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Page 1

AUDITING ENVIRONMENTAL MONITORING

PROGAMS
A QA Manager Perspective!
Presented By:
Matthew Bugg, MSc Pharmaceutical Technology & Quality
Assurance

Slide 1 of
23

Page 2

TOPICS COVERED!
 ○ PIC/S
Code of GMP Annex 1 Microbiological Limits,
What Do They Actually Mean?

○ Auditing Environmental Monitoring Programs

Matthew Bugg, MSc Pharmaceutical Technology & Quality Assurance – Slide 2 of 23

Page 3

UNDERSTANDING THE LIMITS

PIC/S Code of GMP, Annex 1 - EM Limits

Matthew Bugg, MSc Pharmaceutical Technology & Quality Assurance – Slide 3 of 23

Page 4
UNDERSTANDING ENVIRONMENTAL
MONITORING LIMITS!

When is it the right

time to implement
CAPA?

○ Alert Limit or Action

Limit?

○ Presence of new
microorganisms?

○ Type of microorganism
identified?

Matthew Bugg, MSc Pharmaceutical Technology & Quality Assurance – Slide 4 of 23

Page 5

SOURCES OF CONTAMINATION!
○ 2The biggest source of contamination in
clean rooms is people! 80%

○ 1The average adult can shed up to 3kg of

skin particles on average per year.

○ 1The outer layer of human skin can host up

to 1 x 106 microorganisms per square
centimetre.
 1Other sources include but not limited to:
○

Room Surfaces
Room Air
Water (Where Applicable)
Equipment

Matthew Bugg, MSc Pharmaceutical Technology & Quality Assurance – Slide 5 of 23

Page 6
ESTABLISH YOUR CLEANROOM MICROFLORA
PROFILE!

1 Common Species of Gram

Positive Bacteria Found In Question?
Cleanrooms!

○ Micrococcus spp. ○ When detecting EM

○ Staphylococcus spp. microorganisms do you

actually have a compliance
○ Corynebacterium spp.
problem?
○ Bacillus spp.

○ Aspergillus spp
Or
○ Penicillin spp.
○ Are you seeing what you
expect to see?

Matthew Bugg, MSc Pharmaceutical Technology & Quality Assurance – Slide 6 of 23

Page 7
WEEK 1 – EM NON-CONFORMANCE DETECTION CASE STUDY
TRANSFER HATCHES
( Aseptic
WASTE
ISOLATOR 1 Compounding
DESKSPACE CHANGE
ROOM – CIVAS ROOM
Facility
WORKBENCH

ISOLATOR
GRADE (D) – GRADE (C)
Contamination)
S
SHELVING

ISOLATOR 5 ISOLATOR 2 ISOLATOR 3 Week-1 EM Settle

 PARENTERAL NUTRITION ROOM –
Plate Results
GRADE (C)
CYTOTOXIC
ROOM –
Low levels of fungi
GRADE (C)
microorganisms

ISOLATOR 6 ISOLATOR 4 detected on EM TSA

settle plates, still
PREPARATION
ROOM – GRADE (D)
within PIC/S Code
GMP Annex 1 Settle
Plate Grade-D
Cleanroom Limits
LABEL ROOM –
UNCLASSIFIED

Matthew Bugg, MSc Pharmaceutical Technology & Quality Assurance – Slide 7 of 23

Page 8
WEEK 2 – EM NON-CONFORMANCE DETECTION CASE STUDY
TRANSFER HATCHES
( Aseptic
WASTE
ISOLATOR 1 Compounding
DESKSPACE CHANGE
ROOM – CIVAS ROOM
Facility
WORKBENCH

ISOLATOR
GRADE (D) – GRADE (C)
Contamination)
S
SHELVING

ISOLATOR 5 ISOLATOR 2 ISOLATOR 3

Week-2 EM Settle
PARENTERAL NUTRITION ROOM –
Plate Results
GRADE (C)
CYTOTOXIC
ROOM – Low levels of fungi
GRADE (C)

microorganisms
ISOLATOR 4
ISOLATOR 6
detected on EM TSA
settle plates, now
PREPARATION
ROOM – GRADE (D)
spread to TPN &
CIVAS Cleanrooms.

LABEL ROOM –
UNCLASSIFIED

Matthew Bugg, MSc Pharmaceutical Technology & Quality Assurance – Slide 8 of 23

Page 9
WEEK 3 – EM NON-CONFORMANCE DETECTION CASE STUDY
TRANSFER HATCHES
( Aseptic
WASTE ISOLATOR 1 Compounding
DESKSPACE CHANGE
ROOM – CIVAS ROOM
Facility
WORKBENCH

ISOLATOR
GRADE (D) – GRADE (C)
Contamination)
S
SHELVING

ISOLATOR 5 ISOLATOR 2 ISOLATOR 3

Week-3 EM Settle
PARENTERAL NUTRITION ROOM –
Plate Results
GRADE (C)
CYTOTOXIC
ROOM –
Low levels of EM fungi
GRADE (C)
microorganisms
detected on TSA settle
ISOLATOR 6 ISOLATOR 4

plates, now spread

into CYTOTOXIC
PREPARATION
ROOM – GRADE (D) Cleanroom.

