 3 5 minutes Figure 12 Verification of correct system installation for IQ Operational qualification 0Q is the documented collection of activities necessary to demonstrate that an instrument will function according to its operational specification in the selected environment Emphasis should be placed on in the selected environment Testing of instrument hard ware at the user s site is required because instrument characteristics can change when shipped from the vendor to the user for example through mechanical vibration The most frequently asked questions related to 00 testing are what should be tested which are the acceptance criteria and who should perform the
49. ot mean that they have to conduct all qualification activities For example IQ and 00 can be delegated to the instrument vendors or to a 3rd party organization On the other hand PO should be performed by users because the tests are applications specific and require a good knowledge of the application Advantage of using vendors for 10 00 is that they have all the necessary experience and procedures and even more importantly they bring along calibrated tools that are required for the qualification Vendors with worldwide presence typically also offer qualification services around the globe This is important for companies operating in multinational environments Whoever is doing the qualification work should be trained and training certificates should be filed with the qualification documents Quality Assurance The role of the Quality Assurance unit is the same as for any other regulated activity QA personnel are responsible for assuring that the qualification process meets compliance requirements and conforms to internal procedures QA personnel should also train or advise user groups on regulations and lead or help with the vendor assessment process Developers Manufacturers and Vendors Developers and manufacturers are responsible for the design of the instrument or software program and for providing specifications to the user They should validate processes used in development and manufac turing as well as during the entire support period
50. ounts and compare the results with the correct amounts Again a prerequisite to show that this works is to use qualified instruments and validated methods Chapter 2 Regulations and Quality S BA h Regulations and Quality Standards 2 1 Good Laboratory Practice 10 Regulations Qualification of instruments and validation of systems is a requirement of the FDA and equivalent international regulations No or inadequate quali fication can cause regulatory actions such as shipment stops of drugs and APIs The rationale behind this is that analytical test results obtained with no or inadequately qualified instruments can be wrong Because of the importance of compliance we dedicate this chapter to regulations and quality standards The purpose of the regulations and standards are listed together with key requirements Regulations are quite static and typically don t change for several years More dynamic than regulations are inspection and enforcement practices Information can be found in the FDAs inspection documents such as warning letters establishment inspection reports EIR and 483 form inspectional observations Highly important are FDA warning letters They are sent to companies in case of serious regulatory violations Companies are expected to respond within 15 days If there is no response or if the response is in adequate the FDA will take further actions which may cause delay of n
51. p A he manufacturers specification of basic functionality is accepted as user requirements Conformance of group A equipment with user require ments may be verified and documented through visual inspection This means a simple checklist can be enough for documentation The difference between B and C are mainly in areas of vendor qualifica tion and risk assessment For B we only document the vendor s quality system and keep the certificate as a record For computerized systems in C we should have a vendor assessment program Risk assessment is also recommended for C The number of required documents for B and C does not vary much However the size of the documents and the format will be different For example a qualification plan in B can be document ed on a one or two page template For C this could be easily a 20 page text document 55 5 4 Responsibilities Communication and Training 56 A B C Qualification plan Qualification plan Table form template Text document Vendor specifications User requirements User requirements specification specification Risk assessment ISO 9000 certificate ISO 9000 certificate Vendor assessment Checklists used during DQ IQ DO IQ configuration initial inspection baseline 00 and PO tests OQ and PO tests Maintenance repair Maintenance repair and change logs back up and change logs Qualification report Qualification report Figure 27 Recommended qualification tasks for gro
