Frequently Asked Questions about Mechanical Qualification. Ken Boda Applications Engineer Agilent Technologies

Transcription

1 Frequently Asked Questions about Mechanical Qualification Ken Boda Applications Engineer Agilent Technologies

2 Is MQ Acceptable to the FDA? Yes Either FDA or ASTM approach is acceptable Many people (including some FDA auditors) aren t aware this is allowable

3 FDA Documents The Use of Mechanical Calibration of Dissolution Apparatus 1 and 2 Current Good Manufacturing Practice (CGMP) FDA Guidance for Industry January RegulatoryInformation/Guidances/ucm pdf CGMP requires laboratory apparatus be calibrated at suitable intervals in accordance with established written specifications (21 CFR (b)(4))

4 Dissolution Mechanical Qualification Standards Mechanical Qualification of Dissolution Apparatus 1 and 2 US Food and Drug Administration (FDA), DPA-LOP.002, Version 2.0, Effective Date 02 June, DER/UCM pdf Free Download First official mechanical qualification procedure

5 Dissolution Mechanical Qualification Standards Standard Practice for Qualification of Basket and Paddle Dissolution Apparatus American Society for Testing and Materials, International (ASTM), Designation E , Effective date: March 15, Cost: $32.00 USD E2503 is under the jurisdiction of ASTM Committee E55 on Manufacture of Pharmaceutical Products and is the direct responsibility of Technical Subcommittee E55.03 on General Pharmaceutical Standards

6 What is required for Mechanical Qualification per ASTM/FDA? 1) Enhanced mechanical measurements 2) Measurement of dissolution components against USP <711> 3) Preventative maintenance plan 4) Control of vessel variability, dissolved gasses, and vibration 5) Analyst checks before each run for several parameters

7 What are the enhanced measurements? Tighter overall specifications Additional upper and lower centering requirements Paddle/Basket Height Measurements Shaft and vessel verticality

8 Dissolution Mechanical Qualification Specifications and Tolerances Parameter Basket and Paddle Depth Rotational Speed Shaft Wobble Shaft Verticality ICH Harmonized (USP, JP, EP) FDA DPA-LOP.002 ASTM E ± 2 mm 25 ± 2 mm 25 ± 2 mm (or <8%) ± 4% of specified rate No significant wobble Not measured Basket Wobble ± 1 mm ± 2 rpm of target 1.0 mm total runout 0.5 from vertical (x and y 90º) 1.0 mm total runout lower rim ± 2 rpm or within 2% of target (larger) 1.0 mm total runout Within Bubble (x and y 90º) 1.0 mm total runout lower rim USP Toolkit Ver mm ± 1 rpm of target 1.0 mm total wobble Not measured 1.0 mm total wobble

9 Dissolution Mechanical Qualification Specifications and Tolerances Parameter Vessel/Shaft Centering Vessel Verticality Vessel Plate Level Performance Verification Test (PVT) ICH Harmonized (USP, JP, EP) NMT 2 mm from center axis Not Measured FDA DPA-LOP mm from center line (upper/lower) 1.0 from vertical (2-90 positions) ASTM E mm from center line (upper/lower) 1.0 from vertical (2-90 positions) USP Toolkit Ver 2.0 NMT 2.0 mm difference (4-90 positions) NMT 0.5 from vertical Not Measured Not Measured Not Measured NMT 0.5 from horizontal USP Prednisone Tablets RS Not Measured Not Measured USP Prednisone Tablets RS

10 280-DS for Enhanced Mechanical Measurements No direct contact with shaft no bias More precise readings vs. QAII, VK5010, and manual tools Identify trends over time Record and track components Reduce MQ qualification time by >50%

11 280-DS MQS Product Introduction Components 280-DS Mechanical Qualification System (MQS) Vessel Module Instrument Module Software Temperature Probe Personal Computer (Not supplied)

12 280-DS MQS Product Introduction Features Only 2 modules are used to capture ALL necessary measurements. The Vessel Module (VM) measures Rotational Speed, Basket/Shaft Wobble, Vessel Centering, Shaft Verticality, Vessel Verticality, and Basket/Paddle Height. The Instrument Module (IM) measures Vessel Plate Level and Vibration while also acting as a hub for the VM, Temperature probe and connection to the PC. 12 Confidentiality Label October 11, 2012

13 Do I need to fix positions of components? Yes System is qualified on a per-position basis and the position is defined by the components

14 Will older units be able to pass MQ? Good chance of being in tolerance if passing PVT Most common repairs on nonpassing units involve centering issues Will require verification of: Vessels Paddles or Baskets/Basket Shaft

15 If a unit is failing centering, what can I do? Centering is the most common reason for failure, and can be due to several reasons: Unlevel head Vessel Lip or Vessel Plate issues Centering Rings Poor Quality Vessel(s)

16 Diagnosing Centering Begin with centering assembly: Fingers all in place Tight o-rings Vessel plate not warped/chipped/rusted Centering can be improved with newer vessel types such as TruCenter and TruAlign

