Successfully Implementing Mechanical Qualification for Dissolution Apparatus 1 and 2

Transcription

1 Successfully Implementing Mechanical Qualification for Dissolution Apparatus 1 and 2 Ken Boda and Bryan Crist Agilent Technologies Dissolution Systems

2 Agenda Mechanical Qualification Standards When You Shouldn t Do MQ 5 Components of the Mechanical Qualification SOP Considerations Analyst Training Control of Variables in Dissolution

3 Mechanical Qualification Procedures MQ seeks to improve dissolution results by controlling the system more tightly Mechanical Checks are only 1 component No Performance Verification Test (PVT) to assess system holistically Standards available from both FDA and ASTM USP PVT is still acceptable practice

4 Why Consider Moving to MQ? ~40% of labs are performing MQ Cost-savings Quicker qualifications No tablets/standards Failures/Investigations more straight-forward Improved Dissolution Systems

5 When Shouldn t You Move to MQ? High Failure Rate with USP PVT Diagnose + Correct Issue Demonstrate Control over Issue Close out PVT before moving Company not willing to invest in accessory replacement as needed Paddles Baskets Basket Shafts Vessels Centering Rings

6 An Opportunity for Improvement A move to MQ should be viewed as a way to trigger positive changes throughout the dissolution process: Connect qualification to daily work Re-training Opportunity Improve Component and System Quality Improve Daily Dissolution Testing

7 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 June 2, DER/UCM pdf Free Download First official mechanical qualification procedure

8 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

9 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

10 1) Enhanced Mechanical Measurement Requirements Parameter FDA (DPA-LOP.002) ASTM (E ) USP Toolkit, 2.0, includes PVT (Optional) Agilent MQ Procedure Basket / Paddle Depth 25 ± 2 mm 25 ± 2 mm (or within 8% of desired height) mm above bottom of vessel 25 ± 2 mm (or within 8% of desired height) Rotational Speed ± 2 rpm of target within 2% or ± 2 rpm of stated rate (use larger) ± 1 rpm of set value ± 2 rpm of desired speed Shaft Wobble 1.0 mm total runout 1.0 mm total runout 1.0 mm total wobble 1.0 mm total runout Shaft Verticality 0.5 from vertical Within bubble Not measured Within bubble or -0.5 to 0.5 Basket Wobble 1.0 mm total runout 1.0 mm total runout 1.0 mm total wobble 1.0 mm total runout Vessel Centering 1.0 mm from center line 1.0 mm from center line NMT 2.0 mm diff. between smallest/largest measurement 1.0 mm from center line Vessel Verticality 1.0 from vertical 1.0 from vertical at each point NMT 0.5 from vertical Within bubble or 1.0 from vertical Vessel Plate Level Not measured Not measured NMT 0.5 deviation from horizontal Not measured Temperature Not measured Not measured NMT 0.2 C difference between set point / meas. ± 0.2 C between set point / measured value

11 280-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%

12 280-DS MQS Product Introduction Components 280-DS Mechanical Qualification System (MQS) Vessel Module Instrument Module Software Temperature Probe Personal Computer (Not supplied)

13 2) Measurements of Components against USP <711>: 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 13 Restricted September 14, 2011

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15 3) Preventative Maintenance Plan Recommend PM every 6-12 months depending on use, age of equipment, and treatment Check Belt Lubricate Appropriate Components Check Electrical Components Temperature Verification Clean waterbath as needed

16 4) Control of Dissolution Variables Vibration Dissolved Gasses Vessel Quality Controls

17 5) Analyst Checks Prior to each dissolution test, the guidelines generally agree, requiring documentation for: Vessel examination Paddle examination Baskets and basket shaft examination Vessel medium temperature measurement Vibration evaluation

18 SOP Considerations

19 Standard Operating Procedures Impacted Adoption of Mechanical Qualification Impacts Multiple SOPs in typical labs: Calibration/Qualification SOP New measurement tool(s) Dissolution SOP Training SOP Laboratory Controls SOP: Vessel Quality, Deaeration Procedure, Vibration