52. rocedures for seven different instrument categories e Huber authored two validation reference books for the analytical laboratory The first one covers all validation aspects of an analytical laboratory including equipment analytical methods reference compounds and people qualification The second one covers the validation of computerized and networked systems in analytical laboratories e The Parenteral Drug Association PDA developed a technical paper on the validation of laboratory data acquisition system e Coombes authored a book on laboratory systems validation testing and practice The term laboratory systems validation LSV was used to make a distinction from computer system validation LSV and equipment qualification EQ e Chan and colleagues published the book Analytical Method Validation and Instrument Performance Verification This book has several chapters with practical recommendations for instrument qualification e PIC S developed a good practice Guide for Using Computers in a GxP Environment This document has been written by inspectors for Inspectors as a guide to inspect computerized systems All these guidelines and publications follow a couple of principles e Qualification of equipment and validation of computer systems are not one time events They start with the definition of the product or project and setting user requirement specifications and cover the vendor selection process installation
53. s especially when several laboratories are inspected by the same inspector in the same time frame The number of procedures required increases from groups A to C Each company should have a document that specifies which type of procedures should be developed A template with examples is shown in Figure 26 The point here is not to exactly follow the examples and this list does not originate from the USP but it is very important to have a list available within an organization The number of documents increases from A to C An operating instruction and a procedure for reporting problems are enough for group A devices Group B requires additional procedures for qualification change control and preventive maintenance and repair Additional procedures for group C are specific to computer systems for example back up security and system administration A B C Operation Operation Operation Qualification Qualification Change control Configuration management Back up restore and archival Security System administration Preventive Preventive maintenance amp repair maintenance amp repair Problem reporting Problem reporting Problem reporting Periodic peview Retirement Figure 26 Recommended procedures for groups A B and C A company should also provide information on which qualification steps should be executed An example is shown in figure 27 Some recommen dations are from the USP chapter For example it states for grou
54. s may be added to enhance functionality for example an automated sampling system replaces a manual one for unattended operation Vendors may change the firmware to a new revision to remove software errors or application software may be upgraded to be 35 HM 1 1 8 36 Good to know Any changes to instrument hardware firmware and software should follow written procedures and be documented compatible with a new operating system Or a complete system is moved to a newly designed laboratory Some changes are also initiated when new technologies are introduced for example a standard HPLC pump is replaced by a rapid resolution pump for higher sample throughput Any changes to instrument hardware firmware and software should follow written procedures and be documented Requests for changes should be submitted by users and authorized by the user s supervisor or department manager and by QA Before any change request is approved business benefits should be compared with the risks a change may bring USP chapter 1058 states Implementing changes may not always benefit users Users should therefore adopt changes they deem useful or necessary and should also assess the effects of changes to determine what if any requalification is required USP also recommends following the same 4Q model for changes as for initial qualifications This means e Specifications should be updated for example in case a new automated sampling sys
55. st important task for an existing system is to document the system functions used along with any comments about problems with the functions The system should be fully documented for IQ like a new system 00 and PO testing should focus on functions that caused problems in the past After successful OQ and PO testing a summary report should be developed and signed by management This means the system can be released for use in a regulated environment 48 4 10 Validation of Spreadsheet 50 Applications Spreadsheets are widely used in laboratories for data capture data evaluation and report generation For example they can be used to correlate data from a single sample analyzed on different instruments and to obtain long term statistical information for a single sample type The processes may be automated for example enabling the analytical data to be transferred evaluated and reported automatically In all of these programs analytical data are converted using mathematical formulae loday the understanding is that the programs themselves don t have to be validated by the user e g MS Excel What should be validated are the custom calculations and program steps written by the laboratory here should be some documentation on what the application program written by the user as an add on to the core software is supposed to do who defined and entered the formulae and what the formulae are Development and validation of spreadshee
