unicorn 5.0n - GE Healthcare Life Sciences
Contents
1. Instructions describing backup and restore Refers to the creation of the official documents describing in detail exactly how backup and restore routines are performed Suggested Documentation 1 A Backup instruction describing in detail exactly how a complete backup 1s performed 2 A Restore instruction describing how the contents of a media containing a backup are restored partially or totally Amersham Biosciences 25 UNICORN 5 0N 6 3 6 4 6 5 Handling security instructions are the instructions describing how and where backup media should be handled and stored Suggested Documentation Instructions regarding responsibilities frequency for backup generation handling handling of media containing backup storage and accessibility who has the authority to order the use of a backup when backup media is worn out and should be replaced person s in the system responsible for the backup restore changes in backup routines log for backups labelling of media e g tapes Installation Qualification IQ Installation Qualification is defined normally as documented verification that all important aspects of installing the hardware and software adhere to the computerised system specification Installation qualification also includes verification that there are appropriate manuals as built drawings instrument calibration reports and instructions on the operation and maintenance of the syst2. Placebo Batching Edition AB January 2004 Is the use of simulated product to confirm that the computerized system performs in the desired manner The placebo batches should be made both in accordance with the routine process uneventful to confirm proper sequence or outside the norm eventful to confirm the appropriate response to anticipated process or system upsets The placebo batch confirms the acceptability of the computerized system Placebo batches should be made for every product to be made in the system In some instances it may be necessary to make both maximum and minimum placebos to assure that process parameters alarms and sensor locations are appropriate for all batch sizes Placebo batching is also used for non product operations such as cleaning Amersham Biosciences 16 UNICORN 5 0N 5 5 3 System Level Verification Verification of system performance under actual use is called System Level Verification This is performed at the user s site Product Batching Batches of actual product are produced in the system using full automation The batches produced are subjected to full validation testing to ensure their conformance to the required product specifications No intentional upsets are introduced into the process The successful production of product establishes the suitability of the system to make releasable material Comparable verification is performed on other automated activities managed by the c
3. Amersham Biosciences has a unique knowledge how FPLC KTA BioPilot BioProcess OligoPilot and OligoProcess systems have been developed and verified To system owners this knowledge and documentation should be of interest in the validation process assuring that Amersham Biosciences utilises procedures and documentation which complies with accepted standards throughout the pharmaceutical industry Amersham e Biosciences Edition AB January 2004 1 UNICORN 5 0N The following picture UNICORN validation illustrates the relations between the system owner Amersham Biosciences and activities and documentation which should be involved in the validation process for a UNICORN based chromatography system UNICORN Validation Protein eparations Installation de Documentation provided or available from Amersham Biosciences Support available from Amersham Biosciences Fast Trak System Owners input or documentation BMI refers to the instructions and procedures used by Amersham Biosciences in the development of the system See Section 3 Amersham Biosciences Quality Management System System Owner is the person at the users site who is responsible for the correct functioning of the system UNICORN refers to the documentation produced during the development of UNICORN System Doc is the system specific documentation supplied to the system owner from fabrication and final testing of the individual system Installa
4. Sw development handbook 70 5012 08 4 3 Service Maintenance and Spare parts Labcrew Amersham Biosciences instrument service group delivers the background technical maintenance expertise and service that keeps science running smoothly Each member of our service team has the capability to quickly assess a situation identify problems and deliver rapid corrective measures on site From preventative maintenance and instrument repair to software and hardware upgrades Labcrew keeps your equipment in peak condition Spare parts can be ordered through your local Amersham Biosciences office Most commonly used parts are stored locally and can be provided immediately Your local office will also be pleased to arrange delivery of specialist spare parts from our global distribution centres On call from our service centres worldwide Labcrew s mission is to keep your science on track 4 4 Error Reporting In order to ensure that correct actions are taken when an error is reported on a product Amersham Biosciences follows documented routines to ensure correct handling and feedback to customers at all times Users shall always report product issues to the local Amersham Biosciences representative for further action Amersham PE e Y Biosciences Edition AB January 2004 13 UNICORN 5 0N 5 COMPUTERIZED SYSTEM VALIDATION 5 1 Introduction The following text provides a brief description of each of the tasks necessary to comple
5. optional MDD sw Module Design Description or documentation in SDD code model MTD sw Modulte Test Description MTR sw Module Test Report 11 ITR sw Integration Test Report STR sw System Test Report CEV sw Computer Equipment Verification report SVD Sw Version Description 3 part evaluation optional sw QA audit report sw Approval for Use minutes Bug list implemented as extract from dbPlus Sw development handbook 70 5012 08 section Sw steps and documents See BMI for document number of the templates MES OI gt 7 Biosciences UNICORN 5 0N The output from the software development results in an executable documented verified and archived software system Amersham E e Y Biosciences Edition AB January 2004 12 UNICORN 5 0N The figure Test descriptions and reports during Verification summarises the verification performed on the different levels including the documents used to describe the test cases and the test result Test descriptions and reports during Verification tus e i GAMP level Additional verification at customer site 10 00 PQ System verification Verification report System Verification Verification report Integration sw test description in SVP 70 5000 13 D procedure 70 5010 05 Sw application SVP SVR report i abe Sw requirement STD STR report Module Sw integration ITD ITR report Code Sw module MTD MTR report Code
6. 5 3 2 Piping amp Instrument Drawing a iii 14 5 3 3 Instrument Listin o 15 5 3 4 Input Output Las tsi cri ota 15 5 3 5 Waring Checks E de A onda 15 5 3 6 Component Qualification vse 4 lorelai ala 15 5 3 7 Calibration WA A hep gna di dans eave AS na 15 5 4 SOFTWARE DEVELOPMENT VERIFICATION PHASE corno nrrn nn rre nnr rn 15 5 4 1 Quality Assurance Methods for Software Development i 15 5 4 2 Process Operation io ra AR a mined Saad 15 5 4 3 Program Description Application Code sense eeeeeeeetennneaeeeeeeeeeeeennnneeeeeeeentee 16 5 4 4 Software Structural Description usage sara so cepa id da erage ate esa guita Seats 16 5 5 SYSTEM INTEGRATION AND VERIFICATION PHASE non nonnnon anar o nro nrnn nr ana nnnn rr anna 16 5 5 1 Module Level Veritat ott a renali 16 5 5 2 Program Level Verification ici ii iii 16 5 5 3 System Level VeA CAT O raa a aaa Lila licitador 17 5 5 4 Additional Software Verification Requirements ii 17 5 6 OPERATIONAL PHASE a sibili alati nella 17 5 6 1 Charige Control iis aria a air 17 5 6 2 System Recovery Placa ia ela ale 17 5 6 3 Operating Manuals ito aida aida 18 5 6 4 Trainingof Persontiel iia 18 5 6 5 S pport Personne leser cenana a ins docas aleta 18 5 6 6 System Security saose ienaa ins aa ade deta aaa aa a ia a aa a aaa ai tee 18 5 6 7 Operating Procedures ridad eta 18 Amersham o e Y Bioscienc
