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Dr. Tim Sandle
Pharmaceutical Microbiology:
http://www.pharmamicroresources.com
Introduction
 EM guidance
 Background to USP <1116>
 Main changes and debates
 Method limitations
 Incident rates
 Frequencies of monitoring
 Locations of monitoring
 Other changes
 Regulatory issues
 Rapid methods
Pharmaceutical Microbiology:
http://www.pharmamicroresources.com
Sources of EM Guidance
 EU GMP - last EM revision 2009; new annex 1 2016?
 FDA aseptic filling guide (2004)
 PDA Technical Report (2014, 3rd revision)
 ISO 14698 (1998). Future update?
 USP <1116> (2011, published 2012)
 Pharmig Current Review (2010)
 PHSS Biocontamination control guide 2015
Pharmaceutical Microbiology:
http://www.pharmamicroresources.com
Sources of EM Guidance
 ISO 14698
 Under long-term review
 Possible development to a viable cleanroom
classification standard (like ISO 14644)
 No other standard is likely to be reviewed in the short-
term
Pharmaceutical Microbiology:
http://www.pharmamicroresources.com
ISO 14644
 ISO 14644 Parts 1 and 2 revised in December 2015
 A standard for cleanroom classification.
 Some detail about on-going monitoring.
 Does not cover viable monitoring at all.
 Changes:
 New look-up tables
 Increase in counter locations
 Changes to sampling volumes
 Each individual location must pass.
 More risk based.
Pharmaceutical Microbiology:
http://www.pharmamicroresources.com
USP <1116> (2012)
 USP <1116>
 Revision began in 2005
 Objectives of USP committee:
 Focus the chapter on environmental monitoring only,
removing information relating to aseptic process validation.
 Focus the document exclusively on the monitoring of aseptic
environments.
 Reconsider the alert and action level (limit) concept.
 Effective 1st May 2012, 35th edition of the USP
Pharmaceutical Microbiology:
http://www.pharmamicroresources.com
Main changes
 Former title:
“Microbial Control and Monitoring Environments
Used for the Manufacture of Healthcare Products”
 Revised title:
“Microbiological control and monitoring of aseptic
processing environments”
Pharmaceutical Microbiology:
http://www.pharmamicroresources.com
Main changes
 Scope:
 Pharmaceutical sterile products
 Bulk sterile drug substances
 Sterile intermediates
 Excipients
 Environments
 Conventional clearoom with UDAF
 Blow-fill-seal
 RABS
 Isolator
Pharmaceutical Microbiology:
http://www.pharmamicroresources.com
Main changes
 The emphasis on the word “aseptic” in the
introduction implies that the chapter is not applicable
to all “sterile” products.
 This means that terminally sterilised products are
outside the scope of the chapter.
Pharmaceutical Microbiology:
http://www.pharmamicroresources.com
Main changes
 By “aseptic” a low level of contamination is
acknowledged:
“an expectation of zero contamination at all locations
during every aseptic processing operation is technically
not possible and thus is unrealistic”
Pharmaceutical Microbiology:
http://www.pharmamicroresources.com
Main changes
 USP notation system dropped: M3.5 etc. And old FDA
209E classes e.g. Class 100, Class 10,000)
 Replaced by ISO 14644 classes in the operational state
 Difference with EU GMP:
 Class 5 = EU GMP Grade A
 Class 7 = EU GMP Grade B
 Class 8 = EU GMP Grade C
Pharmaceutical Microbiology:
http://www.pharmamicroresources.com
Main Changes
 Relative risks
Picture showing on how process separation and product
protection interact (adopted from Bioquell U.K Ltd).
Pharmaceutical Microbiology:
http://www.pharmamicroresources.com
Main changes
 The design and construction of clean rooms and
controlled environments are covered in ISO 14644.
 ISO 14644 stipulates the total particulate counts
required for a clean environment to meet the defined
air quality classifications. USP accepts this standard
verbatim.
