Parallel Session 1A Sterile Manufacture. Denise Coakley. GMP Conference 12 th November 2014

Transcription

1 Visual nspection Parallel Session 1A Sterile Manufacture Denise Coakley GMP Conference 12 th November 2014

2 EU GMP Annex 1: Filled containers of parenteral products should be inspected individually for extraneous contamination or other defects. 2

3 EU GMP Annex 1: When inspection is done visually, it should be done under suitable and controlled conditions of illumination and background. 3

4 EU GMP Annex 1: Operators doing the inspection should pass regular eye-sight checks, with spectacles if worn, and be allowed frequent breaks from inspection. 4

5 EU GMP Annex 1: Where other methods of inspection are used, the process should be validated and the performance of the equipment checked at intervals. Results should be recorded. 5

6 Manual inspection Ph. Eur

7 Manual inspection Ph. Eur A matt black panel of appropriate size held in a vertical position, A non-glare white panel of appropriate size held in a vertical position next to the black panel, An adjustable lampholder fitted with a suitable, shaded, white-light source and with a suitable light diffuser (a viewing illuminator containing two 13 W fluorescent tubes, each 525 mm in length, is suitable). The intensity of illumination at the viewing point is maintained between 2000 lux and 3750 lux, although higher values are preferable for coloured glass and plastic containers. 7

8 Manual inspection Ph. Eur Remove any adherent labels from the container and wash and dry the outside. Gently swirl or invert the container, ensuring that air bubbles are not introduced, and observe for about 5 s in front of the white panel. Repeat the procedure in front of the black panel. Record the presence of any particles. What else do we look for.?? 8

9 Eye Test G E T Y O U R E Y E S C H E C K E D 9

10 Manual Inspection - Training Frequency/Duration Test kits Management of test kits Line speed Unit size Qualification/disqualification 10

11 Manual Inspection Maintenance Procedure for back ground lighting Lux levels Personnel Frequent breaks 11

12 Training Line speed during training Unit sizes Duration of training Challenge set management 12

13 Manual Inspection - Defects Defect classification -Particles -Cracks -Cosmetic Procedure for management of rejects 13

14 Semi- Automated Visual Inspection Removes the requirement for handling by the operator Units are fed/spun by conveyor for operator viewing What do we look for.?? Exact same as for manual inspection 14

15 Automated Visual Inspection - It is important to know the capabilities and limitations of equipment. - Camera Light reflection - Static division -Light transmittance - Qualified what does this mean? 15

16 Automated Visual Inspection URS Validation Detectability Repeatability How is the machine challenged Particles need to be moving to be detected by both SD and camera Equipment maintenance Management of rejects 16

17 Are there more specific requirements???... Defect classification Particle size visible, sub visible Route of administration What is meant by practically free Risk based approach 17

18 Manual/Semi-Automated and Automated It is accepted that neither the machine or the human can be 100% effective Whatever the system of inspection when a defect trend is detected the production process and where necessary, the inspection process must be investigated and reassessed. 18

19 When things go wrong and they sometimes will... What is the procedure Deviation Re-inspection: Line speed, frequency At what stage is the batch considered rejected What is the source of the defect container closure or production process Is the product compatible with the container closure glass, rubber What is the impact to product on site What is the impact to product on the market Risk Management 19

20 Risk Assessment 20

21 Risk Assessment Critically assess what has happened and why. Do not play down the severity rating of the defect. Do not increase the level of detection rating if the defect has poor or no detectability. Do not decrease the probability of occurrence rating if there is a trend of the defect occurring. State the facts. It is better to identify the problem and fix it. 21

22 Mistakes are the portals of discovery. James Joyce 22

23 Risk Assessment Deviations should be avoided but......they can drive change and improvements. 23

24 Risk Assessment Don t just Risk Assess the problem OUT......Risk Assess the solution IN 24

25 Risk Assessment Improve the manufacturing process by building in preventative controls that scientifically support low probability of occurrence ratings for particulates during risk assessments. Improve the inspection process and ensure that all high detectability ratings assigned during risk assessments are supported by scientifically sound detection-type controls. Identify the key risk-mitigating preventative and detection controls that come out of such risk assessments, and ensure that those controls are validated and proven effective. 25

26 Visual Inspection Deficiencies The controls in place with respect to the sites visual inspection programme were considered deficient in that: Investigations in relation to glass particulates were not considered to have been progressed in a timely manner The SOP was not followed in that the rig speed was not reduced to 50% upon identification of the tramp / loose glass defect. There was no consideration given to re-inspection of the preceding vials that had been inspected up to that point at such a reduced speed. A recurrence check for the previous 3 months was undertaken. It was noted that a 3 month recurrence check was too confined a time limit to place on such assessments. IR X had been raised due to a loose glass defect. The root cause of this defect was not identified. 26

27 Visual Inspection Deficiencies The inspection procedure did not require re-inspection of preceding vials at reduced speed of 50% normal rate, when critical defects, with low detectability, were identified. Where 2 nd re-inspections identified additional defects, at no point during the investigations was consideration given to assessing the effectiveness of the visual inspection programme nor was there any impact assessment performed on those batches which were currently in date and on the market. 27

28 Visual Inspection Deficiencies The investigations concluded that no corrective action was required as the operators were validated to perform visual inspection at a rate of xvpm for x minute intervals. This was despite the inherent issues identified with respect to the sites visual inspection programme, as indicated by the operators in the investigations. No due consideration was given to the statements from the operators nor was there any consideration given to SOP X. 28

29 Visual Inspection Deficiencies The manner in which the trend analysis for defects was conducted was considered deficient in that: Data was not trended for all defect types e.g. tramp/loose glass was trended as particles which covered a number of other critical defect types Additional rejects found during re-inspections were not included in the trend analysis The data captured for trending from visual inspection was inputted by operators into the inspection log database. There was no verification that this data was inputted correctly. 29

30 Visual Inspection Deficiencies The ongoing issue in relation to glass particle defects and the potential impact to product on the market was not reported to the competent authority at the time of the inspection. There was no action taken in relation to the finished product visual inspection process or the post inspection AQL, following observations which confirmed that the visual inspection process was not effective in detecting the critical defect and that batches X, Y and Z, had passed the 100% inspection and post inspection AQL sampling but on subsequent 100% manual inspection, showed evidence of the particle defects. The timelines involved in the move to a tightened AQL for incoming inspection and the subsequent move to Unacceptable Quality Limit sampling was considered an unacceptable delay. 30

31 Visual Inspection Deficiencies In relation to Risk Assessment, X, it did not consider batches manufactured between MMM YY and MMM YY. The application of the same risk rating of High to the detectability of moving and not moving particles, was not considered appropriate given that the system was not capable of detecting the latter and that batches had been noted to pass through the inspection process without such defects being detected. It was considered that the risk assessment placed an over reliance on the use of AQL sampling and statistical analysis of the same, to detect the critical defect There was no information in relation to the ongoing investigations in relation to this defect type in the APQR. 31

32 Conclusion Establish robust procedures Where equipment is used, know the capability and limitation Validation Appropriate defect classification Training Qualification/disqualification Equipment maintenance Risk Management consider that the effectiveness of the current process may need to be critically assessed and improved. 32