7. The following versions of UNICORN have been released from Amersham Biosciences in chronological order UNICORN version Released Operating system 1 10 Sept 1994 OS 2 1 11 Dec 1994 OS 2 1 12 Feb 1995 OS 2 Oct 1996 3 00 May 1998 NT NT Amersham o e Y Biosciences Edition AB January 2004 3 UNICORN 5 0N OBSERVE Upgrading software in a system may have an impact on its functionality and a revalidation may be necessary This should be evaluated prior to performing any modification or upgrading of the software 2 3 Independent UNICORN Audits Already when the first version of UNICORN was developed an independent company Weinberg Associates Inc audited the principles and procedures employed by Amersham Biosciences in the development of UNICORN As a result of this audit Amersham Biosciences obtained a certificate which confirms that the development model complies with relevant regulatory standards Compliance with the FDA 21 CFR Part 11 was obtained starting with UNICORN 3 2 Certificate and audit report from UNICORN 5 0 is included in this support package Amersham o e Y Biosciences Edition AB January 2004 4 UNICORN 5 0N Certification of UNICORN 5 0 Amersham Biosciences The UNICORN 5 0 software of Amersham Biosciences has been audited on 11 12 December 2003 and found to be in full compliance with FDA Regulation 21CFR Part 11 and applicable sections of the regulations Good Ma
8. Validation Documentation from Amersham Biosciences Fast Trak Validation In order to facilitate the successful start up of systems at customer sites Amersham Biosciences Fast Trak Validation has developed a comprehensive set of system qualification protocols The protocols address process equipment and control system documentation The qualification protocols are not a part of this validation support documentation They are available separately from Amersham Biosciences Fast Trak Validation In addition Amersham Biosciences Fast Trak Validation offers a SOP package that consists of the following SOPs Back up Restore Revalidation Log book System security Audit trail 7 REFERENCES 1 Audit Report Amersham Biosciences UNICORN Version 5 0 see separately attached file 2 UNICORN 5 0 21 CFR Part 11 System Assessment checklist see separately attached file 3 Validation concepts for computer systems used in the manufacture of drug products PMA s Computer System Validation Committee Pharm Technol 1986 Vol 10 No 5 24 35 4 Computer system validation staying current Vendor User relationships PMA s Computer System Validation Committee Pharm Technol 1993 Vol 5 No 8 Amersham pa e Y Biosciences Edition AB January 2004 34 UNICORN 5 0N Trademarks UNICORNTM FPLC AKTA BioPilot BioProcessTM OligoPilot OligoProcess and Labcrew are exclusive trademarks of Amersham Biosciences L
9. develop ment Product performance Refined requirements in verification amp validation Project review and swTS lwTS end of life recommend ations Project planning in OPP Requirements in target TS P Third nning Barty pla Product information Production process develop ment validation Financial analysis IPR review Phase 1 Exit review Phase 2 Exit review Phase 3 Exit review Phase 4 Exit review Phase 5 Exit review A Phase Reviews by Business Area Peer technology reviews Procedure for Development D project 70 5010 05 Amersham A e Biosciences UNICORN 5 0N For software development additional procedures are used Figure swBMI steps shows the main activities These procedures also contain information regarding responsibilities verification reviews and approval error handling etc Templates forms are also available see Figure Available templates Project planning swBMI steps Sw project planning including test plans in SDP Project planning HIS sw Human Interface Specification SRS Sw Requirement Specification STD sw System Test Description Edition AB January 2004 Sw development handbook 70 5012 08 Available templates SDP Sw Development Plan SDD Sw Design Description IDD sw Interface Design Description option CEV sw Computer Equipment Verification description ITD sw Integration Test Description Co operation routines
10. and complicated task Amersham Biosciences Fast Trak offers expert services in process optimization The main goal of process optimization is to develop a method that produces a product of a desired purity and quantity Process Optimization includes several steps Raw material considerations Specification of the process Choice of techniques Number of chromatographic steps Yield in each step Method scouting Method optimization Economic considerations Scale up and adjustments Media life length Cleaning in place CIP System sanitation Other activities relevant for the development of the individual process These activities will generate documents which will be beneficial to the verification of the process Accordingly all relevant documentation should be created and properly stored 6 5 4 Method Construction As there are many aspects of how a program should be constructed and how programming should be performed no recommendations are suggested here Regardless of the method used for programming documentation should be created to support and verify the function ofa program Examples of such documents are Functionality model A list of all variables and description of their function Limits for variables and fields Method instructions Description of all modules and subroutines in the program and their functions Signatures and dates of the responsible programmer s Descriptions of all alarms and w
11. maintaining documentation on requested changes etc Process Operating Logic Detailed descriptions of the various procedures to be carried out by the system It is developed by personnel knowledgeable in the pharmaceutical process for the purpose of communicating process information to the programmer It indicates the routine process as well as the desired response to likely process upsets data entry errors component failures etc Logic flow diagrams are sometimes employed for this purpose Amersham s e Biosciences Edition AB January 2004 15 UNICORN 5 0N 5 4 3 Program Description Application Code Paper and or electronic copies of the software that are to be validated The annotation of source code is highly desirable as a means of initial preparation audit and subsequent change At this stage the software can be audited but it cannot be rigorously tested until it is installed on the hardware 5 4 4 Software Structural Description An overview of the software defining the various programs including modules and their functions their relationship to each other any sub routines and sub programs It sometimes includes additional information such as protocol lists batch sequences alarm points etc that are utilized 5 5 System Integration and Verification Phase Once the hardware installation and software development is complete the project enters the integration and verification phase Here the software and hard
12. ND OPERATIONAL QUALIFICATION SERVICES FROM AMERSHAM BIOSCIENCES FAST TRAK VALIDATION tsten etenn Enne EEES EE EEE EEEE EEEEEEEEEEEEEEEEEEEE EEEE EE EEEE EE 34 7 REFERENCES e aTa ae ar aa a Ea cia 34 Amersham o e Y Biosciences Edition AB January 2004 UNICORN 5 0N 1 2 2 1 INTRODUCTION TO THIS DOCUMENT This support package is valid for all UNICORN versions 5 0N The last third digit has been replaced with a letter N see 2 2 in this document The document has been assembled to provide important information on the development and documentation of UNICORN 5 0N It will assure system owners that UNICORN has been developed in a structured manner and verified in accordance with the System Development Life Cycle concept The proper development verification and documentation are vital to the functionality and performance of UNICORN when in operation at a customer s site and should accordingly be of interest to system owners This document gives an overview of how UNICORN is developed It would have been desirable to include all the documents created during the development of UNICORN 5 0N in this information package but this is not practical and realisable Customers who wish to verify the existence of the documentation and development procedures may perform audits in Uppsala and or in Ume Sweden This document provides a comprehensive description of the validation of the UNICORN system that cont