Pharmaceutical Microbiology:
http://www.pharmamicroresources.com
Main Changes
 New guidance for cleanroom operations:
 ISO class 8 = 20 air changes per hours
 ISO class 7 = 50 air changes per hour
 ISO class 5 = 100 air changes per hour
 Isolators = can have a different
justification for air changes
and air velocity
 An EM programme should only be constructed and
executed once airflow mapping and HVAC dynamics
have been optimised.
Pharmaceutical Microbiology:
http://www.pharmamicroresources.com
Environmental monitoring
 USP places emphasis upon particle and viable
monitoring
 Particle counting most important for isolators
 Viable monitoring is regarded as semi-quantitative
 Trending is the most important aspect of the monitoring
programme
 Isolated counts “a normal phenomenon in conventional
cleanrooms” which do not require specific corrective action
and there is the possibility of a false positive
Pharmaceutical Microbiology:
http://www.pharmamicroresources.com
Environmental monitoring
 USP requires monitoring of:
 Surfaces
 Air (room and enclosure)
 Compressed gas
 Changes in trend must be investigated, and include
assessment of:
 Maintenance
 Disinfection
 Unusual events and activities
 Physical changes e.g. temperature and humidity
 Staff training
Pharmaceutical Microbiology:
http://www.pharmamicroresources.com
Environmental monitoring
 SCDM (TSA) is a suitable medium, incubation at ‘low’
and ‘high’ temperatures (20-35oC for not less than 72
hours)
 Consideration given to fungal medium e.g. SDA
 Certain conditions may require micro-aerophilic
monitoring e.g., certain gasses or sterility test failure
using anaerobic media
Pharmaceutical Microbiology:
http://www.pharmamicroresources.com
Methods
 Settle plates:
 EU GMP:
 Semi-quantitative measurement (CFU / 4hours)
 Require desiccation study.
 USP 1116:“The exposure of open agar-filled Petri dishes,
or settling plates, is not to be used for quantitative
estimations of the microbial contamination levels of
critical environments.”
Pharmaceutical Microbiology:
http://www.pharmamicroresources.com
Monitoring methods
 No EM programme can prove sterility
 Environmental control is the most important,
supported by EM and media simulations
 EM can demonstrate that a clean room is operating
with in a consistent state of control
 However, “EM” requirements have evolved in a manner
that did not fully consider analytical capability and
metrology
Pharmaceutical Microbiology:
http://www.pharmamicroresources.com
Monitoring methods
 All monitoring methods are flawed:
 Require people to take them
 Variability in technique
 Risk of false positives
 No one method can detect all types of contamination
 All methods have relatively poor recoveries
(“insensitive”)
 Air-samples are particularly weak
 Surface methods have poor recoveries
 Settle plates are not considered quantitative
 All methods are poor at recovering damaged or stressed
microorganisms
Pharmaceutical Microbiology:
http://www.pharmamicroresources.com
Monitoring methods
 Therefore, numerical targets (as CFU) should:
 Not be used as limits (they are “levels”)
 Not be considered specifications
 Be seen as informational only
 Low or zero counts are not, by themselves, guarantees for microbial
control;
 Equally, excursions beyond numerical limits are not necessarily and
indication of loss of control.
 Instead:
 Count non-zero events.
 Use a contamination recovery rate metric based on historical
findings
 Inference that these should be stable over time with little
variation.
Pharmaceutical Microbiology:
http://www.pharmamicroresources.com
Plate counting debate
 DEBATE
 Should not simply count CFU due to the inaccuracies of
current environmental monitoring methods
 It is more important to count the incidence rates and
investigate out of trend.
 The limit of quantitation (the number of cfu that can be
reported accurately) is 15.
 If CFU below 15 cfu , do not worry if trend is OK.
 If above 15 cfu, investigate.
Pharmaceutical Microbiology:
http://www.pharmamicroresources.com
What does this mean?
 At very low recovery levels there is no way to establish
Alert or Action Levels statistically-the counts are
simply too low to make statistical analysis useful.
