Establishing and Executing Cleaning Validation

Transcription

1 Establishing and Executing Cleaning Validation in a Risk-Based Environment Richard J. Forsyth AAPS Annual Meeting November 12, 2007

2 Determination and Use of Visible Residue Limits (VRL)

3 Agenda Limits Viewing Parameters Experimental Conditions Applications & Risk Assessment

4 Limits

5 Acceptable Residue Limit Visibly Clean Health Based Adulteration Based ADI where adulteration limit takes over Lowest Calculated Limit

6 Visible Residue Limit (VRL) The limit below which a residue is not visible under defined parameters

7 Visible Residue Limit Compound solution/suspension Material of construction Spot known amount Consistent spot size Dry under nitrogen Set viewing parameters 3+ observers

8 Visible Residue Limit Compare VRL to ARL If VRL > ARL, default to ARL If VRL < ARL, potential for use under defined parameters

9 Viewing Parameters

10 Distance The viewing distance is the distance between the equipment surface and the observer s eyes Defined for consistency Importance as factor increases as distance increases Dramatic drop-off at a certain point

11 Distance Equipment dependent Size Degree of disassembly for cleaning

12 Ambient Light Intensity Light under which VRLs observed Perpendicular (90 ) to surface Defined at set level Defined as intensity range Handheld light where necessary

13 Ambient Light Intensity Room dependent Distance from ceiling light source Equipment dependent Size Degree of disassembly Shadows

14 Viewing Angle The viewing angle is the angle between the flat equipment surface and the observer s eyes

15 Viewing Angle Equipment dependent Size Shape Degree of disassembly Shadows

16 Residue Residue appearance can be characteristic of compound White to gray

17 Experimental Conditions

18 Clinical Facilities Equipment generally smaller Manual cleaning process Disassembly required

19 Clinical Facilities Distance 1 ft Light Intensity lux Viewing Angle 30

20 Aprepitant Observations Detection of Spots by observers A-D µg cm lux 1000 lux 800 lux 600 lux 400 lux A B C D A B C D A B C D A B C D A B C D 74.4 Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y 40.1 Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y 14.2 Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y 12.0 Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y 7.44 Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y 5.90 Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y 2.98 Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y 1.45 Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y 0.00 N N N N N N N N N N N N N N N N N N N N

21 VRLs is a trademark of Merck & Co. in certain countries Visible Limit (ug/cm 2 ) at Specified Illuminance API Product Diluent 400 Lux 600 Lux 800 Lux 1000 Lux 1400 Lux Losartan Potassium Cozaar 1/1 ACN/water <2.68 <2.68 <2.68 <2.68 <2.68 Indinavir Sulfate Crixivan 1/1 ACN/water <1.38 <1.38 <1.38 <1.38 <1.38 Aprepitant Emend 1/1 ACN/water Alendronate Sodium Fosamax 1/1 ACN/water Rizatriptan Benzoate Maxalt 1/1 ACN/water <0.873 <0.873 <0.873 <0.873 <0.873 Famotidine Pepcid 1/1 ACN/water <1.46 <1.46 <1.46 <1.46 <1.46 Finasteride Proscar 1/1 ACN/water <2.72 <2.72 <2.72 <2.72 <2.72 Montelukast Sodium Singulair 1/1 ACN/water <1.47 <1.47 <1.47 <1.47 <1.47 Simvastatin Zocor 4/1 ACN/water Compound A 1/1 ACN/water Compound B 1/1 ACN/water <0.591 <0.591 <0.591 <0.591 <0.591

22 VRLs VRL (µg/cm 2 ) APIs Formulations Excipients Detergents Total % Total < % % % % > % Total %

23 VRL variability Variability of VRL detection Number of Compounds

24 Commercial Facilities Equipment generally larger More CIP cleaning Disassembly more limited Viewing parameters restricted