13. OQ Services from Amersham Biosciences Fast Trak Validation which will provide a customer with test protocols and documentation proving that the system is capable of performing its required functions Method Development and Verification The development of methods are dependent on many factors as the system is complex and allows the user to freely construct and make modifications as desired Method development is of great importance to the demands you may have on documentation security levels and operating procedures An KTA system used for scientific research normally has much lower requirements in these aspects than a BioProcess systems which is used under FDA regulations to produce pharmaceuticals The level you choose is highly dependent on the systems use It may appear unnecessary to apply this way of developing systems in many cases such as R amp D activities however it is common that processes are developed on an KTA and scaled up to a BioProcess system at a later stage If this is the case structured development and good documentation will be beneficial to the scaling up and documentation of the process at a later stage Amersham s e Biosciences Edition AB January 2004 26 UNICORN 5 0N It is recommended that the system use is determined first and then the required level of quality These two factors should be the fundamentals for the development of your own methods Keep in mind that you never can test quality into your
14. Q of the system The following figure illustrates an example of an Activity Schedule with sub levels describing the development of a backup system Amersham pa e Y Biosciences Edition AB January 2004 21 UNICORN 5 0N Activity Schedule Amersham E e Y Biosciences Edition AB January 2004 22 UNICORN 5 0N Amersham e Y Biosciences Edition AB January 2004 23 UNICORN 5 0N Target Finished Activit Responsible date Activity 1 2003 12 10 Activity 2 B Berg 2003 12 15 Backup G Gren 2003 12 24 Activity 4 S Stenson 2003 12 31 Activity N Olsson 200N NN NN N select technique y Activity 1 purchase of equipment y Activity Scedule a install HW SW a A Activity 2 i Tl tal a x y select procedure amp routines Activity 4 tenson 2003 12 31 Activity Responsible at dat Activity 4 2003 12 10 2003 12 08 Activity 2 erg 2003 12 15 Activity N ison 200N NN N Activity N N N 200N NN NN N B a C k u p ua i 3 test of back up a SOP s desc BU Restore g handling security SOP s Activity 4 The Activity Schedule should in this case contain information describing who is responsible for the development of a backup procedure and a date when this activity should be finished It should also refer to the Backup activity document below in which more d
15. UNICORN 5 0N FAST _ a TRAK VALIDATION UNICORN Validation Support Package for UNICORN 5 0N i Amersham 04 0021 58 e Y Biosciences UNICORN 5 0N TABLE OF CONTENTS 1 INTRODUCTION TO THIS DOCUMENT cicci 1 2 INTRODUCTION TO UNICORN VALIDATION iii 1 2 1 GENERAL UNICORN INFORMATION 1 2 2 VERSION NUMBERING goreh ra aea i add PARI FARAI ICRA RO Re nantes nb ig ana ta 3 23 INDEPENDENT UNICORN AUDITS eiieeii piee quedare candrinoda iaia era aaa 4 3 AMERSHAM BIOSCIENCES QUALITY MANAGEMENT SYSTEM 7 3 1 INTRODUCTION java tina strass avian iinet Wacken den a ola lM eee ees 7 3 2 PROTEIN SEPARATIONS QUALITY POLICY iii 7 3 3 TSO CERTIFICATION 60d AA RR 7 4 PRODUCT DEVELOPMENT ail lei 9 4 1 INTRODUCTION ili tandas 9 4 2 DEVELOPMENT MODEL ronisin er lide ans dt decai ei Dia so db inte 9 43 SERVICE MAINTENANCE AND SPAREPARTS 13 44 ERROR REPORTING uta taa epi an tadas 13 5 COMPUTERIZED SYSTEM VALIDATION iii 14 5 1 INTRODUCTION anaa aa a a aa a aa id tia 14 32 DESIGN amp SPECIFICATION PHASE did lindaa cid 14 5 2 1 Functional Requirements aria 14 5 2 2 System Specification T ria iii 14 5 3 HARDWARE INSTALLATION amp QUALIFICATION PHASE 0oococccccononnnncnccnnnnnonnnnnncnnnnnnnnnnnnnnnrnnnnnnnnnnns 14 5 3 1 System Description with Schematic Drawings i 14
16. achieved ISO 9001 certification in February 1993 On September 26 2003 the company received Certificate of Approval to the Quality Management System Standard ISO 9001 2000 see certificate below Amersham pa e Y Biosciences Edition AB January 2004 7 UNICORN 5 0N CERTIFICATE OF APPROVAL This is to certify that the Quality Management System of Amersham Biosciences Uppsala Sweden has been approved by Lloyd s Register Quality Assurance to the following Quality Management System Standards ISO 9001 2000 The Quality Management System is applicable to Research design development procurement manufacture marketing sales service support and distribution of chemicals instruments and services for separation characterization quantification and synthesis of biomolecules Approval Original Approval 19 February 1993 Certificate No 655790 Current Certificate 26 September 2003 Certificate Expiry 28 February 2005 Issued by LRQA RotteNdam This document is subject to the provision on the reverse This approval is carried out in accordance with the LRQA assessment and certification procedures and monitored by LRQA The use of the UKAS Accreditation Mark indicates Accreditation in respect of those activities covered by the Accreditation Certificate Number 001 Aimes oor 161 Pa Amersham Biosciences Edition AB January 2004 8 es UNICORN 5 0N 4 PRODUCT DEVELOPMENT 4 1 Introduction Amersham Bioscience
17. arnings Protocols from tests performed by the programmer s Security and access levels Other relevant information Amersham Da e Y Biosciences Edition AB January 2004 28 UNICORN 5 0N When a program has been constructed by the programmer s it should be subject to testing and evaluation in order to be approved for use as intended The testing procedures are dependent on the demands and validation level intended for the system and cannot therefore be specified here The test should not only prove that the program performs as intended but should also include worst case simulations in which warnings and alarms are triggered These tests should not be carried out or constructed by the person s who constructed the program Suggested documentation Test plan Test description Responsible and responsibilities Criteria for approval Protocol from test Criteria for approval of test Other relevant documentation 6 5 5 Backup Restore Backup and restore are preventive actions to avoid accidental data loss from the system These actions assure that if data were lost from the computer s hard disk they could be restored Another new hard disk is normally used for the restoration It is important that these issues are dealt with prior to the start of production A functioning backup system is one of the validation demands the system owner should have in order to approve of the system s use in production Differe
18. as an operating system in a PC but is far more complex and accordingly harder to validate The same difficulties that may occur in the validation of a PC operating system can also be found in the validation of the network operating system significantly complicating the validation effort The validation effort can be simplified by following the recommendations of PDA s committee on vendor evaluation namely one can evaluate the network operating system vendor to assess their technical competence and ability to supply and support the proposed system In addition for widely used programs and versions one should perform an evaluation of the previous uses For many applications this should indicate that the program is well functioning and reliable e g MS DOS or UNIX Some suggested validation documents and activities are presented in Table 1 Table 2 lists some SOPs that should be implemented for a validated network system Table 1 Suggested Validation Documents Activities e Network description of all hardware and software Printout and copies of all system unique files such as start up files and settings for the system and login scripts for users e Drawings protocol used drivers netware boards Function tests such as communication checksum tests or other of transferred data stability and stress tests Security definition tests Test of backup restore RAID or other system SOPs Evaluation of netware supplier Evalu
