usp1116presmar2016-160306010258.pptx

Dr. Tim Sandle
Pharmaceutical Microbiology:
http://www.pharmamicroresources.com

Introduction
 EM guidance
 Background to USP <1116>
 Main changes anddebates
 Method limitations
 Incident rates
 Frequencies of monitoring
 Locations of monitoring
 Otherchanges
 Regulatory issues
 Rapid methods

Sources of EM Guidance
 EU GMP - last EM revision 2009; new annex 12016?
 FDA aseptic filling guide(2004)
 PDA Technical Report (2014, 3rd revision)
 ISO 14698 (1998). Futureupdate?
 USP <1116> (2011, published 2012)
 Pharmig Current Review (2010)
 PHSS Biocontamination control guide2015

Sources of EM Guidance
 ISO 14698
 Under long-term review
 Possible development toaviablecleanroom
classification standard (like ISO 14644)
 Nootherstandard is likely to be reviewed in the short-
term

ISO 14644
 ISO 14644 Parts 1 and 2 revised in December2015
 A standard for cleanroomclassification.
 Some detail about on-goingmonitoring.
 Does notcoverviable monitoring atall.
 Changes:
 New look-uptables
 Increase in counterlocations
 Changes to samplingvolumes
 Each individual location mustpass.
 More risk based.

USP <1116> (2012)
 USP <1116>
 Revision began in 2005
 Objectives of USP committee:
 Focus thechapteron environmental monitoring only,
removing information relating to aseptic processvalidation.
 Focus thedocumentexclusivelyon the monitoring of aseptic
environments.
 Reconsiderthealertand action level (limit) concept.
 Effective 1st May 2012, 35th edition of the USP

Main changes
 Formertitle:
“Microbial Control and Monitoring Environments
Used for the Manufacture of HealthcareProducts”
 Revised title:
“Microbiological control and monitoring ofaseptic
processing environments”

Main changes
 Scope:
 Pharmaceutical sterileproducts
 Bulk sterile drugsubstances
 Sterile intermediates
 Excipients
 Environments
 Conventional clearoom with UDAF
 Blow-fill-seal
 RABS
 Isolator

Main changes
 The emphasis on the word “aseptic” in the
introduction implies that thechapter is notapplicable
to all “sterile” products.
 This means that terminally sterilised productsare
outside the scope of thechapter.

Main changes
 By “aseptic” a low level of contaminationis
acknowledged:
“an expectation of zero contamination at all locations
during every aseptic processing operation is technically
not possible and thus isunrealistic”

Main changes
 USP notationsystem dropped: M3.5 etc. And old FDA
209E classes e.g. Class 100, Class10,000)
 Replaced by ISO 14644 classes in the operationalstate
 Difference with EU GMP:
 Class 5 = EU GMP Grade A
 Class 7 = EU GMP Grade B
 Class 8 = EU GMP Grade C

Main Changes
 Relativerisks
Picture showing on how process separationand product
protection interact (adopted from Bioquell U.K Ltd).

Main changes
 The design and construction of clean rooms and
controlled environments are covered in ISO14644.
 ISO 14644 stipulates the total particulate counts
required fora clean environment to meet thedefined
air quality classifications. USP accepts this standard
verbatim.

Main Changes
 Newguidance forcleanroom operations:
 ISO class 8 = 20 air changes perhours
 ISO class 7 = 50 air changes perhour
 ISO class 5 = 100 air changes perhour
 Isolators = can have adifferent
justification for airchanges
and air velocity
 An EM programme should only be constructed and
executed once airflow mapping andHVACdynamics
have beenoptimised.

Environmental monitoring
 USP placesemphasis upon particleand viable
monitoring
 Particle counting most important forisolators
 Viable monitoring is regarded assemi-quantitative
 Trending is the most importantaspect of the monitoring
programme
 Isolated counts “a normal phenomenon in conventional
cleanrooms” which do not requirespecific correctiveaction
and there is thepossibilityof a false positive

 USP requires monitoringof:
 Surfaces
 Air (room andenclosure)
 Compressed gas
 Changes in trend must be investigated, andinclude
assessment of:
 Maintenance
 Disinfection
 Unusual events andactivities
 Physical changes e.g. temperature andhumidity
 Staff training

 SCDM (TSA) is a suitable medium, incubationat ‘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 orsterility test failure
using anaerobic media

Methods
 Settle plates:
 EU GMP:
 Semi-quantitative measurement (CFU / 4hours)
 Require desiccationstudy.
 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.”