 Instead, emphasis should be on incidents.
 “Hits” in ISO 5 aseptic environments should be
infrequent.
Pharmaceutical Microbiology:
http://www.pharmamicroresources.com
What was the pre-USP 2012
situation?
 Take active air-samples:
 Microbiological cleanliness levels ‘In Operation’ cfu/m3
Area EU GMP FDA Guide USP
Aseptic core <1 <1 <3
Support for
aseptic filling
<10 <10 <20
Controlled
process area
<100 <100 <100
Controlled
support area
<200 Not specified Not specified
Pharmaceutical Microbiology:
http://www.pharmamicroresources.com
USP contamination rates
Class Active air
sample
Settle plate Contact plate Swab
Isolator or
Closed RABS
(ISO 5 or
better)
<0.1% <0.1% <0.1% <0.1%
ISO 5 <1% <1% <1% <1%
ISO 6 <3% <3% <3% <3%
ISO 7 <5% <5% <5% <5%
ISO 8 <10% <10% <10% <10%
Pharmaceutical Microbiology:
http://www.pharmamicroresources.com
USP contamination rates
 NOTE: Contamination recovery rates should be based
upon actual monitoring data and should be re-
tabulated monthly.
 When contamination recovery rates are observed that
exceed the recommendations in the table or are
greater than established process capability corrective
actions should be taken.
Pharmaceutical Microbiology:
http://www.pharmamicroresources.com
USP contamination rates
 For example
 Grade B cleanroom
 Active air-sampling
 One year of data reviewed
Pharmaceutical Microbiology:
http://www.pharmamicroresources.com
USP contamination rates
0.00%
20.00%
40.00%
60.00%
80.00%
100.00%
120.00%
0
200
400
600
800
1000
1200
1400
Frequency
Bin
Grade B routine active air (April 2010 - April
2011) Histogram
Frequenc
y
Cumulati
ve %
Count (cfu) Frequency
Cumulative
percentage
0 1240 80.78%
1 191 93.22%
2 52 96.61%
3 20 97.92%
4 8 98.44%
5 7 98.89%
6 2 99.02%
7 3 99.22%
8 2 99.35%
9 1 99.41%
10 0 99.41%
Pharmaceutical Microbiology:
http://www.pharmamicroresources.com
USP contamination rates
0
5
10
15
20
25
30
35
1 105 209 313 417 521 625 729 833 937 1041 1145 1249 1353 1457
Count(cfupercubicmetre)
No. samples / time
Grade B AFS routine active air (April 2010 - April 2011)
Active air counts
(cfu)
Pharmaceutical Microbiology:
http://www.pharmamicroresources.com
USP contamination rates
 Corrective actions may include but are not limited to:
 Sanitization program including types of disinfectants,
application methods, and frequencies.
 Personnel practices by supervisory staff.
 Microbiological sampling methods and techniques.
 Training on gowning practices.
Pharmaceutical Microbiology:
http://www.pharmamicroresources.com
Frequencies of sampling
 Isolators
 Active Air Sampling-once/day
 Surface sampling-at end of each campaign
 Glove sampling-left to the users discretion
 Note differences to EU GMP for continuous
monitoring.
Pharmaceutical Microbiology:
http://www.pharmamicroresources.com
Frequencies of sampling
 RABS
 Open RABS and closed RABS are different regarding
contamination risk.
 Open RABS is more similar to a conventional clean
room.
 Closed RABs are advanced aseptic processing systems.
Pharmaceutical Microbiology:
http://www.pharmamicroresources.com
Frequencies of sampling
 Cleanrooms
 Unchanged from the previous version of <1116>
appearing in PF31(2).
 ISO class 5 = Each operating shift
 ISO class 7 = Each operating shift
 ISO class 8 = Twice per week
 Other areas = Once per week
Pharmaceutical Microbiology:
http://www.pharmamicroresources.com
Sampling locations
 ISO 14644 grid approach for particles discussed, but
dismissed
 “Microbiological sampling sites are best selected with
consideration of human activity during manufacturing
operations.”