EM Non-Conformance
detected in Isolator 3,
1 CFU on settle plate.
LABEL ROOM –
UNCLASSIFIED

Matthew Bugg, MSc Pharmaceutical Technology & Quality Assurance – Slide 9 of 23

Page 10
CAUSE OF CONTAMINATION IDENTIFIED AS CLADOSPORIUM Characteristics

SOURCE: DEMOLITION OF BUILDING LOCATED NEXT DOOR TO ➢Most commonly

THE ASEPTIC COMPOUNDING FACILITY! identified outdoor fungus.
Often found indoors in
numbers less than
outdoor numbers.

➢It is commonly found on

the surface of fibreglass
duct liners in the interior
of supply ducts.

➢A wide variety of plants

are food sources for this
fungus.
 ➢Itis found on dead
plants, woody plants,
food, straw, soil, paint,
and textiles. Produces
greater than 10 antigens.

Matthew Bugg, MSc Pharmaceutical Technology & Quality Assurance – Slide 10 of 23

Page 11

AUDITING ENVIRONMENTAL
MONITORING PROGRAMS

Matthew Bugg, MSc Pharmaceutical Technology & Quality Assurance – Slide 11 of 23

Page 12

PIC/S CODE OF GMP, ANNEX 1

MANUFACTURE OF STERILE MEDICINAL PRODUCTS
 Sole reliance for sterility or
other quality aspects must not
be placed on any terminal
process or finished product test!

Matthew Bugg, MSc Pharmaceutical Technology & Quality Assurance – Slide 12 of 23

Page 13

OOS GUIDANCE DOCUMENTS!

○ US FDA Guidance for Industry Investigating Out-

Of-Specification (OOS) Test Results for
Pharmaceutical Production, October 2006.

5What is new?

○ MHRA Out of Specification Investigations, 2013 Out Of Specification

Investigations.

○ Updated to complement the US FDA guidance

document and to include expectations for
managing Microbiological non-conformances!
Link: MHRA OOS Guidance Document

Matthew Bugg, MSc Pharmaceutical Technology & Quality Assurance – Slide 13 of 23

Page 14

5MHRA

KEY CONSIDERATIONS!
○ All potential sources of contamination need to be considered –
process flow the issue from sample storage to the test environment.

○ Due to the variability of microbiological results don’t limit the

investigation to the specific batch it should be broader to review
historical results and trends.

○ The laboratory and manufacturing investigations need to be in

depth.

○ Are the organisms of an expected type, determine likely source –

would it be likely to be found where it was?

○ Evaluate area/environmental trends for test area and support

areas.

Matthew Bugg, MSc Pharmaceutical Technology & Quality Assurance – Slide 14 of 23

Page 15

STRUCTURE EM INVESTIGATIONS!
3 ISHIKAWA DIAGRAM !

EQUIPMENT PROCESS/METHODS PEOPLE

!

! TRAINING
HVAC/AHU CLEANING
.! PROTOCOL

!
SAMPLING TOOLS .! PROCESS
MANUFACTURING GMP COMPLIANCE
.!
! PROBLEM
MANUFACTURING EQUIPMENT SAMPLING METHOD HYGIENE/SICKNESS REPORTING

! OR
.!
STARTING MATERIALS RESOURCES
.! AIR CHANGE
.! RATES
EFFECT
!
PACKAGING MATERIALS CAPACITY PRESSURE CASCADES
!
SAMPLING MEDIA FUNDING TEMP/HUMIDITY CONTROLS
!
 ! MATERIALS MANAGEMENT ENVIRONMENT

KEEP A TIMELINE OF EVENTS!

Matthew Bugg, MSc Pharmaceutical Technology & Quality Assurance – Slide 15 of 23

Page 16

HOW ALIGNED ARE YOUR QMS SYSTEMS?

! RFS

CAPACITY

SUPPLIER APPROVAL EM TRENDS CAPA

STABILITY
PPM CHANGE DATA
CONTROL

PRODUCT
STAFF DEVIATION
COMPLAINTS
TRAINING

OOS OOT
BATCH PQR
DOCUMENTATION
REVIEW

QMS MAZE

QUALITY MANAGER

ENTER AT YOUR OWN

RISK!

Matthew Bugg, MSc Pharmaceutical Technology & Quality Assurance – Slide 16 of 23

Page 17
QMS ALIGNMENT FOR EM NON-CONFORMANCE!

What has gone wrong? What has changed?

CHANGE
DEVIATION OOS CAPA
CONTROL
 LOCATION GROUP TRENDING LOCATION

SETTLE CONTACT AIR

PRODUCT PROCESS PEOPLE
PLATE PLATE SAMPLE

PQR RFS

Matthew Bugg, MSc Pharmaceutical Technology & Quality Assurance – Slide 17 of 23

Page 18

EM MONITORING
TOOLS!

