Compliance Updates. Paul Smith Spain May 2014

Transcription

1 Compliance Updates Paul Smith Spain May 2014

2 Contents EU GMP A Tale of Change (Vs. CFR)... FDA Warning Letters Data Gathering.. Instrument Qualification - GAMP / <1058>. Quality by Design... Data Integrity.. FDA Warning Letters a Deeper Dive.. How Do You Know?... Questions. Appendix More FDA Warning Letters.. CAG EMEAI FY14 Agilent Restricted Page 2

3 EU GMP Current Update Status (Vs. CFR Vs. FDA Guidance) Section Title Issue Date Current Proposed CAG EMEAI FY14 Agilent Restricted Page 3

4 FDA Warning Letters

5 EudraGMDP European Non-Compliance 1 Listed for Spain: CAG EMEAI FY14 Agilent Restricted Page 5

6 FDA Warning Letter Page Recent Warning Letters Recent FDA Warning Letters A B C D E F G H I J CAG EMEAI FY14 Agilent Restricted Page 6

7 What an FDA Warning Letter Might Contain Unique Reference e.g. ucm Audit Dates Location References to 21 CFR and / or USP requirements Common Words: FD&C Adulterated Drug Definition (Chapter 9, section 351) Adulterated Misbranded FD&C Misbranded Drug Definition (Chapter 9, section 352) Acknowledgement of Response: We acknowledge receipt of your reply, but.. Lacks sufficient detail / corrective actions Often Basic Errors. Was not considered as > 15 days from WL Details of non-conformance Expression of audit / response concerns Expression of WL response requirements: Risk-Assessment for US distributed products Copies of anything promised (procedures, validation) Counter arguments (if difference of opinion) A ucm number is assigned to each FDA web page. Google will find it, if links broken. How many audit days (but not how many people), days to WL Auditors Carry GPS Analysis of Look Up [+ EIR Data] Tone of response Consequences of what they found, how you responded, what you CAG EMEAI FY14 promised.. Agilent Restricted Page 7

8 Example Warning Letter ucm a live rodent that you brushed off your Shoulder onto the floor, and then kicked under a pallet. Days to Issue [ 74 Days, 53 Working Days ] Audit Days [ 15 Working Days ] Tone CFR Look Up [ Google CFR ] Non-Conformance CAG EMEAI FY14 Agilent Restricted Page 8

9 FDA Warning Letter Trends FDA Audits: 97 % of US Facilities [pharmaceutical, every 2 years] FDA Audits: 7 % of Non US Facilities [pharmaceutical every year] Trend Downwards In Terms of Number of Warning Letters Trend Upwards! > 10 Times Increase 1720? [Source: Journal of Validation Technology; D. W. Vincent, Winter 2012 edition] US Audits: Down 40 % 976 [2013] down to 591 [2014] Overseas Audits: Up 30 % 604 [2013] up to 843 [2014] ? Margaret Hamburg Joined FDA ( 21 st Commissioner, May 18 th 2009 ) [other regulators UK MHRA ] CAG EMEAI FY14 Agilent Restricted Page Source: Pharmaceutical Manufacturing.com Mutual Recognition Audits [Tougher National Audits] Move From Fixed Time Triggers To RISK Based Triggers Whistle Blowers.

10 How Many? How Many Times are Techniques Cited? CAG EMEAI FY14 Agilent Restricted Page 10

11 FDA Warning Letters A Valuable Resource / Tool By Country Country Number Austria 6 Belgium 15 China 143 Denmark 16 France 31 Germany 75 Hungary 2 India 48 Ireland 12 Israel 14 Italy 42 Netherlands 13 Spain 23 Switzerland 27 United Kingdom Warning Letters by Country Updated: 31/Mar./2014 CAG EMEAI FY14 Agilent Restricted Page 11

12 FDA Warning Letters 5 Year Trend By Country Warning Letters by Country Last 5 Years CAG EMEAI FY14 Agilent Restricted Page 12

13 2012 Last Full Year, Warning Letters as % of FDA Drug Audits How Good Are Pharmaceutical Companies in Spain? Drug Audits Spain = 6 Warning Letters, 15 Drug Inspections (= 40 %!) CAG EMEAI FY14 Agilent Restricted Page 13