56. such as this one that appears in the U S cGMP current Good Manufacturing Practice regulations Equipment shall be routinely calibrated inspected and checked according to a written program to ensure proper performance or by the more general requirement Equipment should be suitable for its intended use Although there were lots of discussions about the approach for qualification of analytical instruments in the 90 s and in the early years of this century this has changed since the USP has published the final version of the chapter 1058 entitled Analytical Instrument Oualification Following a literature and regulatory overview this primer will provide information on the entire qualification and validation process from planning writing specifications as well as vendor qualification to installation initial and on going operation It covers e Literature overview with milestones on instrument qualification and system validation in laboratories e Overview on regulations and quality standards with impact on analytical instrument qualification e Qualification of equipment hardware for example a spectrometer or liquid chromatograph e Validation of analytical computerized systems e mplementing USP chapter 1058 1 1 Literature Overview Good to know FDA guidelines publications from industry task forces and reference books help to imple ment analytical instrument qualification Special focus
57. tem replaces a manual one e Q documents should be updated if a new firmware revision is installed Installation documents should also be updated when a system is moved to a new laboratory e OO documents with new test cases and test protocols should be added if the software is upgraded with new functionality and e PQ tests need to be updated to verify ongoing system suitability of a new rapid resolution HPLC pump Before any change is approved and implemented a thorough evaluation should be made if 00 tests should be repeated Depending on the change an instrument may need no partial or full testing of a system Chapter 4 Validation of Com pute Validation of Software and Computer Systems 38 Good to know When hardware is qualified at the user s site the integrated firmware is also essentially qualified No separate on site qualification of the firmware Is needed USP 1058 Validation of software and computer systems follows the same principle as the qualification of instrument hardware USP 1058 has a short chapter on software validation Software is divided into three categories 1 Firmware integrated as chips into instrument hardware for control through local user interface 2 Software for instrument control data acquisition and data processing An example would be a chromatography data system 3 otandalone software for example a Laboratory Information Management S
58. testing 32 Instrument BestBalance Serial number 55235A Maximal weight 110g Control weight 1 10 000 mg Limit 10 mg Control weight 2 1 000 mg Limit 1 mg Control weight 3 100 mg Limit 0 1 mg Test engi bate Weigh Weight 2 Weight 3 o k N ib km Figure 13 00 test example Performance qualification PO is the documented collection of activities necessary to demonstrate that an instrument consistently performs according to the specifications defined by the user and is appropriate for the intended use Here emphasis is placed on the word consistently Important for consistent instrument performance are regular preventive maintenance making changes to a system in a controlled manner and regular testing The PO test frequency is much higher than for 00 Another difference is that PO should always be performed under conditions that are similar to routine sample analysis For a chromatograph system this means using the same column the same analysis conditions and the same or similar test compounds PO should be performed on a daily basis or whenever the instrument is used The test frequency depends on the criticality of the tests on the Good to know PO testing can mean system suitability testing or the analysis of quality control samples ruggedness of the instrument and on everything in the system that may contribute to the reliability of analysis results For a liquid chromatograph this ma
59. tests USP answers all the questions in a single sentence Users or their qualified designees should perform these tests to verify that the instrument meets manufacturer or user specifications in the user s environment Designees could be for example vendor representatives f a system is comprised of several modules it is recommended to perform system tests holistic testing rather than performing tests module by module modular testing Individual module tests should be performed Good to know If a laboratory uses the same type of instruments from different vendors it is more efficient to use the same test procedures for all instruments than to use different ones for different vendor instruments as part of the diagnosis if the system fails USP does not give a detailed answer on what exactly should be tested The extent of testing that an instrument undergoes depends on its intended applications Therefore no specific 00 tests for any instrument or application are offered in this chapter Our recommendation is to look at the vendor s test procedures as a starting point and to only make adjustments if there is a specific reason If a laboratory uses the same type of instruments from different vendors it is more efficient to use the same test procedures for all instruments than to use different ones for different vendor instruments We also recommend using the same test procedure for a specific instrument throug