Viable Monitoring Non-Viable Monitoring

○ Continuous Particle
○ Settle Plates
Monitoring
○ Contact plates

○ Forced Air Sampling

EM Indicators!
○ Media Types (TSA and/or ○ EM Indicators
SDA) Temperature controls

○ Exposure Time! Humidity Controls

Pressure Differentials

Matthew Bugg, MSc Pharmaceutical Technology & Quality Assurance – Slide 18 of 23

Page 19

EM MICRO TRENDS

Systematic Indicators Unsystematic Indicators

○ Seasonal
Variation –
○ Correlation – Specific Work
days? Summer/Winter?

○ Correlation – Between
○ Correlation with throughput
Bacteria and Fungal levels of
(capacity – workload/people)
detection?
○ Correlation with cleaning
agents?
○ Links to contractors i.e.
cleaning/maintenance
personal

○ Links to PPM
○ HVAC/AHU Performance

Matthew Bugg, MSc Pharmaceutical Technology & Quality Assurance – Slide 19 of 23

Page 20

EM TRENDING EXAMPLE!
EXAMPLE ONLY - RESULTS NOT PRODUCED ON REAL-TIME
DATA GRADE-D CHANGE ROOM
EM TSA CONTACT PLATE RESULTS TSA CP RESULTS
GRADE-D GRADE-C GRADE-C GRADE-A (DAILY TRENDING)
DATE CHANGE MIX ROOM FILLING ASEPTIC DAY EXAMPLE DATA ONLY
ROOM (L1) (L3) ROOM (L4) FILL(L1)

29/02/2016 37 12 2 0 MON
90

01/03/2016 23 5 0 0 TUE

02/03/2016 15 2 0 0 WED
80

03/03/2016 25 6 0 0 THU
70
04/03/2016 33 11 1 N/S FRI

07/03/2016 52 18 2 0 MON
60
08/03/2016 14 1 0 0 TUE

09/03/2016 23 4 0 0 WED
50
10/03/2016 37 13 2 0 THU
11/03/2016 45 16 2 0 FRI
40
14/03/2016 77 28 0 0 MON

15/03/2016 57 21 2 0 TUE
30
16/03/2016 36 12 2 0 WED
 17/03/2016 14 2 0 0 THU 20
18/03/2016 8 0 0 0 FRI

21/03/2016 23 3 0 N/S MON

10
22/03/2016 17 1 0 0 TUE

23/03/2016 15 1 0 0 WED 0
E I E D I E I E I
24/03/2016 10 0 0 0 THU N D N N D N D
U E HU R
F U E HU R
F U E HU R
F U E HU R
F
25/03/2016 8 0 0 0 FRI MO T W T MO T W T MO T W T MO T W T
LIMITS CFU
ACTION LIMITS <50 <25 <25 <1
GRADE-D CHANGE ROOM (L1)

ALERT LIMITS <25 <12 <12 N/A ACTION LIMITS

ALERT LIMITS
(L) = SAMPLE POINT LOCATION
NO GROWTH: 0
N/S = NOT SAMPLED
Matthew Bugg, MSc Pharmaceutical Technology & Quality Assurance – Slide 20 of 23

Page 21

EM NON-CONFORMANCE MANAGMENT

Do! Don’t!

○ ensure you have historical EM ○ have gaps in your EM Data! If so

results trended and up to date, raise deviation!
previous 3 weeks essential!

○ make assumptions – the devil is

○ have a structured approach to EM
only and always in the detail!
non-conformance investigations!

○ ensure good working relationships ○ assume because when you

between Quality, Manufacturing assume you make an ASS/U/ME!
and Supply Chain!

○ have a culture of everything being

○ communicate routine EM results to
on a need to know basis!
the staff working in the area.
Transparency improves EM results!

○ invest in STAFF CONTINUOUS ○ underestimate the importance of

GMP TRAINING! allowing time for staff GMP
training!
Matthew Bugg, MSc Pharmaceutical Technology & Quality Assurance – Slide 21 of 23

Page 22

REFERENCES
1. Dr Tim Sandle, A Rreview of Cleanroom Microflora: Types, Trends and
Patterns, PDA Journal Pharm Sci and Tech 2011, 65 392-403
 2. Hall, G. S.; Mackintosh, C. A.; Hoffman, P. N. The dispersal of bacteria and
skin scales from the body after showering and after application of a skin

lotion. Journal of Hygiene 1986, 97 (2), 289–298.

3. ICH Q9 Quality Risk Management

4. ISO 14644-4 Design, Construction and Start UP

5. MHRA, Out Of Specifications Investigations, 2013

6. PIC/S Code of GMP, Annex 1 Manufacture of Sterile Medicinal Products.

7. PIC/S Code of GMP, Annex 2 Manufacture of Biological Medicinal Products

for Human Use.

8. PIC/S Code of GMP, Annex 9 Manufacture of Liquids, Creams and

Ointments
Matthew Bugg, MSc Pharmaceutical Technology & Quality Assurance – Slide 23 of 23

Page 23

THANK YOU
&
QUESTIONS!

Matthew Bugg, MSc Pharmaceutical Technology & Quality Assurance – Slide 22 of 23