14 Instrument Qualification USP <1058> and GAMP

15 Hardware & Software All instruments contain some level of software (unless only electro-mechanical / mechanical) All instruments and Software must be suitable for intended use in GXP work Qualify the Instrument Validate the Software For Simple Instruments these are combined For Complex Systems these are independent For Simple Instruments calibrate (e.g. ph Meter) For Complex Instruments qualify (e.g. HPLC) For Complex Systems validate (e.g. CDS) Qualify the Instrument Can t qualify without software control. USP <1058> Validate the Software Can t validate the software without the instrument. GAMP CAG EMEAI FY14 Agilent Restricted Page 15

16 USP <1058> - Implemented in August 2008 Risk Based Categorisation: A, B, C: Strength of <1058> A Verify by Observation (e.g. Stirrer) - No calibration or Measurement B Verify by Calibration - Calibrate by SOP / Document (e.g. ph Meter) Addressed in <1058> Update C Qualify (e.g. HPLC) - Complex Systems - Verify by Full Qualification CAG EMEAI FY14 Agilent Restricted Page 16

17 Summary of USP <1058> Definitions Roles: User QA Supplier Responsibilities DQ / IQ / OQ / PQ Simplification of the Life Cycle Process: Areas of <1058> Flexibility What is done in OQ / PQ Risk Management by Categorisation: A / B / C Observe Calibrate Qualify Components of Data Quality / Integrity - Principles Apply to All Labs. A B C Examples CAG EMEAI FY14 Agilent Restricted Page 17

18 GAMP Software Categories From PIC/S Guidance GAMP Defines Different Software Categories: Infrastructure Firmware Group B Non-Configured Software Configured Software (COTS) Bespoke Software USP <1058> Analytical Instrument Qualification GAMP Good Practice Guide A Risk-Based Approach to GxP Compliant Laboratory Computerized Systems GAMP 5 CAG EMEAI FY14 Agilent Restricted Page 18

19 GAMP GPG Risk-Based Approach to GXP Compliant Laboratory Computerized Systems GPG Edition 1 Contents: 19 Sections - Process Based Approach (Table of Contents Available on Line) Contents: GPG 7 Sections Edition 2 - Risk Based Model (Table of Contents Available on Line) Aligned With GAMP 4 Risk Management by Instrument Categorisation. 7 Categories Examples: A - Sonicator B - ph Meter C - Key Pad HPLC D - PC HPLC E - NMR F - Spread sheet G - Bespoke Aligned With GAMP 5 Risk Assessment... No Formal Categorisation! (Fixed Categories VS. Risk Based Thinking) Appendices: 1. Determining System Impact 2. Testing Priorities 3. Supplier Assessment Scheme Glossary References Available From ISPE Appendices: 1. Categories of Software 2. System Description 3. Data Integrity 4. Simple Systems 5. Medium Systems 6. Complex Systems 7. System Interface Considerations 8. Robotic Systems 9. Defining Electronic Records and Raw Data Expansion and Examples Security Management for Laboratory Computerized Systems 11. Supplier Documentation and Services CAG EMEAI FY14 Agilent Restricted Page 19

20 GAMP and USP <1058> Common Goals USP AIQ <1058> Good Evolution May 1987 FDA Process Validation Guide Lines Simplify Process Risk by Categorisation - Software -(GAMP) Hardware (<1058>) GAMP 4 5 pages! Easy to Follow A and B Simple Flexible Harmonisation Draft New <1058> With USP Panel Integrates <1058> & GAMP AIQ <1058> Draft 2013 Roles and Responsibilities Maximise use of Supplier Documentation GAMP ISPE Very Comprehensive Great For Custom Software GAMP 5 Good Practice Guide GAMP 5 for Lab. Worked Examples Inclusion of <1058> Principles Life Cycle Mgt. CAG EMEAI FY14 Agilent Restricted Page 20

21 Pharmaceutical Engineering Publication CAG EMEAI FY14 Agilent Restricted Page 21

22 Proposed <1058> Classification Awaiting Feedback Bob McDowall & Chris Burgess Publication CAG EMEAI FY14 Agilent Restricted Page 22