19. ated does not specify any particular level of validation it simply means that the system owner has approved of its fitness for its intended use Validation of a system should not be performed simply to please authorities but to obtain a system that operates as intended Regulations emphasise that the system should not produce harmful or sub quality products The following document contains a suggested validation strategy for UNICORN controlled systems Following the procedures explicitly will not give any guarantee that a system that complies with official regulations is obtained However if the procedures suggested here are performed completed and modified as needed a validated system can be obtained We strongly advise you to be well informed of the regulatory aspects that are related to your product and process From a regulatory point of view the system owner is always responsible for the performance of his her system and an established opinion of inspectors is that if written evidence of an activity cannot be presented the activity has not been performed These recommendations are mainly based on the U S FDA s Good Manufacturing Practice GMP since they are widely accepted throughout the world Validation of UNICORN controlled systems can be performed according to the following illustration Figure Validation order Amersham e Biosciences Edition AB January 2004 19 UNICORN 5 0N Validation order Design and Requirement
20. ation of hardware suppliers Network failures consequences Storage and access of documentation Interfaces to other validated systems verifications Education of users and network operators Manuals hardware software and system specific Other relevant activities documents to verify the function of the network Table 2 Suggested SOPs e Backup restore handling of backup media frequency storage responsibility generation handling of backups e How to add new users deletes old ascertain correct access levels for users Authorisation to add new users change access levels deletion of users Documentation of access level changes for users Security routines and responsibility New hardware adding new PCs printers and modifications of the net Access times for the network Responsibilities for the system Changes in documentation Start and stop of the system Amersham e Biosciences Edition AB January 2004 33 UNICORN 5 0N Catastrophe routine including who authorises catastrophe recovery activities Frequent controls volume controls correct access levels for users New soft and hardware tests and how to document approval criteria Logbook for the system what to denote and how Virus controls frequency and anti virus program to use Revalidation procedure frequency data to use in a revalidation expected results Education of users Manuals updating distribution versions 6 9
21. cations needed to obtain the desired validation level This includes not only items mentioned here but also other relevant activities e g supplier audits The earlier chapters of this documentation describe the development instructions and procedures Amersham Biosciences uses to develop and supply UNICORN This information is part of a validation procedure of UNICORN controlled systems and can be included in the owners validation documentation As mentioned earlier tests of the system during its operation will almost certainly not be all inclusive This implies that the design of a system is of great importance 6 2 3 Activity Schedule From the Validation Plan an Activity Schedule can be extracted specifying each activity and responsible person s The activity schedule can be constructed in different ways but it is important to recognise what activities must precede others A few activities however can be performed independently of others e g system and general education General education is dependent mainly on two factors that the personnel involved in the development and the handling of the system should have been selected and the education should be performed prior to use of the system in production System education can be divided in two major parts system specific education and handling education the latter being dependent on the existence of an operative system System specific education can be performed during the IQ and O
22. ch device should be included Vendor manuals for each piece of hardware are required Hardware qualification elements are outlined below 5 3 1 System Description with Schematic Drawings A schematic representation of the entire system showing the major elements of the system It should include both process and control system components as well as any other computer systems with which the system communicates 5 3 2 Piping amp Instrument Drawing Schematic representation of the equipment in the field There may be as many of these as necessary to depict all of the process equipment They are generally produced early in the project Amersham pa e Y Biosciences Edition AB January 2004 14 UNICORN 5 0N 5 3 3 5 3 4 5 3 5 5 3 6 5 3 7 5 4 5 4 1 5 4 2 Instrument List A listing of all instruments in the system including their operating ranges output signals selected manufacturer proposed calibration frequency accuracy etc Each instrument in the list is uniquely identified and can also be found on the Piping amp Instrument drawings Input Output List A list of all signals and inputs received by the system as well as all outputs from the system Includes communications with other computer systems Wiring Checks Verification of the accuracy of cabling and connections to and from all field devices and I O racks Also includes verification of cabling between items in the control system and betwe
23. cribe the physical hardware security employed to protect the system as well as software security Verification of security measures is strongly recommended Operating Procedures Standard operating procedures SOPs required for manual steps must be completed These procedures should include operations performed on a routine basis as well as procedures needed for occasional use i e calibration preventative maintenance Amersham s e Biosciences Edition AB January 2004 18 UNICORN 5 0N 6 6 1 VALIDATION OF A UNICORN BASED CHROMATOGRAPHY SYSTEM Introduction Validation is a process in which the system owner who is responsible for the system performs actions to determine that a system and process are consistently capable of producing a product which meets its pre determined specifications and quality attributes These actions should involve Design and Requirements analysis Installation Qualification Operation Qualification Method Development and Verification Education and other actions that the system owner finds relevant in order to allow the system to start The validation process should end with an approval from the system owner of all previous activities meaning that a high degree of assurance which ensures that the system is fit for its intended use has been obtained After the system owner has approved the system to start production or other intended activity the system can be called validated The word valid
24. e tests should be attached to the revalidation procedure e Component tests e Program test e Total system test e Performance test Additional items should be included if they are relevant to the functionality of the system 6 6 Education Each user and operator should be educated for his her specific function This is not only a regulatory demand but a way to ensure a system that runs smoothly with a minimum of errors Most of the mishandling errors are caused by inexperienced users Education is of course especially important for the person s responsible for handling the operating system Mistakes in the operating system can lead to all types of disturbances in the functioning of the system The operating system has by necessity many powerful commands that can be fatal to the system if exercised without the knowledge of their effects on UNICORN This suggests that the person s responsible for the operating system should have sufficient and updated knowledge in its handling and that its use should be minimised It is also important that the knowledge is current Education should take place shortly before production start up of the system If the system is to be used to produce GMP controlled substances general GMP education is also required If the system is modified users should be informed and educated about the effects of the changes All education should be documented and maintained properly 6 6 1 System education Syst