 From careful observation and mapping of the clean
room
 The most likely route of contamination is airborne
Pharmaceutical Microbiology:
http://www.pharmamicroresources.com
Other changes / main features
 Strong emphasis upon staff training, including those
who take microbiological samples
 Need for a qualified site microbiologist
 Staff health checks and control of entry to critical
areas
 Importance of correct gowning
 Importance of risk assessment and risk mitigation
Pharmaceutical Microbiology:
http://www.pharmamicroresources.com
Other changes / main features
 USP is strongly supportive of the use of “RMMs” in
Environmental Monitoring and all forms of
microbiological analysis.
 All references to validation have been removed from
the chapter.
Pharmaceutical Microbiology:
http://www.pharmamicroresources.com
Regulatory differences
 Results:
 EU GMP Annex 1 discusses averaging of micro data.
 FDA mandates response to individual excursions.
 USP focuses on incident rates.
 Disinfection residues
 FDA and EU GMP suggest microbial resistance to sanitizers is
possible.
 USP does not cover this.
 Media fills.
 All guidances use the same media fill criteria.
 USP provides no details for large fills.
Pharmaceutical Microbiology:
http://www.pharmamicroresources.com
Future developments
 Development of a chapter on Microbiological Control
& Monitoring of Non-Aseptic Processing
Environments <1111> has been discussed by USP MSA
 Problems:
 Operations vary much more widely than in aseptic
processing.
 No widely accepted standards for the various facility
designs.
 Significant differences in approach for the same product
types.
 A clear path?
Pharmaceutical Microbiology:
http://www.pharmamicroresources.com
Summary
 The challenge in aseptic processing is always
personnel: as a source of microbial and particle
contamination.
 Environmental monitoring continues to be especially
contentious.
 The contamination rate concept is a significant
departure from the alert and action level system that
has been used in industry since the early 1980’s.
Pharmaceutical Microbiology:
http://www.pharmamicroresources.com
Pharmaceutical Microbiology:
http://www.pharmamicroresources.com
Pharmaceutical Microbiology:
http://www.pharmamicroresources.com

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USP &lt;1116> and its impact on Microbiology

  • 1. Dr. Tim Sandle Pharmaceutical Microbiology: http://www.pharmamicroresources.com
  • 2. Introduction  EM guidance  Background to USP <1116>  Main changes and debates  Method limitations  Incident rates  Frequencies of monitoring  Locations of monitoring  Other changes  Regulatory issues  Rapid methods Pharmaceutical Microbiology: http://www.pharmamicroresources.com
  • 3. Sources of EM Guidance  EU GMP - last EM revision 2009; new annex 1 2016?  FDA aseptic filling guide (2004)  PDA Technical Report (2014, 3rd revision)  ISO 14698 (1998). Future update?  USP <1116> (2011, published 2012)  Pharmig Current Review (2010)  PHSS Biocontamination control guide 2015 Pharmaceutical Microbiology: http://www.pharmamicroresources.com
  • 4. Sources of EM Guidance  ISO 14698  Under long-term review  Possible development to a viable cleanroom classification standard (like ISO 14644)  No other standard is likely to be reviewed in the short- term Pharmaceutical Microbiology: http://www.pharmamicroresources.com
  • 5. ISO 14644  ISO 14644 Parts 1 and 2 revised in December 2015  A standard for cleanroom classification.  Some detail about on-going monitoring.  Does not cover viable monitoring at all.  Changes:  New look-up tables  Increase in counter locations  Changes to sampling volumes  Each individual location must pass.  More risk based. Pharmaceutical Microbiology: http://www.pharmamicroresources.com
  • 6. USP <1116> (2012)  USP <1116>  Revision began in 2005  Objectives of USP committee:  Focus the chapter on environmental monitoring only, removing information relating to aseptic process validation.  Focus the document exclusively on the monitoring of aseptic environments.  Reconsider the alert and action level (limit) concept.  Effective 1st May 2012, 35th edition of the USP Pharmaceutical Microbiology: http://www.pharmamicroresources.com