60. the corporate master plan but has been customized according to specific circumstances and requirements of that site Frame work Corporate Master forms templates examples Frame work Site Master forms templates optional examples master list Schedule tasks owners deliverables test plan Project Figue 4 Link between master plan and project plan The project plan outlines what is to be done in order to get a specific system into compliance For inspectors it is a first indication of the control a laboratory has over a specific instrument or system and it also gives a first impression of the qualification quality 21 3 2 Design Oualification 22 For simple equipment qualification a template in table form can be used to outline planned activities A template example is shown in Figure 5 The left column can be the same for all instruments in the same category which makes the whole qualification process very efficient eee di Demi alta Sap ooo Cwemde s pper sama 0 ETC A aa Co A KAR Umememmtmd OOo wwa SSS Figure 5 Template for instrument qualification project plan Design qualification DO is the documented collection of activities that define the functional and operational specifications of the instrument and criteria for selection of the vendor based on the intended purpose of the instrument Design qualification is a shared responsibility betwe
61. the pharmaceutical industries in the three regions to discuss scientific and technical aspects of product registration The purpose is to make recommendations on ways to achieve greater harmonization in the interpretation and application of technical guidelines and requirements for product registration in order to reduce or obviate the need to duplicate the testing carried out during the research and development of new medicines ICH publishes guidelines that are either signed into law by member countries for example in Europe or recommended as guidelines by national authorities e g by the US FDA Examples for such guidelines are e Testing Q1A e Validation of Analytical Procedures 02A 02B e Impurities in New Drug Substances 03A and e GMP Guide for Active Pharmaceutical Ingredients 07A and e Quality Risk Management 09 One of the most important ICH documents is the GMP Guide for Active Pharmaceutical Ingredients Opposite to other official documents Q7A has very specific requirements for equipment and computer systems in chapters 5 3 and 5 4 e Equipment calibrations should be performed using standards traceable to certified standards if existing Records of these calibrations should be maintained The current calibration status of critical equipment should be known and verifiable Instruments that do not meet calibration criteria should not be used Deviations from approved standards of calibration on critic
62. to know Equipment shall be calibrated or e Calibration programs shall be established for key quantities or values of checked to establish that it meets the instruments where these properties have a significant effect on the the laboratory s specification results requirements ISO IEC 17025 e Before being placed into service equipment including that used for sampling shall be calibrated or checked to establish that it meets the laboratory s specification requirements and complies with the relevant standard specifications It shall be checked and or calibrated before use Each item of equipment and its software used for testing and calibration and significant to the result shall when practicable be uniquely identified Equipment that has been subjected to overloading or mishandling gives suspect results or has been shown to be defective or outside specified limits shall be taken out of service 2 6 21 CFR Part 11 FDA s In 1997 the United States Food and Drug Administration FDA issued a Regulation on Electronic regulation that provides criteria for acceptance by the FDA of electronic Records and Signatures records electronic signatures and handwritten signatures With this regulation entitled Rule 21 CFR Part 11 electronic records can be equivalent to paper records and handwritten signatures The rule applies 15 2 7 Learning from Regulations 16 and Quality Standards to all industry segments regulated
63. ts should follow a standard operating procedure Recommended steps are e A user drafts a proposal for a new spreadsheet The proposal should include a description of the problem that the spreadsheet should solve how it is handled now and how the spreadsheet can improve efficiency e he system owner writes a project plan e he system owner collects inputs from anticipated users on requirement specifications and writes requirement specifications e he programmer defines and documents required functions Functions are reviewed by users e The programmer develops design specifications for example which formulas are used and the location of input output cells For complex spreadsheets and for spreadsheets with VBA scripts the design specifications are reviewed by peers of the programmer e he programmer develops the worksheet and creates functional tests The code is reviewed by peers of the programmer structural testing for spreadsheets with VBA scripts e he programmer writes a user manual e he system owner develops a test protocol for users e Users load the spreadsheet onto their computer e Users test the spreadsheet and document the results Chapter 5 Implementin Chapter lt 1058 gt Implementing USP Chapter 1058 5 1 1058 Instrument Groups 52 USP 1058 is the authoritative guide for analytical instrument qualification Even though as a chapter with a number above 1000