25. em Installation qualification of software includes verifying that the proper version of the program has been installed and that the appropriate backup copies exist The Installation Qualification verifies that the delivered system is complete and verifies that all components in the system meet specified requirements Amersham Biosciences has a unique knowledge of all components in the system and has developed a complete package for this purpose Much time and effort can be spared by using the Amersham Biosciences Fast Trak Validation Services More details describing these services are described in Section 6 9 IQ and OQ Services from Amersham Biosciences Fast Trak Validation Operational Qualification OQ The PDA has defined Operational Qualification of a computerised system as documented verification that the system operates in accordance with the computerised systems specification throughout all anticipated operating ranges Operational Qualification may be performed on the integrated system or on each subsystem and includes the identification of all important operating parameters their anticipated ranges appropriate acceptance criteria and the tests to be performed to demonstrate that the system meets the acceptance criteria Operational Qualification also includes performing specified tests and reporting the results Amersham Biosciences Fast Trak Validation offers extensive services in this task described in Section 6 9 IQ and
26. em operators require specific education in UNICORN the computer s operating system and the chromatography part of the system Relevant and updated knowledge are essential for the proper functioning of UNICORN and the entire system Amersham pa e Y Biosciences Edition AB January 2004 31 UNICORN 5 0N 6 6 2 6 7 6 8 6 8 1 6 8 2 Method education When the system is designed a plan for the education of the personnel should be established The plan should specify the education requirements for each user function of the system Education should be performed previous to the production start of the system Verifying that all personnel have updated and adequate education for his her function should be a part of the validation for the system Validation Approval As mentioned in 6 1 Introduction the person responsible for the system should approve of its fitness for its intended use This requires checking that everything included in the Validation Plan has been performed documented and approved by the personnel responsible for each activity in accordance with the Activity Schedule Other things that are relevant to the functionality of the system but not included in the Validation Plan should also be included in the Validation Approval This may include things that have been discovered or things that the persons involved in the validation process find relevant to the system All documents generated during the validat
27. en the control system and other computer systems with which it must communicate Component Qualification Documentation that all physical components in the control system are installed in accordance with the vendors recommendations Includes the satisfactory completion of all self tests possible on each piece of equipment To the extent that the computer system can be tested without application software that testing should be performed and documented Issues such as electrical grounding isolation from power lines protection from excessive heat and humidity must be addressed Calibration Documented calibration of all field devices from the sensor to the control system It includes verification that all locations where a variable is stored displayed or transmitted are within the required tolerances Includes the completion of SOPs for the routine calibration of the instruments and the initial frequency with which they will be calibrated Software Development Verification Phase Activities associated with the detailed design preparation and verification of the software to be utilized on the system Quality Assurance Methods for Software Development Copies of procedures utilized by the developers of the program external and internal which indicate the software quality assurance measures which are to be followed in the preparation of the code Such measures include the use of modular concepts consistent and logical use of variable names
28. es Edition AB January 2004 UNICORN 5 0N 6 VALIDATION OF A UNICORN BASED CHROMATOGRAPHY SYSTEM 19 6 1 INTRODUCTION caridadea eean aea a Eaa a a ariana 19 6 2 DESIGN VALIDATION PLAN AND ACTIVITY SCHEDULE i 21 6 2 1 Design and Requirements analysis e non nnnn non rra naar corr n nr narran rn nn nn nra nenes 21 6 2 2 Validation PDA A A A id A 21 6 2 3 Activity Schedules oinin RO SERRA TALES PRAIA ARA AR 21 6 3 INSTALLATION QUALIFICATION IQ iii 26 6 4 OPERATIONAL QUALIFICATION OQ ii 26 6 5 METHOD DEVELOPMENT AND VERIFICATION occcococononcnononononcnononononononononononnnnononononononrnonononenenenon 26 6 5 1 Product Specification iaa iaa 27 6 5 2 Method Development Plutarco 28 6 5 3 Process Optimiza iena 28 6 5 4 Method Construction nta dai alta edicts heaacedbaacctvebeadates 28 6 5 5 Backup y Restore rece 29 6 5 6 Verification lalla 30 6 5 7 Operating INStruCHOAS Aranda 30 6 5 8 R validationi lisina ail eat 30 6 6 EDUCATION uniendo gii iaa 31 6 6 1 System education opa illegali 31 6 6 2 Methodieducation saem A sade ew asta a ds STR 32 6 7 VALIDATION APPROVA Li ea 32 6 8 VALIDATION OF PC BASED NETWORKS ccococononononononononononononononononcnnnonnnconononnnrnonnnnnrnnnononnnrnonenonnn 32 6 8 1 Introduction esses anced i A DE ASAS ED aliada 32 6 8 2 Validation Strategy masei naw aata a ii and IR ee aa 32 6 9 INSTALLATION QUALIFICATION A
29. etailed information can be found The Backup activity document should describe the specific steps and responsible persons for these needed to obtain a complete and documented routine It should also include an official approval when completed from the person responsible for the Backup activity Amersham PE e Y Biosciences Edition AB January 2004 24 UNICORN 5 0N Edition AB January 2004 Select technique as a suggested first step would be to determine which different backup techniques are available and which one of these is preferable considering security volume economic technical aspects and the effects of a loss of data These considerations should of course be made in conjunction with the system owners expectations of the system Suggested documentation A document describing the investigation considering all aspects involved Purchase of equipment refers to the ordering and delivery of the necessary hard and software Suggested documentation Notes concerning which equipment was ordered by whom and when Delivery note s for the equipment including hardware HW and software SW Install HW and SW should describe how where when and by whom the backup system was installed and connected to the system Suggested documentation A document describing how the installation was performed which directory holds the software the files in this directory function of the files and
30. for the same period of time as any other regular production document 5 6 2 System Recovery Plan Focuses on the data recovery and system restart procedures For example database journaling may be used to keep track of all transaction operations that affect the values of database items A copy of the software including essential files should be kept off line to be used in disaster recovery The system recovery plan should address all aspects of recovery from loss of a hard drive corruption of a file or loss of power to the system Procedures for returning the system to full and proper performance must be in place Provisions for safeguarding product and essential data must be defined The validation of these procedures is recommended Amersham e Biosciences Edition AB January 2004 17 UNICORN 5 0N 5 6 3 Operating Manuals Operating manuals should be available to the users of the system at all necessary locations These manuals must be written at a level such that the actual operators can use them Verification of user manual correctness can be a concern for systems with many features Training of Personnel All users of the system must be trained on the various functions they will be performing All training should be documented Support Personnel A listing of support personnel and their responsibilities and qualifications should be included as part of the documentation System Security The documentation should des