23 Quality by Design

24 Example Laboratory Lean Sigma Application How Many Days to Test Product Batches of Material Before Impressive Results: 50 % Reduction In Tests Times are Common Improved Testing Control Mean Workflow Optimisation Moderately Robust HPLC Method Less-Robust HPLC Method After Mean Sample Based Testing Product Team [analysts perform all tests] Optimised for Control / Speed Test Based Testing HPLC Team [HPLC specialists ] Designed to Reduce Problems CAG EMEAI FY14 Agilent Restricted Page 24

25 What is Quality By Design? Specification Historical Pharmaceutical Process Validation Variable Quality Raw Materials Inputs Pharmaceutical Manufacturing Process Fixed Process Validated Registered Can t be Changed Output Variable Quality Drugs Pharmaceutical Manufacturing 2.5 Design Space Quality by Design Pharmaceutical Process Validation Variable Quality Raw Materials Inputs Pharmaceutical Manufacturing Process Fixed Output Variable Process Validated Design Registered Can Change Within Design Space QbD CAG EMEAI FY14 Agilent Restricted Page 25

26 Wider Application of QbD Principles.. Pharmacopeia Forum Application of QbD To Analytical Method Development & Validation <1224> Analytical Method Transfer <1225> Analytical Method Validation <1226> Analytical Method Verification <220> Basic Requirements for Validation <1220> Lifecycle Management of Analytical Procedures CAG EMEAI FY14 Agilent Restricted Page 26

27 Example Why QbD is Needed Significant QC Problems With Method Variable Resolution CAG EMEAI FY14 Agilent Restricted Page 27

28 Example - Why Analytical QbD is Needed.. For This Method: Temperature Minimal Effect ph Critical Effect on Resolution Method Conditions Mobile Phase ph 4.5 Column Oven Temp. 35 o C 3D Graph Called Response Surface Measure Effect With QbD Design A DIFFERENT ph Would Have been Used ph 3 [flat part of response] Here QbD used in Problem Solving If Can t Change Method CONTROL ph Change Method Conditions ph & Temperature CAG EMEAI FY14 Agilent Restricted Page 28

29 Range of Use (Best Practice to Qualify Range of Use) Why Range of Use is Important? Qualification should bracket THE RANGE OF USE (good science & easier to defend users may have to do extra qualification ) Flow Rate (ml/min.) Max. Flow 1 ml/min. 45 o C Oven Temperature ( o C) Range of Highest Temp. Qualification Space Use Customer HPLC Method 1 ml/min. (Pump) 45 o C (Oven) 245 nm (Detector) Min. Flow Lowest Temp. Wavelength (nm) Lowest Wavelength 245 nm Highest Wavelength CAG EMEAI FY14 Agilent Restricted Page 29

30 Design Space = Qualification Space Sharmista Chatterjee Jan QTPP = Quality Target Product Profile ATP = Analytical Target Profile MODR = Method Operable Design Region EQP = Equipment Qualification Plan EQR = Equipment Qualification Report Analytical Instrument EQP (Equipment Qualification Plan) (Process Operability) (Range of Use) Pharmaceutical QbD Analytical QbD Instrument Qualification CAG EMEAI FY14 Agilent Restricted Page 30

31 Example Range of Use Warning Letter The qualification MUST BE representative, of how the instrument is used.. 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. Specifically, your firm has failed to conduct adequate qualifications of your analytical instruments and test equipment. For example, the residual solvent method used to test (b)(4) API has an initial starting gas chromatograph (GC) oven temperature of (b)(4). Your firm s current qualification of the GC oven temperature does not include temperatures below 100 C. Qualify the Range of Use CAG EMEAI FY14 Agilent Restricted Page 31

32 Data Integrity

33 What Triggered The Current FDA Focus? FDA Part 11 Add On Audits Jan Data Integrity has always been an FDA focus. Part 11 Add on Audits Fundamental Data Integrity 21 CFR Part Implementation 2003 Guidance FDA DATA INTEGRITY FOCUS PAI Consent Decree Data Integrity Training Scientific Validity ICH Q9, Q10, Q11 support Science Based GMP Decisions (e.g. cgmp for 21 st Century) CAG EMEAI FY14 Agilent Restricted Page 33