64. turing standard for all member countries Like GLP also all CGMP regulations include chapters on equipment design calibration and maintenance for example U S CGMP regulation for pharmaceutical drugs sections 211 140 b and 211 681 e aboratory controls shall include the calibration of instruments apparatus gauges and recording devices at suitable intervals in accordance with an established written program containing specific directions schedules limits for accuracy and precision and provisions for remedial action in the event accuracy and or precision limits are not met Instruments apparatus gauges and recording devices not meeting established specifications shall not be used e Automatic mechanical or electronic equipment or other types of equipment including computers or related systems that will perform a function satisfactorily may be used in the manufacture processing packing and holding of a drug product If such equipment is so used it shall be routinely calibrated inspected or checked according to a written program designed to assure proper performance Written records of those calibration checks and inspections shall be maintained _ gt 2 3 International Conference for The International Conference on Harmonization of Technical Harmonization Requirements for Registration of Pharmaceuticals for Human Use ICH brings together the regulatory authorities of Europe Japan and the United States and experts from
65. um Regulatory Notification required Yes LJ No Roll Back Plan In Case of Severe Problems Change Approval lYes LJ No Comments Approved by Name Signature Date Figure 24 Example for change request form Figure 24 shows a form that can be used to request changes The form should include information on the priority and on business benefits versus costs for additional validation tasks This information is important to assess if the change has a business advantage and should be approved or rejected The form should also include information about whether regulatory notification is required and the roll back plan A roll back plan is like a contingency plan that becomes effective when a change introduces an error which causes the system to fail The roll back plan ensures that the system can be brought back to the last working system configuration 4 8 Validation Report Good to know The validation report should be organized in such a way that it has all the elements and follows the outline of the validation plan 4 9 Validation of Existing Legacy Systems At the end of validation a summary report should be developed This should be a mirror of the validation project plan It should be organized in such a way that it has all the elements and follows the outline of the validation plan This makes it easy to check if all plan items have been completed successfully Deviations should be documented if there ar
66. ups A B and C Implementation of USP 1058 should be communicated to everybody in the organization who is involved in qualification and validation of instruments and systems People should receive training on the USP chapter on why the company decided to implement the chapter and what it means for day to day operation The training should be documented and supervisors should follow up to verity effectiveness Vendors should also be informed about implementation of USP and they should be advised to study the chapter and follow up to fulfill vendor requirements USP lt 1058 gt has a chapter on roles and responsibilities for users the quality assurance unit and manufacturers Users Users of analytical equipment have the ultimate responsibility for instru ment operations and data quality It is an FDA GMP requirement that analysts must sign the analytical test result and therefore also have the ultimate responsibility to make sure instruments and computer systems Good to know Whoever is doing the qualification work should be trained and training certificates should be filed with the qualification documents are qualified and validated Users should be adequately trained in the instrument s use Training can be provided by anybody who is proven to be competent for example by vendor representations 3rd parties and by internal resources The fact that users have ultimate responsibilities for instrument qualification does n
67. ures Records of procedures should be maintained Good Manufacturing Practice GMP regulates manufacturing and its associated quality control GMP regulations have been developed to ensure that medicinal pharmaceutical products are consistently pro duced and controlled according to the quality standards appropriate to their intended use In the United States the regulations are called 11 12 Current Good Manufacturing Practices CGMP to account for the fact that the regulations are dynamic rather than static They are defined in Title 21 of the U S Code of Federal Regulations 21 CFR 210 Current Good Manufacturing Practice for Drugs General and 21 CFR 211 Current Good Manufacturing Practice for Finished Pharmaceuticals Drugs marketed in the United States must first receive FDA approval and must be manufactured in accordance with the U S cGMP regulations Because of this FDA regulations have set an international regulation benchmark for pharmaceutical manufacturing In Europe local GMP regulations exist in many countries These are based on the EU directive Good Manufacturing Practice for Medicinal Products in the European Community This EU GMP is necessary to permit free trade in medicinal products between the member countries Regulations in the EU allow the marketing of a new drug in the member countries with the acquisition of Just a single marketing approval The intention of the EU GMP is to establish a minimum manufac