  • 7. Main changes  Former title: “Microbial Control and Monitoring Environments Used for the Manufacture of Healthcare Products”  Revised title: “Microbiological control and monitoring of aseptic processing environments” Pharmaceutical Microbiology: http://www.pharmamicroresources.com
  • 8. Main changes  Scope:  Pharmaceutical sterile products  Bulk sterile drug substances  Sterile intermediates  Excipients  Environments  Conventional clearoom with UDAF  Blow-fill-seal  RABS  Isolator Pharmaceutical Microbiology: http://www.pharmamicroresources.com
  • 9. Main changes  The emphasis on the word “aseptic” in the introduction implies that the chapter is not applicable to all “sterile” products.  This means that terminally sterilised products are outside the scope of the chapter. Pharmaceutical Microbiology: http://www.pharmamicroresources.com
  • 10. Main changes  By “aseptic” a low level of contamination is acknowledged: “an expectation of zero contamination at all locations during every aseptic processing operation is technically not possible and thus is unrealistic” Pharmaceutical Microbiology: http://www.pharmamicroresources.com
  • 11. Main changes  USP notation system dropped: M3.5 etc. And old FDA 209E classes e.g. Class 100, Class 10,000)  Replaced by ISO 14644 classes in the operational state  Difference with EU GMP:  Class 5 = EU GMP Grade A  Class 7 = EU GMP Grade B  Class 8 = EU GMP Grade C Pharmaceutical Microbiology: http://www.pharmamicroresources.com
  • 12. Main Changes  Relative risks Picture showing on how process separation and product protection interact (adopted from Bioquell U.K Ltd). Pharmaceutical Microbiology: http://www.pharmamicroresources.com
  • 13. Main changes  The design and construction of clean rooms and controlled environments are covered in ISO 14644.  ISO 14644 stipulates the total particulate counts required for a clean environment to meet the defined air quality classifications. USP accepts this standard verbatim. Pharmaceutical Microbiology: http://www.pharmamicroresources.com
  • 14. Main Changes  New guidance for cleanroom operations:  ISO class 8 = 20 air changes per hours  ISO class 7 = 50 air changes per hour  ISO class 5 = 100 air changes per hour  Isolators = can have a different justification for air changes and air velocity  An EM programme should only be constructed and executed once airflow mapping and HVAC dynamics have been optimised. Pharmaceutical Microbiology: http://www.pharmamicroresources.com
  • 15. Environmental monitoring  USP places emphasis upon particle and viable monitoring  Particle counting most important for isolators  Viable monitoring is regarded as semi-quantitative  Trending is the most important aspect of the monitoring programme  Isolated counts “a normal phenomenon in conventional cleanrooms” which do not require specific corrective action and there is the possibility of a false positive Pharmaceutical Microbiology: http://www.pharmamicroresources.com
  • 16. Environmental monitoring  USP requires monitoring of:  Surfaces  Air (room and enclosure)  Compressed gas  Changes in trend must be investigated, and include assessment of:  Maintenance  Disinfection  Unusual events and activities  Physical changes e.g. temperature and humidity  Staff training Pharmaceutical Microbiology: http://www.pharmamicroresources.com
  • 17. Environmental monitoring  SCDM (TSA) is a suitable medium, incubation at ‘low’ and ‘high’ temperatures (20-35oC for not less than 72 hours)  Consideration given to fungal medium e.g. SDA  Certain conditions may require micro-aerophilic monitoring e.g., certain gasses or sterility test failure using anaerobic media Pharmaceutical Microbiology: http://www.pharmamicroresources.com
  • 18. Methods  Settle plates:  EU GMP:  Semi-quantitative measurement (CFU / 4hours)  Require desiccation study.  USP 1116:“The exposure of open agar-filled Petri dishes, or settling plates, is not to be used for quantitative estimations of the microbial contamination levels of critical environments.” Pharmaceutical Microbiology: http://www.pharmamicroresources.com
