1. Did all batches compressed at 75N - 85N pass dissolution, consider that Hardness increases?
2. Did they pass for EU markets (100 RPM paddle speed) or for CA market (50 RPM paddle speed)?
3. How didnt we have broken Famciclovir 750mg tablets
4. what was there hardness limit
5. in E-12-090 they said IAT of 65 degrees was high, and 1200m3/hr was high
6. Objective
   1. To investigate Compression and Coating Processes and determine at which stage tablet breakages and chipping occur
   2. To identify recommendations to prevent re-occurrence
7. Introduction
   1. Two commercial batches as per protocol PIP-027
      1. 937664
      2. 937665
   2. Commercial batch in same campaign
      1. 949054
   3. Commercial batches as per Memorandum ME 15-006
      1. 976767
      2. 976768
      3. 976769
      4. 989752
      5. HOW WHERE THESE BATCHES COATED?
8. Method of Manufacture
   1. Granulation
   2. Drying
   3. Milling
   4. Blending
   5. Compression
   6. Coating
   7. Yields and Losses
9. Results
   1. Hardness and Friability Study
   2. Compression In-Process Hardness and Friability
   3. Visual Inspection after Compression
   4. Coating Friability and Hardness
   5. Visual Inspection after Coating
   6. Study on Tablets Compressed at 120N Average Hardness
10. Discussion
    1. Discussion of Formulation and Manufacturing Process
       1. Blend is fine
       2. Blend is dry
       3. Blend has poor flow
    2. Discussion of Previous occurrences of broken, chipped, physically disintegrated tablets
       1. 2nd Blend Split validation batch H0062
       2. 1st Full Blend validation batch 439083 40 RPM with 28 stations
          1. Broken Core Tablets in buckets 1-4 HN 488/11
       3. 472968
          1. Broken Coated tablets were found when batch was about to be blister packed
       4. 764103
          1. Customer Complaint: Broken Tablet in Blister
       5. 839214
          1. E-13/1826
       6. 897031
          1. Customer Complaint - broken and physically disintegrating tablets
    3. Discussion of Results
       1. Formulation and Manufacturing Process
       2. Previous Deviations
       3. Investigation Results Interpretation
          1. Tablet Hardness and Friability Study
          2. Compression Run
          3. Coating
          4. Loss on Drying
          5. Moving Hardness Limit for an upper Limit of 120N
11. Recommendations
    1. Granulation
       1. Specify Peristaltic Pump in Equipment List
       2. Specify maximum pneumatic pressure for delivery of Granulation Solution
    2. Drying
       1. Specify Airflow settings for specific 400L FBD models
       2. Specify 20 minute duration for Air 1 settings
       3. Specify Target LOD of 0.8 - 1.2%
       4. Specify Exhaust Temperature of 34 degrees
       5. Stipulate Filter Pulse Times to every 10 seconds
    3. Compression
       1. Change Hardness Limit from 50N - 88N to 65N - 88N
       2. Change Target Hardness Range from 65N - 75N to 75N - 85N
       3. Stipulate use of smaller deduster with downward spiral Kramer E-80
       4. Instruction to check bucket for broken tablets when rejections occur when using the Korsch XL-400 model
    4. Coating
       1. Stipulate manual Jog at 2 RPM instead of automatic Jog
       2. Limit Pan Speed from 2-5 RPM to 2 - 4 RPM
       3. Stipulate starting at a Pan Speed of 2 RPM for X minutes
       4. Change Limit on Inlet Air Temperature from 45 - 75 to 45 - 65
       5. Change target Inlet Air Temperature to 55 - 60
       6. Stipulate Spraying to start at exhaust temperature of 30 degrees instead of 34
       7. Reduce exhaust temperature to 30 - 34
       8. Reduce pump speed to prevent over-wetting
    5. Revalidation at higher target Hardness Range with an upper limit of 120N
12. Conclusion
    1. The onset of the Coating process was found to be the most contributing stage at which tablets are broken to a degree where AQL limits are exceeded (NMT 1 broken tablet in 125)
    2. The Compression process also causes broken tablets by physical impacts, from the Korsch XL-400 rejection mechanism but this is to a lower extent.