31. how the backup device is connected to the computer Select procedure amp routines refers to two things 1 If the system owner has decided that the system should meet high demands in these respects a procedure where generations of backups are created should be established 2 Decide backup and restore routines that will meet the security demands the system owner has for the system The routines should involve issues such as handling of backup media storage accessibility and who decides when under which circumstances a restore shall be performed how frequently the backup media should be replaced how the media should be labelled responsibility for the routines and other relevant considerations Suggested documentation A document describing key issues and why and by whom routines and functions were chosen Test of backup should verify that the routine works as intended and that the contents of a backup can be restored Observe that the whole routine should be tested not only that the files included in the backup can be restored Apart from the knowledge that a backup routine works as intended and the contents of the hard disk can be restored the test of backup would also provide knowledge of any obstacles that may occur during the procedure and the time it takes to perform a restore to another computer Suggested Documentation A protocol describing how the test was performed with results and evaluation of the test
32. ibilities for backup and restore For the restore routine it is important to state which company function that has the responsibility for deciding when and under which circumstances a restore shall be performed An example of how a backup restore routine can be developed is described under Activity Schedule 6 2 3 Amersham s e Biosciences Edition AB January 2004 29 UNICORN 5 0N 6 5 6 Verification As mentioned earlier the performance of the system is highly dependent on its design not only the fluid handling side and the hardware but also the programmable part of the computer program The program should therefore be constructed with a functionality model that minimises the risk of errors caused by poor design When verification of the computer program and of the chromatographic process have been performed according to the Method Development Plan the method should be approved by the person designated to be responsible for the system 6 5 7 Operating Instructions The Operating Instructions are an important part of the validation process Their main function can be described as instructions in how to handle the system when in operation In the System Development Life Cycle the chapter entitled Operation and Maintenance addresses these questions and specifies what should be considered In cases where the system is intended for production regulated by official rules these recommendations should be modified accordi
33. imited In view of the risk of trademark degeneration it is respectfully suggested that authors wishing to use the designations refer to the trademark status at least once in the article Amersham and Amersham Biosciences are trademarks of Amersham plc Any use of UNICORN software is subject to Amersham Biosciences Standard Software End User License Agreement All goods and services are sold subject to the terms and conditions of sale of the company within the Amersham Biosciences group that is available on request Amersham Biosciences AB 2004 All rights reserved Amersham Biosciences AB Bj rkgatan 30 SE 751 84 Uppsala Sweden Amersham Biosciences UK limited Amersham Place Little Chalfont Buckinghamshire England HP7 9NA Amersham Biosciences Corporation 800 Centennial Avenue P O Box 1327 Piscataway NJ 08855 USA Amersham Biosciences Europe GmbH Munzinger Strasse 9 D 79111 Freiburg Germany Amersham Biosciences KK Sanken Building 3 25 1 Hyakunincho Shinjuku ku Tokyo 169 0073 Japan Amersham pa e Y Biosciences Edition AB January 2004 35
34. ion process and the findings of the persons involved in validating the system should provide information on the suitability of the system to start 1ts intended production Validation of PC based Networks Introduction The validation of a PC based network is a complex and difficult task In a regulated industry one should consider this complexity prior to connecting a PC to a network There is even a risk that the network benefits will not warrant the required validation efforts There are three reasons for this 1 The published literature only provides an overview of the principles involved in validation of networks A great amount of work may be required to interpret and apply these principles to the individual network 2 Regulators have not yet provided guidance on the requirements for computer networks and it is therefore difficult to know exactly what is required for regulatory compliance 3 There is a conflict between the normal use and handling of a PC network and its use in a regulated environment In the latter case the system must be validated and its use controlled by SOPs that ensure every change is evaluated prior to its implementation Situations may occur in which changes considered minor by network operators may be considered major by QA personnel In a regulated environment program version changes upgrading of hardware and additions of new functionality are all considered major changes These three issues do not i
35. mply that it is impossible to validate a PC network and to maintain the desired quality level but rather that the selected technical solution employ a minimum of hardware and software The validation effort needed will most likely increase exponentially with the complexity of the network and the number of programs involved Validation strategy The validation of a PC network can be performed by breaking it down into three units applications e g chromatography network and interfaces where data is transferred Amersham s e Biosciences Edition AB January 2004 32 UNICORN 5 0N from one unit to another The same basic principles as those recommended for any computer system used in a regulated environment should be followed But it is extremely important that the interfaces to other validated units on the network are specified and documented and any other aspects that affect another unit must also be considered After completion of the validation of these three units the entire PC network is validated as a whole by testing it under normal situations as well as performing stress tests to verify the correct behaviour of the system under different situations Stress testing may include communication failure simulation and security challenges PC networks require a network operating system which handles the network communications file management user access etc The operating system has control over the network in much the same manner
36. ngly Observe that these recommendations are not batch specific which means that they do not specify what procedures documentation etc are required for such production The Operating Instructions should contain the following instructions and documentation Routines for backup and restore Adding modifying deleting users Responsibilities for the system Functions in the system Organisation around the system Security routines and responsibilities Change control procedures Log book for the system External contacts and companies suppliers User education User manuals Frequency of revalidation System maintenance schedule and procedures Cleaning instructions Calibration schedule and procedures Other relevant instructions for the operation of the system The Operating Instructions are a part of the validation and specify how the system should be handled when in operation The Operating Instructions should be updated whenever any system related changes are made Such changes shall also be recorded dated and signed in the system logbook in accordance with the Change Control Procedures An important part of the revalidation is to verify that the Operating Instructions are updated and handled correctly 6 5 8 Revalidation The U S FDA recommends that all computerised systems are frequently revalidated and that there is a specific revalidation procedure for each system Since there is no recommended f