Monitoring methods
 No EM programme can provesterility
 Environmental control is the mostimportant,
supported by EM and mediasimulations
 EM can demonstrate thataclean room is operating
with in a consistentstateof control
 However, “EM” requirements have evolved in amanner
that did not fully consider analytical capability and
metrology

Monitoring methods
 All monitoring methods areflawed:
 Require people to takethem
 Variability in technique
 Risk of falsepositives
 Noone method can detect all typesof contamination
 All methods have relatively poorrecoveries
(“insensitive”)
 Air-samples are particularlyweak
 Surface methods have poorrecoveries
 Settle plates are notconsidered quantitative
 All methodsare poorat recovering damaged orstressed
microorganisms

Monitoring methods
 Therefore, numerical targets (as CFU) should:
 Not be used as limits (theyare “levels”)
 Not be consideredspecifications
 Be seen as informationalonly
 Low or zerocounts are not, by themselves, guarantees for microbial
control;
 Equally, excursions beyond numerical limits are not necessarilyand
indication of loss of control.
 Instead:
 Count non-zeroevents.
 Use a contamination recovery rate metric based on historical
findings
 Inference that theseshould be stableovertimewith little
variation.

Plate counting debate
 DEBATE
 Should not simplycount CFU due to the inaccuracies of
current environmental monitoring methods
 It is more important tocount the incidence ratesand
investigate out of trend.
 The limitof quantitation (the numberof cfu thatcan be
reported accurately) is 15.
 If CFU below 15 cfu , do not worry if trend isOK.
 If above 15 cfu, investigate.

What does this mean?
 Atvery low recovery levels there is noway toestablish
Alert or Action Levels statistically-the counts are
simply too low to make statistical analysis useful.
 Instead, emphasis should be onincidents.
 “Hits” in ISO 5 aseptic environments shouldbe
infrequent.

What was the pre-USP 2012
situation?
 Takeactiveair-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
processarea
<100 <100 <100
Controlled
supportarea
<200 Not specified Not specified

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%

 NOTE: Contamination recovery rates should bebased
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 betaken.

 Forexample
 Grade B cleanroom
 Activeair-sampling
 One year of datareviewed

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%

0
5
10
15
20
35
30
25
1
Count
(cfu
per
cubic
metre)
105 209 313 417 521 625 729 833 937 1041 1145 1249 1353 1457
No. samples / time
Grade B AFS routine active air (April 2010 - April 2011)
Active air counts
(cfu)

 Correctiveactions may include butare not limited to:
 Sanitization program including types ofdisinfectants,
application methods, and frequencies.
 Personnel practices by supervisorystaff.
 Microbiological sampling methods and techniques.
 Training on gowning practices.

Frequencies of sampling
 Isolators
 Active AirSampling-once/day
 Surface sampling-at end of eachcampaign
 Glove sampling-left to the usersdiscretion
 Note differences to EU GMP forcontinuous
monitoring.

 RABS
 Open RABS and closed RABS are differentregarding
contamination risk.
 Open RABS is more similartoaconventional clean
room.
 Closed RABs are advanced aseptic processingsystems.

 Cleanrooms
 Unchanged from the previous version of<1116>
appearing in PF31(2).
 ISO class 5 = Each operatingshift
 ISO class 7 = Each operatingshift
 ISO class 8 = Twice per week
 Other areas = Once per week

Sampling locations
 ISO 14644 grid approach forparticlesdiscussed, but
dismissed
 “Microbiological sampling sites are best selected with
consideration of human activity duringmanufacturing
operations.”
 From careful observation and mapping of theclean
room
 The most likely route of contamination isairborne

Other changes / main features
 Strong emphasis upon staff training, includingthose
who take microbiologicalsamples
 Need for a qualified sitemicrobiologist
 Staff health checksand control of entry tocritical
areas
 Importance of correctgowning
 Importance of risk assessmentand risk mitigation

Other changes / main features
 USP is stronglysupportiveof the useof “RMMs” in
Environmental Monitoring and all forms of
microbiological analysis.
 All references tovalidation have been removed from
thechapter.

Regulatory differences
 Results:
 EU GMP Annex 1 discusses averaging of microdata.
 FDA mandates response to individualexcursions.
 USP focuses on incidentrates.
 Disinfection residues
 FDA and EU GMP suggest microbial resistance tosanitizers is
possible.
 USP does not coverthis.
 Media fills.
 All guidances use the same media fill criteria.
 USP provides no details forlarge fills.

Future developments
 Development of a chapteron Microbiological Control
& Monitoring of Non-Aseptic Processing
Environments <1111> has been discussed by USPMSA
 Problems:
 Operationsvary much more widely than in aseptic
processing.
 Nowidelyaccepted standards forthevarious facility
designs.
 Significantdifferences in approach forthe same product
types.
 A clearpath?

Summary
 The challenge in aseptic processing is always
personnel: as a sourceof microbial and particle
contamination.
 Environmental monitoring continues to beespecially
contentious.
 The contamination rate concept is a significant
departure from thealertand action level system that
has been used in industrysince theearly 1980’s.

usp1116presmar2016-160306010258.pptx

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