34 So, What is Data Integrity? The Degree to which a collection of data is complete, consistent and accurate * *(FDA Glossary of Computer System Software Development Terminology (9/95) Data: (Collins Complete and Unabridged English Dictionary) PLURAL NOUN, a series of observations, measurements, facts, information. Integrity: (Collins Complete and Unabridged English Dictionary) NOUN, adherence to moral principles, honesty; or the quality of being unimpaired; soundness, or unity; wholeness The definition can influence the SCOPE that people Interpret Data Integrity: Narrow:- Specific to 21 CFR Part 11 Wide:- Anything that causes a concern with the validity of the data This means there is risk of confusion and poor preparation for defending YOUR Data Integrity in an audit ( effects your audit preparation) THE FDA will base their audit on what they find NOT YOUR DEFINITION! CAG EMEAI FY14 Agilent Restricted Page 34

35 One Slide History Data Integrity FDA Warning Letters: HPLC & GC warning letters show high level of Data Integrity related issues (so not new) 2 Key Areas to Note: History of Generic Drug Issues Generic Drug scandal in the late 80 s, early 90 s (falsified data, bribes to FDA.. Etc.). Food Drug & Cosmetics Act Amended by: - Generic Drug Enforcement Act (GDEA) Reference Publication [Hyperlink] Debarment of Individuals and Companies Clinical ANDA Data Clinical Data Investigations Monica Cahilly (Now Trained ALL FDA Auditors in Data Investigations) CPG [Hyperlink] FDA PAI 3 Focus Areas: - Objective 3, Data Integrity Audit mcahilly@gmqa.net ISPE Conference on Risk-Based Systems Validation - New Jersey, USA, th September 2011 FDA Data Integrity Auditing Training (AGILENT) - Dublin, Ireland, 9-10 th July 2012 Train the Trainer Data Integrity Auditing - Dublin, Ireland, th May 2014 CAG EMEAI FY14 Agilent Restricted Page 35

36 Is Paper Good Enough? Reference Publication [Hyperlink] Paper Hybrid Electronic Need to implement data integrity improvements strategically, as many laboratories: Still define paper as raw data Use Excel to calculate results May have imbedded compliance risks Data Mapping / Flow / Fish Bone CAG EMEAI FY14 Agilent Restricted Page 36

37 Who Next? The UK MHRA is setting an expectation that pharmaceutical manufacturers, importers and contract laboratories, as part of their self-inspection programme must review the effectiveness of their governance systems to ensure data integrity and traceability. This aspect will be covered during inspections from the start of 2014, when reviewing the adequacy of self inspection programmes in accordance with Chapter 9 of EU GMP. It is also expected that in addition to having their own governance systems, companies outsourcing activities should verify the adequacy of comparable systems at the contract acceptor. The MHRA invites companies that identify data integrity issues to contact: GMPInspectorate@mhra.gsi.gov.uk 16 December 2013 Unknown the situation in other EU inspectorates Spain? CAG EMEAI FY14 Agilent Restricted Page 37

38 FDA Warning Letters HPLC and GC

39 Examples Search on HPLC Enter Search Criteria (e.g. HPLC) 2. Select Sort By (Default is Alphabetical) 3. Select Sort Criteria (e.g. Descending) 4. Select Go A B C D Select ALL (Copy & Paste into Excel) Select Warning Letter (to open) Use Ctrl F to FIND KEY WORDS CAG EMEAI FY14 Agilent Restricted Page 39

40 FDA HPLC Warning Letters 13 years on FDA Warning Letter Page: 46 % - last 4 Years Key Points: HPLC has the Highest FDA Focus of ANY Analytical Technique High focus area in recent years CAG EMEAI FY14 Agilent Restricted Page

41 FDA Warning Letters That Mention HPLC or GC Audit Duration [ (HPLC & GC) = 84 ] Days to Issue Warning Letter [ 84 ] Days to Issue Warning Letter FDA Takes 10 x Longer To Issue Warning Letters Than Companies Have to Respond [HPLC Only] CAG EMEAI FY14 Agilent Restricted Page 41

42 Review of FDA Warning Letters About GC Most of these categories cause concern over the validity of the analytical results. Read Evaluate Categorise Knowledge No GC 1 N/A 3 GC in Name, GC in SOP.. Method 2 GC Methods Capability of the Method Calibration 4 Calibration Data Integrity Would trust this data? 7 Data Integrity: Now Biggest Category GC Warning Letters Most are relatively Recent! CAG EMEAI FY14 Agilent Restricted Page 42