20 Calibration/Qualification SOP Change Qualification from PVT to Mechanical Qualification Specify Specific Procedures for Component Replacements Vessel Breakage Basket Replacement Paddle Replacement Measurement Frequency 6 month overall calibration interval May want measurements of some portions more frequently

21 Recommendations for Replaced Items Only need to replace impacted position Only need to re-measure impacted parameters Replace with verified component Visual Check of Vessels also recommended

22 Required Re-measurements Basket Paddle/Basket Shaft Vessel Depth X X X Shaft Wobble Shaft Verticality Basket Wobble X X Vessel/Shaft Centering X X Vessel Verticality X X X

23 Recommended Measurement Frequency Full IQOQMQ Upon Installation Only Preventative Maintenance Every 6/12 Months Full Mechanical Qualification Every 6 Months Partial Mechanical Qualification (Centering, Shaft/Vessel Verticality, Shaft Wobble, Vibration) Every 3 months minimum or as components are exchanged Waterbath Cleaning Monthly Basket Wobble Every 1-2 weeks if used Visual Checks and manual vibration evaluation Every Run

24 New Measurement Tools MQ will likely require new tool(s) to be purchased Define use Training on new equipment Calibration frequency and procedure (NIST traceable)

25 Dissolution SOP The Mechanical Qualification guidances both place a larger burden on the analyst Analyst responsible to make sure system is fit between MQs Analysts need to assess the condition of the units prior to use and document acceptability Overall condition Vibration Condition of components Temperature

26 Analyst Checks

27 Overall Condition System Qualified? System Clean? Any issues with wear? Paddles/Baskets at right height? (eyeball)

28 Vibration Should be evaluated each test, not necessarily measured Feel vessel plate, drive unit, and laboratory bench Evaluate for any potential issues with vibration in the lab Other equipment Sources of jarring movement Stereos

29 Condition of Components Most likely part of system to change over time Critical in maintaining proper alignment, etc. Need to assess Paddles Baskets and Basket Shafts Vessels

30 Dissolution Mechanical Qualification Standards Vessel Examination, must be free from: Scratches Cracks Pits Residue Surface irregularities Vessels should be evaluated when dry

31 Dissolution Mechanical Qualification Standards Paddle Examination, must be free of: Defects Rusting Corrosion Peeling or loose coating Knicks, dents or misshapen appearance

32 Stainless Steel Paddles Advanced Corrosion

33 Teflon Paddles Good, Okay, and Terrible

34 Dissolution Mechanical Qualification Standards Basket and Basket Shaft, must be free from: Defects Rusting Corrosion Loose wires Clogged mesh openings Dented sides or bottom Knicks, dents or misshapen appearance O-ring are not compliant; three clips required

35 Baskets From New to Dead

36 Condition of Components Subjective exam of components Analysts should be thoroughly trained and feel empowered to replace components as needed Limited re-measurements only Standard should be available for comparison Poster Photobook Detailed description

37 Maintaining Components Baskets Handle by top ring only Clean by sonication in alcohol Store in protective container Paddles and Basket Shafts Wash w/ soapy water and non-abrasive cloth or sponge When not in use, don t put them loose in a drawer Vessels Use proper care for glass Beware of dropping shafts

38 Control of Variables

39 4) Control of Dissolution Variables Vibration Both internal and external sources Dissolved Gasses Depends on Formulation, should be validated for each method Vessel Quality Controls

40 Vibration from the Lab and Beyond Vibration can come from inside or outside the lab Maintain PMs Avoid Vibration Sources in lab Sturdy bench tops and floors Take and trend vibration measurements over time

41 Vessels Special Considerations Check COA/COC upon receipt Check vessels visually as well Feel for Warps Use vessels and centering rings from equipment vendor

42 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 Check vs. USP using f2 or other metric

43 Summary to a Successful MQ

44 Mechanical Qualification is a Series of Changes Adapt SOPs to MQ and related SOPs, change run sheet New methods should evaluate for degassing (if not already) Re-train Chemists on daily procedures Be able to identify in Quality Components Encourage proper handling of components Invest in replacements as needed

45 Proper MQ Implementation When properly implemented MQ can give you: Regulatory compliance Lower costs and downtime Improved dissolution performance Fewer investigations, OOTs, etc. More scientifically relevant dissolution