37. nt media storing techniques for the contents of the computer s hard disk can be used but magnetic tapes in cassettes are the most common Magnetic tapes are inexpensive have a large storage capacity and can be overwritten with new data when so desired One disadvantage is that they are quite time consuming to use therefore many systems use automatic routines which perform backups at night When a backup routine is developed generations of backups should be considered since not all problems that may occur in a system and originate from the hard disk are discovered instantly If magnetic tapes are used they should be replaced at timely intervals according to the supplier s specification Backup routines should be tested in order to verify that the desired files really are restored from the media when the restore routine is used Verification of this should be included in the validation of the system Storage and handling of the media containing backups should also be considered when a backup routine is constructed To prevent simultaneous loss of both backup media and contents on the computers hard drive they should be stored in different locations When designing routines for the backup remember that the media with backups may hold vital confidential information about your production process Operating procedures describing how a restore is performed should be developed and tested There should also be documents stating the respons
38. nufacturing Practices Good Laboratory Practices and Good Clinical Practices ty lo Dr Sandy Weinberg y Amersham o e Y Biosciences Edition AB January 2004 5 UNICORN 5 0N Amersham e Y Biosciences Edition AB January 2004 6 UNICORN 5 0N 3 AMERSHAM BIOSCIENCES QUALITY MANAGEMENT SYSTEM 3 1 Introduction Amersham Biosciences quality management system BMI Business Management Information is based on a process and system approach as described in the Protein Separations Quality Manual It encompasses the steering structures and procedures needed to achieve the business objectives 3 2 Protein Separations Quality Policy The Quality System should support the strategy of Protein Separations by assuring quality through active management of the following e Identification and documentation of customer needs e Development manufacturing and delivery of products and services to meet or exceed those needs consistently e Feedback from customer assessment leading to improvement in performance for Protein Separations minimising cost and complaints 3 3 ISO Certification ISO 9000 is an internationally accepted series of quality management standards Certification requires rigorous auditing by an independent accredited agency which examines the quality documentation system and confirms that the organisation actually operates in accordance with stipulated principles and instructions Amersham Biosciences first
39. od Development and Verification as part of Validation Plan Product Specification 54 Design and Requirements Analysis 2 1 Method Development Plan Lo Validation Plan y Activity Schedule y Installation Qualification y Operation Qualification q y Verification Method Development and Verification y y Operating Instructions 5 Method education L y d Process Optimisation and Method Construction i 3 4 D Backup Restore uoneonpa esjaueb uoneonpa wajs s V9 9 5 8 Revalidation Procedure Validation Approval Product Specification The first step in the development of a new process is to determine process goals Requirements for product purity activity and quantity should be specified Economic considerations can also be included in the Product Specification Amersham s e Biosciences Edition AB January 2004 27 UNICORN 5 0N 6 5 2 Method Development Plan The activities needed to obtain a method which complies with the Product Specification should be specified in the Method Development Plan The plan should also describe which documentation should result from the activities Responsibilities for each activity should be stated 6 5 3 Process Optimization Developing a process to optimize yield is often a complex
40. ontrol system to confirm their acceptability i e cleaning data reduction etc 5 5 4 Additional Software Verification Requirements Additional testing is required to establish that other software features are correct and function as desired Examples of the types of additional software capabilities which must be validated include verification of security measures confirmation of communication capabilities with other computer systems verification of data archive systems and protocol management In general all the features and capabilities of the computerised system must be validated 5 6 Operational Phase The procedures and systems needed to ensure the acceptability of the system over time should be inspected at the time of system start up 5 6 1 Change Control Change control procedures must be developed whereby changes in the process process equipment software and computer hardware may be evaluated approved and documented As necessary additional qualification and or validation may be needed to evaluate a change The procedure should allow for both planned and emergency changes to the system Emergency change methods are needed when situations requiring immediate action to protect personnel equipment or product are encountered Change control procedures must include provision for the updating of pertinent documentation on the system including many of the elements of this document Records of changes to the system must be kept
41. requency for revalidation this has to be decided by the system owner Revalidation does not mean that the system has to be validated all over again but rather that there should be a specific procedure that ensures the system owner that the system works as intended after a specific period of time Accordingly it is recommended that the system owner develop a Standard Operating Procedure that describes the frequency and protocols for revalidation Observe that calibrations which should be carried out frequently are not revalidation Amersham s e Biosciences Edition AB January 2004 30 UNICORN 5 0N Wherever applicable the revalidation procedure should contain specific test data sets and procedures which when processed in the system should give specified results that are to be compared to those expected A suggested revalidation procedure cannot be specified here since it is site dependent however the following items should be included Verification of the following documentation e Log book e Updated user manuals and SOPs for all activities e Documents from the system validation Verification that the following has been carried out in accordance with SOPs System changes according to change control procedures Log book entries Security procedures Calibrations Sanitation s Errors and disturbances reports Education Service and maintenance Backup Adding deleting users System test procedure data for thes
42. rols KTA BioProcess OligoPilot and OligoProcess systems It also suggests a validation order and documentation that may be generated through the different steps in the validation procedure Installation Qualification and Operational Qualification services available through Amersham Biosciences Fast Trak Validation are described in section 6 9 A standardised source code escrow agreement for UNICORN can be ordered through Amersham Biosciences Fast Trak Validation INTRODUCTION TO UNICORN VALIDATION General UNICORN information Amersham Biosciences UNICORN system affords state of the art control over Amersham Biosciences chromatography systems providing a level of sophistication and refinement not available in other competitive chromatography control systems The configurable nature of UNICORN allows considerable variation in systems to meet the requirements of an individual customer These activities involve the participation of both Amersham Biosciences and the system s owner from the start of the purchasing activity through system start up at the owner s location Each UNICORN system is delivered with the same software but many of its capabilities can only be accessed if the particular system itself is equipped for that specific function The sophistication of the software allows even the most complex chromatographic separations to be implemented since they can be assembled from software components included with each UNICORN
