Professional Documents
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Luisa Stoppa
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors Nanjing, the Peoples Republic of China 16-20 November 2009
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors 2 | Nanjing, the Peoples Republic of China, 16-20 November 2009
aseptic process:
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors 3 | Nanjing, the Peoples Republic of China, 16-20 November 2009
Despite such measures, contamination is an ever-present danger because aseptic processing is a process being operated in a controlled but not sterile- environment and sample numbers are too small; so that only gross contamination is likely to be detected
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors 4 | Nanjing, the Peoples Republic of China, 16-20 November 2009
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors 6 | Nanjing, the Peoples Republic of China, 16-20 November 2009
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors 7 | Nanjing, the Peoples Republic of China, 16-20 November 2009
filling machine
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Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors 11 | Nanjing, the Peoples Republic of China, 16-20 November 2009
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors 12 | Nanjing, the Peoples Republic of China, 16-20 November 2009
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors 13 | Nanjing, the Peoples Republic of China, 16-20 November 2009
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors 14 | Nanjing, the Peoples Republic of China, 16-20 November 2009
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors 15 | Nanjing, the Peoples Republic of China, 16-20 November 2009
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors 16 | Nanjing, the Peoples Republic of China, 16-20 November 2009
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors 17 | Nanjing, the Peoples Republic of China, 16-20 November 2009
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Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors 23 | Nanjing, the Peoples Republic of China, 16-20 November 2009
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13150
14430 15710 16960
7
8 9 10
The table indicates the maximum permitted number of contaminated units per various Media Fill run sizes to indicate a 0,10% contamination limit with a 95% confidence level
Health Canada
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors 26 | Nanjing, the Peoples Republic of China, 16-20 November 2009
Contamination
The root cause of a failure (contamination), or at least the most probable one, must be identified It is important to be able to isolate and identify (to species level) the microorganisms An appropriate corrective action / preventive action plan must be implemented
The impact of the failure on product lots already released (if any) must be evaluated
After the corrective actions have been implemented, a new media fill study is performed to confirm their efficacy
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors 27 | Nanjing, the Peoples Republic of China, 16-20 November 2009
Contamination
Contamination rate increasing during filling
This could indicate a contamination originated in the liquid media path (i.e. wrong aseptic connection to the media tank, contamination in the recirculation loop). It is important to keep under aseptic conditions the media bulk tank at the end of filling, while waiting the media fill results, for verifying this hypothesis
Contamination rate
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors 28 | Nanjing, the Peoples Republic of China, 16-20 November 2009
Contamination
Contamination rate decreasing during filling
This could be indicative of a contamination occurred during the line set-up (stopper bowl / guides, dosing pumps / needles), partially or totally washed out during filling.
Contamination rate
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors 29 | Nanjing, the Peoples Republic of China, 16-20 November 2009
Contamination
Contamination spike during filling
A spike (some contaminated units in a short time interval could be linked to a not correctly performed critical intervention during filling. For this reason it is crucial to have an accurate time traceability of the filled units and the interventions performed (videotaping the filling operations can be helpful)
Filling chronology (time or units)
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors 30 | Nanjing, the Peoples Republic of China, 16-20 November 2009
Contamination rate
Contamination
Contamination spike followed by an increase
Similar to the previous example, but in this case the wrong intervention could have affected the liquid path/loop (i.e. change of media tank, replacement of a pump / needle)
Contamination rate
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors 31 | Nanjing, the Peoples Republic of China, 16-20 November 2009
Contamination
Isolated events (few contaminated units per run)
Unfortunately, this occurrence is the most common and also the most difficult to be investigated. If repeated on multiple runs, it could indicate that this profile is representative of the background noise of the process, so requiring radical actions (i.e. change of garments/dressing code, disinfectants, air flow patterns)
Contamination rate
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors 32 | Nanjing, the Peoples Republic of China, 16-20 November 2009
Contamination
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors 33 | Nanjing, the Peoples Republic of China, 16-20 November 2009
Contamination
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors 34 | Nanjing, the Peoples Republic of China, 16-20 November 2009
Conclusion
Even if all media fills are negative in a Company, it does not necessarily indicate that no products were ever possibly contaminated because the frequency requirement of media fill testing is so minimal that it is not statistically significant
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l.stoppa@aifa.gov.it
Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009
36 |
Reference documents
WHO GMP guidelines Technical Report series n. 937 EU GMP guidelines, Part I annex 1 & 15 ICH Q7A or EU GMP Part II chapter 13 FDA Guidance for Industry: sterile drug products produced by aseptic processing cGMP PIC/S Recommendations PI 007-5 USP <797> media fill testing / <71> growth promotion test EP 2.6.1 sterility
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors 37 | Nanjing, the Peoples Republic of China, 16-20 November 2009