  • 19. Monitoring methods  No EM programme can prove sterility  Environmental control is the most important, supported by EM and media simulations  EM can demonstrate that a clean room is operating with in a consistent state of control  However, “EM” requirements have evolved in a manner that did not fully consider analytical capability and metrology Pharmaceutical Microbiology: http://www.pharmamicroresources.com
  • 20. Monitoring methods  All monitoring methods are flawed:  Require people to take them  Variability in technique  Risk of false positives  No one method can detect all types of contamination  All methods have relatively poor recoveries (“insensitive”)  Air-samples are particularly weak  Surface methods have poor recoveries  Settle plates are not considered quantitative  All methods are poor at recovering damaged or stressed microorganisms Pharmaceutical Microbiology: http://www.pharmamicroresources.com
  • 21. Monitoring methods  Therefore, numerical targets (as CFU) should:  Not be used as limits (they are “levels”)  Not be considered specifications  Be seen as informational only  Low or zero counts are not, by themselves, guarantees for microbial control;  Equally, excursions beyond numerical limits are not necessarily and indication of loss of control.  Instead:  Count non-zero events.  Use a contamination recovery rate metric based on historical findings  Inference that these should be stable over time with little variation. Pharmaceutical Microbiology: http://www.pharmamicroresources.com
  • 22. Plate counting debate  DEBATE  Should not simply count CFU due to the inaccuracies of current environmental monitoring methods  It is more important to count the incidence rates and investigate out of trend.  The limit of quantitation (the number of cfu that can be reported accurately) is 15.  If CFU below 15 cfu , do not worry if trend is OK.  If above 15 cfu, investigate. Pharmaceutical Microbiology: http://www.pharmamicroresources.com
  • 23. What does this mean?  At very low recovery levels there is no way to establish Alert or Action Levels statistically-the counts are simply too low to make statistical analysis useful.  Instead, emphasis should be on incidents.  “Hits” in ISO 5 aseptic environments should be infrequent. Pharmaceutical Microbiology: http://www.pharmamicroresources.com
  • 24. What was the pre-USP 2012 situation?  Take active air-samples:  Microbiological cleanliness levels ‘In Operation’ cfu/m3 Area EU GMP FDA Guide USP Aseptic core <1 <1 <3 Support for aseptic filling <10 <10 <20 Controlled process area <100 <100 <100 Controlled support area <200 Not specified Not specified Pharmaceutical Microbiology: http://www.pharmamicroresources.com
  • 25. USP contamination rates Class Active air sample Settle plate Contact plate Swab Isolator or Closed RABS (ISO 5 or better) <0.1% <0.1% <0.1% <0.1% ISO 5 <1% <1% <1% <1% ISO 6 <3% <3% <3% <3% ISO 7 <5% <5% <5% <5% ISO 8 <10% <10% <10% <10% Pharmaceutical Microbiology: http://www.pharmamicroresources.com
  • 26. USP contamination rates  NOTE: Contamination recovery rates should be based upon actual monitoring data and should be re- tabulated monthly.  When contamination recovery rates are observed that exceed the recommendations in the table or are greater than established process capability corrective actions should be taken. Pharmaceutical Microbiology: http://www.pharmamicroresources.com
  • 27. USP contamination rates  For example  Grade B cleanroom  Active air-sampling  One year of data reviewed Pharmaceutical Microbiology: http://www.pharmamicroresources.com
  • 28. USP contamination rates 0.00% 20.00% 40.00% 60.00% 80.00% 100.00% 120.00% 0 200 400 600 800 1000 1200 1400 Frequency Bin Grade B routine active air (April 2010 - April 2011) Histogram Frequenc y Cumulati ve % Count (cfu) Frequency Cumulative percentage 0 1240 80.78% 1 191 93.22% 2 52 96.61% 3 20 97.92% 4 8 98.44% 5 7 98.89% 6 2 99.02% 7 3 99.22% 8 2 99.35% 9 1 99.41% 10 0 99.41% Pharmaceutical Microbiology: http://www.pharmamicroresources.com