43. s Analysis 2 1 Validation Plan y Activity Schedule y w Installation Qualification Operation Qualification Method Development and Verification y Method education y Validation Approval uoljeonpe eJauab uoljeonpe wa sAs ta The figure Validation order illustrates that validation is a process with components and not just a task that has to be carried out before a system 1s put into production Amersham pa e Y Biosciences Edition AB January 2004 20 UNICORN 5 0N 6 2 Design Validation Plan and Activity Schedule 6 2 1 Design and Requirements analysis System design is vital to its function Amersham Biosciences provides design assistance to its customers and most systems delivered are designed in accordance with customer demands The design phase should not only involve the construction of the chromatography unit but also take into consideration the intended use of the system The intended use will dictate the required level of validation For example the requirement for production of a therapeutic product is quite stringent 6 2 2 Validation Plan A Validation Plan should include all components required to obtain the desired validation level The plan and specified activities are fundamental in the validation of the system and should be approved by the system owner The Validation Plan should include all tests and verifi
44. s utilises structured and documented procedures to provide customers with high quality products To comply with this customer expectation opinions and other relevant information are gathered together with Amersham Biosciences development principles and technical modifications These are considered when UNICORN software is developed Adherence to Amersham Biosciences procedures is verified throughout all phases of product development 4 2 Development model The procedure for product development defines the phases main activities and responsibilities reviews and phase exits to be performed This is visualised in the Figure Development D project Amersham pa e Y Biosciences Edition AB January 2004 9 UNICORN 5 0N Descrhe market needsin PDR Estimate cost end of Definition Phase Edition AB January 2004 Development D project Phase 1 Phase 3 Phase 4 Phase 5 Definition Detailed Planning Development Market Readiness Launch Preparation Business opportunity Team building and Design Registration and Launch support detailed planning General approach legislation Software local Hardware local Available technology System requirements in Chemistry local E Launch preparation System verification plan Manufacturing System integration and support verification Manufacturing scale Product definition in atch PTD System product design inDD Manufacturing process
45. system quality begins at design level We suggest as earlier mentioned that the system is handled in accordance with PMA s System Development Life Cycle when your own programs and methods are developed Amersham Biosciences Fast Trak Validation offers a large number of services to support customers in these matters To verify that a developed method works as intended we suggest that you start with a Product Specification describing the aim of the process After this a Method Development Plan should be established and include details of the activities needed to fulfil the Product Specification The Process Optimisation and Method Construction are integrated activities intended to develop a method which chemically fulfils the Product Specification The procedure should continue with a Verification in which the earlier activities are verified and approved The last steps in the Method Development and Verification are to establish Operating Instructions and a Revalidation Procedure The Operating Instructions should be operating procedures for every function in the system and should describe the responsibilities for each function of the system who is responsible for what The Revalidation Procedure should describe what should be controlled tested and verified regularly and the criteria for the approval of a revalidation This can graphically be presented as shown in Figure Method Development and Verification as part of Validation Plan Meth
46. te the validation effort For comparison to the life cycle diagram in the PMA concept paper the requirements have been separated into major headings which correspond to the major segments of the PMA life cycle The following list is not intended to be all inclusive Depending on the application and sophistication of the system the details of any individual system may be significantly different from that described herein 5 2 Design Specification Phase This portion of the project establishes the groundwork for the entire effort 5 2 1 Functional Requirements A description of the functions which the computerised system must provide It defines the scope of the hardware and software required to complete the project It is essentially a shopping list indicating the desired features of the completed system It is sufficiently detailed to establish the design while allowing for flexibility in the design at the same time 5 2 2 System Specification A detailed compilation of the system as designed to meet the elements of the Functional Requirements It identifies specific hardware features CPU printers CRTs storage devices UPSs and their overall arrangement and an overview of software considerations report formats levels of alarms scan time menus etc 5 3 Hardware Installation amp Qualification Phase This activity includes documentation and verification of the hardware required Hardware configuration specifications for ea
47. tion refers to the Installation Qualification and Operational Qualification IQ and OQ for the system These document templates can be ordered separately from Amersham Biosciences Fast Trak Validation by the customer but are not a part of the documentation delivered with the system Method refers to the customer s method development and other relevant procedures i e education of users These procedures are described in more detail in the Section Validation of a UNICORN based Chromatography System Protein Separations is the knowledge and activities needed to optimize the process as the choice of chemicals media product materials buffers etc Amersham o e Y Biosciences Edition AB January 2004 2 UNICORN 5 0N 2 2 Version numbering When UNICORN software is changed modified the numbering system is used to indicate which degree of modification has been performed The following text describes the principles used The version number used consists of 3 digits and is written X YZ Example 4 12 X New version e new operating system e major new functionality Y Update e adaptations for new hardware components e minor new functionality e correction of software errors e no new functionality specifications not extended e software manual not affected Bug fixes are separate from updates new functionality and new version releases When X is incremented Y and Z are set to zero When Y is incremented Z is set to zero
48. ware are combined and verification of the combination is performed Usually this verification is performed in a modular fashion but eventually all parts of the system must be placed into service Verification reports are prepared for all of the testing performed in this phase The results of all the testing done at this phase are included in a formal verification report 5 5 1 Module Level Verification Testing of individual modules to demonstrate their adherence to the specifications Verification at this level consists of individual functions e g alarms report formats screen displays data transmission Testing of individual modules in a distributed control system is an example of this type of verification 5 5 2 Program Level Verification Program Level Verification is testing of individual programs to confirm their conformance to specifications Testing at this level is performed in one or more of the following ways Simulation Simulation is the use of simulated inputs to the control system to confirm that the computer system responds in the desired way to each input The inputs should be both in accordance with the routine process uneventful to confirm proper sequence or outside the norm eventful to confirm the appropriate response to anticipated process or system upsets The simulation trial confirms the acceptability of the computer system Simulation should be performed on every module which will be utilised on the system
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