43 Primary Cause HPLC Warning Letters Impact of Instrument Repair / Failure Sterlity Stability Testing Data Integrity - Fraud 3 Data Integrity - Security 4 Would trust this data? Data Integrity Data Integrity - Incomplete Data 3 Data Integrity - Data Deletion 1 Defecient HPLC Method HPLC Method Validation 5 Poor HPLC Use / Training 11 Using the Method Chromatography - Unknown Peak Problems With System Suitability 2 2 Poor HPLC Use / Training HPLC Methods Capability of the Method OOS Problems N/A 7 HPLC Methods 8 Decisions & Justification No Calibration Calibration Defeciency 8 Would trust this data? 9 Calibration: Biggest Single Category CAG EMEAI FY14 Agilent Restricted Page 43

44 Your Equipment - How DO You Know? How Do You Know If Your Equipment Is Set up Correctly? Measure How it Is Setup Mechanical Qualification ASTM E FDA DPA-LOP.002 How Do You Know If Your Equipment Is Working Correctly? Use a method sensitive to Variation in the instrument performance USP Performance Verification Test USP <711> Dissolution Problems are one of the Top 10 reasons for Pharmaceutical Product Recall! (Cindy Bhuse, FDA, AAPS, 2011) CAG EMEAI FY14 Agilent Restricted Page 44

45 Dissolution and Hydrodynamics Paddle (Rotates) Dissolution Vessel (In the.) Dissolution Medium (Which contains.) Anything that influences the flow in the vessel will Change the results! Drug Product (Particles) Dissolution Medium - Sweeping past particles Scratches on paddle or vessel Seams if not certified vessel Vibration Air bubbles (if not degassed) Bent shaft / Wobble...Etc. Drug Particle To PASS the PVT The Instrument Must be Working Well! CAG EMEAI FY14 Agilent Restricted Page 45

46 Dissolution Snapshot. Dissolution Qualification 49% - USP PVT 20 % - MQ Only (FDA / ASTM) 29 % - Both (PVT + MQ) 2 % - In House Methods May CAG EMEAI FY14 Agilent Restricted Page 46

47 Questions? CAG EMEAI FY14 Agilent Restricted Page 47

48 Appendix Additional Information

49 Word Warning - Deeper Dive Additional Information

50 HPLC Analysis % Included in Warning Letter 71 % of HPLC letters Include Reference to Stability Testing Stability Poor Response / CAPA Complete Data 43 Data Review 27 External Consultant Required 16 Reaccurance 30 Data Integrity - Incomplete Records 43 Data Integrity - Data Deletion 13 Data Integrity - Security 27 Defecient Methods 17 Method Validation 43 SSC 27 OOS 51 Training 27 Calibration CAG EMEAI FY14 Agilent Restricted Page 50

51 Detailed Analysis HPLC Warning Letters - Stability 37 % Stability Testing Solution Stability 17 % Not Stability Indicating 78 % 71 % of HPLC warning letters Include Reference to Stability 16 % Facilities 38 % Protocol Storage Temperature 50 % Storage Excursion 50 % Validation of Deficiencies 40 % 67 % Deviations 21 % 38 % Stability Results Specification Failure 54 % Storage Not Supported 29 % Calculation of Results 21 % CAG EMEAI FY14 Agilent Restricted Page 51

52 GC Analysis % Included in Warning Letter 79 % of GC letters Include Reference to aspect of Data Integrity Stability 36 Poor Response / CAPA 79 Complete Data 36 External Consultant Required 7 GC Data Integrity Review (%) Reaccurance Data Integrity Audit Trail Incomplete Records Data Deletion Methods SSC Data Change 7 OOS 36 Manufacturing 21 Training 21 Security Data Integrity Calibration CAG EMEAI FY14 Agilent Restricted Page 52

53 Proposed <1058> Sub Classification (McDowall & Burgess) Group A: Apparatus Group B: Instruments Type 1: Firmware Type 2: Firmware plus built in calculations Type 3: Firmware plus user defined programs Group C: Systems Type 1: Low complexity system - instrument plus non-configured software Type 2: Medium complexity system - instrument plus configured software Type 3: High complexity system - Instrument plus configured software & macros CAG EMEAI FY14 Agilent Restricted Page 53