US & EU GMP Guidelines on Analytical Instrument Qualification and Related Warning Letters

1. US & EU GMP Guidelines on Analytical Instrument Qualification and Related Warning Letters Confidentiality Label

2. Overview • FDA/EU/USP Requirements and enforcement practices • Examplesof FDA warningletters • The 4Q modelforequipmentqualification • Essential steps and example templates for Instrument Qualification: DQ, IQ, OQ, PQ • Validation ofexistingsystems • Requalification: what, when Reference material: www.labcompliance.com/agilentAvailable until March 10, 2014

3. Regulations and Quality Standards EU and FDA • Good Laboratory Practices • GMP Manufacturing Practices • Good Clinical Practices • 21 CFR Part 11: E-Records&signatures • IS0 17025 • Equipment should be suitable for its intended use • Equipment should be calibrated and maintained

4. US FDA; 21 CFR Part 211 - 211.68 • 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. Calibration, inspection, routine checks Written program Calibration records

5. Other Regulations and Guidelines Europe • EU GMP Annex 15 (draftFebruary 2014) • Validation and qualification activities should consider all stages from initial development of the user requirements specification through to the end of use of the equipment • Stepsinclude: User requirementspecifications, design qualification, installationqualification, operational qualificationandperformancequalification (4Q model) United States Pharmacopeia • .USP general chapter <1058>: “Analytical Instrument Qualification” • Global standardforlaboratoryequipmentqualification • Followsthe 4Q model(see Annex 15 above)

6. FDA Warning Letters OQ • Failure of your quality control unit/laboratory to ensure that analytical instrumentation and test equipment used to assure the quality of your APIs has been appropriately qualified and calibrated for their intended use. • All laboratory instrumentation and equipment that you use to test material manufactured for the U.S. market should have an Operational Qualification (OQ) and should be calibrated to include applicable operating ranges (W-288) Perform Operational Qualification Equipment Ref: www.fdawarningletter.com

7. FDA Warning Letters IQ/OQ • Lacks documentation of installation and operation qualification of equipment (160) • The Validation Master Plan does not contain an operational qualification for xxx (164) • There is no requirement for a Performance Qualification protocol (164) PQ Perform IQ/OQ/PQ for Equipment Ref: www.fdawarningletter.com

8. FDA Warning Letter/483/EIR • The calibration program for your stability chambers is deficient ill that it does not include specific directions and schedules. • You do not perform re-qualification of the stability chambers. No requalification of equipment – • Develop a program for equipment calibration and calibration. Include a schedule • Conduct regular requalification of equipment

9. FDA Warning Letters • Failure to have a complete calibration program for the HPLCs in that the gradient accuracy and detector linearity is not being verified (W-110) Qualification Incomplete Perform Operational Qualification for all equipment functions Ref: www.fdawarningletter.com

10. FDA Warning Letters • No chromatographic system suitability testing (W-016) No System suitability testing • Develop written procedures for type and frequency of system suitability testing • Ensure that the procedure is followed Ref: www.fdawarningletter.com

11. Analytical Instrument Qualification and and other Quality Checks • Quality control checks • Verifies accuracy of sample analysis • System suitability tests • Verifies that the system performs according to analysts expectations • Analytical methods validation • Proof that analytical procedure does what it purports to do • Analytical instrument qualification • Forms the base for generating quality data • Proof suitability of the instrument for intended use

12. Design Qualification Installation Qualification Operational Qualification Performance Qualification Qualification/Validation Phases 4Q Model • User requirement specifications • Functional specifications • Operational specifications • Vendor qualification • Check arrival as purchased • Check proper installation of hardware and software Validation Report Validation Plan • Test of operational functions • Performance testing • Test of security functions • Test for specified application • Preventive maintenance • On-going performance tests Required by FDA, Europe and USP

13. Design Qualification (DQ) Activities and Documentation • Vendors • Design, develop and manufacture instruments in quality control environment, e.g., ISO 9001:2008 • Develop functional and operational product specifications • Users • Develop user requirement specifications • Verify that the vendor’s instrument meets user’s requirements: product specifications, delivery and support • Verify that the vendor operates in a quality system environment

14. Design Qualification - Template

15. Documenting Equipment Supplier Selection Slide 15

16. Vendor • Provides the user with environmental specifications and a site prep document • Provides • Offers services for IQ with inspection ready documentation • User • Verify that facilities, utilities, and environment meet vendor requirements • Assemble and install equipment • Perform initial diagnostics and testing • For complex equipment: run reference sample • Document installation, including drawings Installation Qualification (IQ) Equipment lacks documentation of installation and operation qualification (160)

17. Equipment Documentation for IQ Example: HPLC detector

18. Operational Qualification (OQ) • Vendor • Provides services for OQ with traceable tools • Delivers inspection ready OQ documentation • Makes recommendations for frequency of requalification • User • Test functions to verify that the instrument operates in theuser’s environment as intended by the manufacturer and required by the user. • Test secure data handling, storage, back-up and archiving • Tests can be holistic or modular. • Tests can be done by users or qualified designees. Conductivity meters not calibrated to a NIST traceable device (156)

19. Test engineer Date Weight 3 o.k. Weight 1 Weight 2 Name Signature yes 2/3/06 9999.8 999.9 100.0 Hughes OQ Test - Example

20. Vendor • Provides recommendation for PQ tests, e.g., for system suitability testing • Provides software for PQ testing, e.g., for system suitability and quality control charts • User • Preventive maintenance to ensure trouble free operation for the intended application • Performance checks, based on the instrument’s typical on-site applications • Test frequency depends on the ruggedness of the instruments and the criticality of the tests • System suitability and QC tests can imply suitable performance Performance Qualification (PQ) There is no requirement for a Performance Qualification protocol (164)

21. Documentation of PQ Testing Example: HPLC System

22. Summary Report Template Mirror of the Plan

23. Define System Use Installation Qualification Operational Qualification Performance Qualification Validation Phases – 4Q Model APPROACH FOR EXISTING EQUIPMENT • Document equipment use • Document applications • Document used functions • Enter all modules and systems in a database • Hardware, Firmware, Software Validation Report Validation Plan • Document past tests • Test of functional specifications • Test of performance functions • System test (system suitability testing) • Preventive maintenance + Change Control

24. Recommendation: Apply risk assessment OQ - Requalification • Required • when the instrument undergoes major repairs or modification • After transport to an other location, if the move ‘disturbs’ instrument operation • May not be required to be repeated at regular intervals No recalibration after equipment move (154) The calibration program for your stability chambers is deficient in that it does not include specific directions and schedules.(231)

25. Thank You I would like to thank • All attendees for your attention • Agilent Technologies forinvitationandorganization Dr. Ludwig Huber Ludwig_huber@labcompliance.com For links to Analytical Instrument Qualification references, please check www.labcompliance.com/agilent(Available until March 10, 2014)