17 Diagnosing Centering Vessels: Change orientation can vary mm depending on how it faces Mark vessel location Look at vessel for odd shape, etc. Shimming

18 What is vessel shimming? Vessels with glass lips can have irregularities in rim which lead to being off-center or not vertical Tape or other material can be used beneath lip to prop or shim the vessel Appropriate material needs to be selected

19 Diagnosing Centering Overall System Alignment: Check levelness of head vs. levelness of vessel plate Verticality of support legs Verticality of shafts

20 What is required for Mechanical Qualification per ASTM/FDA? 1) Enhanced mechanical measurements 2) Measurement of dissolution components against USP <711> 3) Preventative maintenance plan 4) Control of vessel variability, dissolved gasses, and vibration 5) Analyst checks before each run for several parameters

21 What is an acceptable COC/COA? 21 Restricted September 14, 2011

22 A COC/COA needs: Critical Parameters for a part Acceptable Ranges for each parameter As Found Values NIST Traceable Tool used to measure values Serial # of the part Analyst performing the work 22 Restricted September 14, 2011

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24 Do COC/COAs expire? Unlike rulers, calipers, etc. there is not a predetermined frequency of requalification It is the responsibility of the chemist to check the items as acceptable for use prior to using them

25 Vessel Examination

26 Stainless Steel Paddles Minor Rusting

27 Stainless Steel Paddles Advanced Corrosion

28 Teflon Paddles Good, Okay, and Terrible

29 Baskets From Good to Bad

30 If a component is damaged, what do I need to do? Replace damaged item with another component with COC/COA Reperform appropriate remeasurements for that position Ensure documentation shows new s/n for that location No need to test any other positions or redo entire MQ

31 What is required for Mechanical Qualification per ASTM/FDA? 1) Enhanced mechanical measurements 2) Measurement of dissolution components against USP <711> 3) Preventative maintenance plan 4) Control of vessel variability, dissolved gasses, and vibration 5) Analyst checks before each run for several parameters

32 Laboratory Controls How am I supposed to control for: Vessel Variability? Dissolved Gasses? Vibration?

33 Vibration Vibration is a source of variability in dissolution testing and often (but not always) leads to higher results Vibration can come from: Dissolution Unit itself Other Equipment nearby Laboratory Issues External Issues

34 Dissolution Unit Vibration Follow Proper PM schedule Check water bath level Vibration from heater or unit head? Heater should not touch dissolution unit

35 Vibration from Other Equipment Fume hoods Vacuum pumps Construction Mechanical shakers Bench top centrifuges Ultrasonic baths Heater circulators or pumps Worn parts or bearings Stereo

36 Vibration from the Lab and Beyond Inadequate benches Foot traffic Slamming/Dropping Construction

37 Minimizing Vibration Follow manufacturer PM procedure and frequency Keep equipment off bench that could induce vibration Place equipment in areas of the lab away from fume hoods, refrigerators, etc. Use vibration dampening pads

38 What is the best way to measure vibration? If you have a vibration sensor, it is most useful in measuring trends over time and can help identify: Need for maintenance Specific sources of vibration Look for intermittent sources of vibration No set specification exists for vibration

39 Feeling for vibration No Significant Vibration A slight hum is okay Feel along spindles as well as head of tester and bench top

40 Dissolved Gasses Dissolved Gasses are another source of high variability in dissolution, and unless validated use USP procedure Other acceptable approaches when validated: Helium sparging Media preparation devices No degassing

41 Vessels Check COA/COC upon receipt Check vessels visually as well Feel for Warps Use vessels from equipment vendor Keep clean Replace as Needed

42 Vessels are Key! Vessel Type % Pass Rate % CV Mean Easealign glass 92% 5.2% 32 TruCenter 100% 4.3% 33 Generic 57% 4.8% 34 Mixed set 33% 6.3% 33 TruAlign 100% 4.4% 33 Confidentiality Label 42 October 11, 2012

43 What is required for Mechanical Qualification per ASTM/FDA? 1) Enhanced mechanical measurements 2) Measurement of dissolution components against USP <711> 3) Preventative maintenance plan 4) Control of vessel variability, dissolved gasses, and vibration 5) Analyst checks before each run for several parameters

44 Why are Analysts Required to Perform Checks Prior to Running? Check for condition of components Ensure unit is clean Check for any noticeable issues In a way, act as a surrogate for testing of analyst in PVT

45 What Savings Can I Expect From MQ? Time Savings Qualification of an instrument in 25 minutes 3 hours Less Instrument Downtime Qualify and Run on the same day No more tablets and standards Improved ability to diagnose issues

46 280-DS MQS Product Introduction Resources 280-DS Online Cost Savings Calculator: ds_calculator.aspx 46 Confidentiality Label October 11, 2012

47 QUESTIONS AND DISCUSSION