25 Commercial Facilities Distance ft. Light Intensity lux Viewing Angle

26 VRL Detection vs. Distance and Viewing Angle 120% 100% % Spots Visible 80% 60% 40% 20% 0% 5 ft. 10 ft. 15 ft. 20 ft

27 ARL Detection vs. Distance and Viewing Angle 120% 100% % Spots Visible 80% 60% 40% 20% 0% 5 ft. 10 ft. 15 ft. 20 ft

28 ARL/VRL Detection at 400 lux and Maximum Light Intensity 120% % Spots Visible 100% 80% 60% 40% 20% 0% 5 ft. 10 ft. 15 ft. 20 ft. 5 ft. 10 ft. 15 ft. 20 ft. VRL ARL 400 lux Spotlight

29 ARL/VRL Detection vs. Decreasing Light Intensity % Spots Visible 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 400 lux 300 lux 200 lux 100 lux ARL VRL

30 Limitations Residue Distance - > 10 ft. Light Intensity - < 200 lux Viewing Angle - < 30

31 Training Needs to be thorough most APIs Some have similar appearance Stress viewing conditions Light & viewing angles Redundancy Two pairs of eyes Rotational

32 Applications & Risk Assessment

33 New Compound Introduction Establish VRL before first use Assess cleaning procedure effectiveness after first manufacture Determine if current cleaning procedure is appropriate or additional validation is necessary

34 New Compound Introduction Facility Issues Clinical Facility Large # cpds Limited batches Equipment down time Method development Commercial facility Small # cpds Large # batches Manufacturing rotation

35 Risk Assessment Assessment based on two factors Probability of the application being identified as a problem Seriousness impact to operation if application fails

36 New Compound Introduction Risk Assessment Low based on acceptable VRL and inspection of cleaned equipment Risk Mitigation VRL determination Redundant inspection Evaluate API/formulation physical properties and cleanability

37 Periodic Assessment Use VRL for periodic assessment of cleaning effectiveness Supplements routine inspections

38 Periodic Assessment Risk Assessment Low based acceptable VRL and limited potential for carryover Risk Mitigation Redundant inspections Periodic swab confirmation Periodic assessments trending performance based on visual inspections

39 Technology Transfer Transfer VRL data and training to contractor Assess cleaning based on VRL

40 Technology Transfer - Facility Issues Clinical Facility Large # cpds Limited batches Equipment down time Method development Commercial facility Small # cpds Large # batches

41 Technology Transfer Risk Assessment Low based on acceptable VRL Risk Mitigation Train personnel at site or send personnel to inspect

42 New Equipment Introduction Use VRL to assess application of current cleaning procedure to new equipment First three uses of equipment

43 New Equipment Introduction Risk Assessment Low VRL will determine whether cleaning procedure works or not before the chance of cross-contamination Risk Mitigation Redundant inspection Evaluate against current equipment configurations

44 Campaign Length Extension Use VRL to extend campaign length beyond previously validated limit

45 Campaign Length Extension Risk Assessment Low to none cleaning procedure and formulation and dirty hold time are the same.

46 Cleaning Procedure Optimization Use VRL to assess changes in cleaning procedure Cycle times Length of manual scrubbing Changing detergents Need for detergents

47 Cleaning Procedure Optimization Risk Assessment None to assess cleaning parameters Low- to implement changes to cleaning procedure Risk Mitigation Revalidation after optimization Surface sampling after optimization Solid documentation/rationale for change

48 Reduced Cleaning Documentation Use VRL to reduce documentation for each step of a manual cleaning procedure

49 Reduced Cleaning Documentation Risk Assessment Low to none based on validation of cleaning procedure Risk Mitigation All cleaning parameters demonstrated during validation Data to demonstrate VRL<ARL

50 Validation of Cleaning Program Use VRL to validate a facilities cleaning program

51 Validation of Cleaning Program Risk Assessment Medium to high based on VRL documentation and validation rationale No historical precedent Risk Mitigation Solid documentation of VRL determination, viewing parameters and training. Some type of secondary confirmation of validation (e.g. photos)

52 Thank you!