68. y be the chromatographic column or a detector s lamp n practice PO testing can mean system suitability testing or the analysis of quality control samples This is supported by USP 1058 Some system suitability tests or quality control checks that are performed concurrently with the test samples can be used to demonstrate that an instrument is performing suitably For system suitability testing critical system performance characteristics are measured and compared with documented preset limits For example a well characterized standard can be injected 5 or 6 times and the standard deviation of amounts is then compared with a predefined value If the limit of detection and or quantitation is critical the lamp s intensity profile or the baseline noise should be tested For chromatographic equipment SST tests are recommended in USP chapter 621229 For ongoing quality control checks samples with known amounts are interspersed among actual samples at intervals determined by the total number of samples the stability of the system and the specified precision The advantage of this procedure is that quantitative system performance is measured more or less concurrently with sample analyses under conditions that are very close to the actual application Figure 14 shows a template with examples for a PO test protocol Test Test Expected Actual Pass Case Result Result Fail Baseline T10 0 5 x 10 4 AU 0 5 x 10 AU Noise Resolution between
69. you to three text books 1 P Coombes Laboratory Systems Validation Testing and Practice DHI Publishing LTD Raleigh USA 2002 2 C C Chan H Lam Y C Lee X M Zhang Analytical Method Validation and Instrument Performance Verification Wiley Interscience Hoboken USA 2004 3 L Huber Validation and Qualification in Analytical Laboratories Interpharm Informa Healthcare New York USA 1998 Second revision 2007 some text information and figures in this primer have been taken from 2 and 3 with permission from the publishers ee The concepts and ideas expressed in this primer are my own and do not necessarily reflect official Agilent or Labcompliance policies Regulatory requirements and inspection and enforcement practices are quite dynamic What is appropriate today may not be appropriate tomorrow Requirements in some areas may go up in others down Regulations don t change quickly but guidelines and especially inspection practices can A timely update of all information is important and only possible using on line information tools such as the Internet To take this fact into account recommend a couple of websites with regular updates related to compliance in general and specifically for laboratories http www fda gov This is the primary resource for FDA compliance directly from the Unites otates Food and Drug Administration http www agilent com chem pharmaqaqc The Agilent website for pharmaceutical Q
70. ystem LIMS package Most valuable is the statement about firmware Firmware is considered as a component of hardware of the instrument itself Indeed the qualification of hardware is not possible without operating its firmware Thus when the hardware is qualified at the user s site the integrated firmware is also essentially qualified No separate on site qualification of the firmware Is needed The chapter further recommends recording the firmware version as part of IQ and keeping it under change control For software categories two and three the chapter refers to the 40 activities and recommends the FDA guide on software validation for more detail In general the effort to validate a computer system is higher than for instrument hardware Depending on what it is the costs for software validation and computer system validation can be 5096 or more of the costs for the software itself with an increasing trend The main reason is that software offers more and more functionality All software functions with high impact on drug or API quality should be validated This does not mean correct functionality should always be tested in the user s laboratory but as a minimum all functions should be specified and the need for testing should be evaluated This chapter will go into more detail on what is important for validation of software and computer systems We will follow the same 40 Lifecycle model as for instrument hardware The main focus is
71. ystem suitability test or analyzing a well characterized sample through the system and comparing the results with results previously obtained e Regression testing reprocessing data files and comparing the results with previous results e Regular removal of temporary files e Regular virus scan e Auditing computer systems Most efficient is to use software for automated regression testing The software runs typical data sets through a series of applications and calcu lates and stores the final result using processing parameters as defined by the user During regression testing the data are processed again and results are compared with previously recorded results Normally these tests don t take more than five minutes but give assurance that the key functions of the system work as intended The purpose of configuration management is to be aware of the lifetime composition of the system from planning to retirement The initial or baseline configuration of a system has been documented as part of IQ Any changes to specifications programming codes or the initial set up of computer hardware should follow written change control procedures and be documented Changes may be initiated because errors have been found in the program or because additional or different software functions or hardware may be desirable Requests for changes should be submitted by users and authorized by the user s supervisor or department manager 47 48 a om

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