  • 29. USP contamination rates 0 5 10 15 20 25 30 35 1 105 209 313 417 521 625 729 833 937 1041 1145 1249 1353 1457 Count(cfupercubicmetre) No. samples / time Grade B AFS routine active air (April 2010 - April 2011) Active air counts (cfu) Pharmaceutical Microbiology: http://www.pharmamicroresources.com
  • 30. USP contamination rates  Corrective actions may include but are not limited to:  Sanitization program including types of disinfectants, application methods, and frequencies.  Personnel practices by supervisory staff.  Microbiological sampling methods and techniques.  Training on gowning practices. Pharmaceutical Microbiology: http://www.pharmamicroresources.com
  • 31. Frequencies of sampling  Isolators  Active Air Sampling-once/day  Surface sampling-at end of each campaign  Glove sampling-left to the users discretion  Note differences to EU GMP for continuous monitoring. Pharmaceutical Microbiology: http://www.pharmamicroresources.com
  • 32. Frequencies of sampling  RABS  Open RABS and closed RABS are different regarding contamination risk.  Open RABS is more similar to a conventional clean room.  Closed RABs are advanced aseptic processing systems. Pharmaceutical Microbiology: http://www.pharmamicroresources.com
  • 33. Frequencies of sampling  Cleanrooms  Unchanged from the previous version of <1116> appearing in PF31(2).  ISO class 5 = Each operating shift  ISO class 7 = Each operating shift  ISO class 8 = Twice per week  Other areas = Once per week Pharmaceutical Microbiology: http://www.pharmamicroresources.com
  • 34. Sampling locations  ISO 14644 grid approach for particles discussed, but dismissed  “Microbiological sampling sites are best selected with consideration of human activity during manufacturing operations.”  From careful observation and mapping of the clean room  The most likely route of contamination is airborne Pharmaceutical Microbiology: http://www.pharmamicroresources.com
  • 35. Other changes / main features  Strong emphasis upon staff training, including those who take microbiological samples  Need for a qualified site microbiologist  Staff health checks and control of entry to critical areas  Importance of correct gowning  Importance of risk assessment and risk mitigation Pharmaceutical Microbiology: http://www.pharmamicroresources.com
  • 36. Other changes / main features  USP is strongly supportive of the use of “RMMs” in Environmental Monitoring and all forms of microbiological analysis.  All references to validation have been removed from the chapter. Pharmaceutical Microbiology: http://www.pharmamicroresources.com
  • 37. Regulatory differences  Results:  EU GMP Annex 1 discusses averaging of micro data.  FDA mandates response to individual excursions.  USP focuses on incident rates.  Disinfection residues  FDA and EU GMP suggest microbial resistance to sanitizers is possible.  USP does not cover this.  Media fills.  All guidances use the same media fill criteria.  USP provides no details for large fills. Pharmaceutical Microbiology: http://www.pharmamicroresources.com
  • 38. Future developments  Development of a chapter on Microbiological Control & Monitoring of Non-Aseptic Processing Environments <1111> has been discussed by USP MSA  Problems:  Operations vary much more widely than in aseptic processing.  No widely accepted standards for the various facility designs.  Significant differences in approach for the same product types.  A clear path? Pharmaceutical Microbiology: http://www.pharmamicroresources.com
  • 39. Summary  The challenge in aseptic processing is always personnel: as a source of microbial and particle contamination.  Environmental monitoring continues to be especially contentious.  The contamination rate concept is a significant departure from the alert and action level system that has been used in industry since the early 1980’s. Pharmaceutical Microbiology: http://www.pharmamicroresources.com