Environmental Monitoring Management

in Pharmaceutical Facilities to Comply

with PIC/S GMP Requirements
by
Pramote Cholayudth
TiTEC/KMUTT & BIOLAB
cpramote2000@yahoo.com
September 5, 2013

GMP and Supporting Guidelines

Quality Management
System (QMS)

ICH Quality
Guidelines
(Q5,Q8,Q9,Q10)

Biotech. Products,
Pharm. Develop.,
Qual. Risk, Qual. Syst.

Clinical Study
Reports, Good
Clinical Practice,
Clinical Trials

Carcinogen. Stud.,
Toxicity Testing,
Biotech. Products

General/Specific GMP
(Q, S, E, Security)

ICH Safety
Guidelines
(S1,S4,S6)

Reduced Regulatory
Burden:
Reduction of
Submissions on
Changes/Variations
Inspection of Quality
Systems

ICH Efficacy
Guidelines (E3,
E6, E7-E11)

GMP Goals
GMP Goals
Product Quality
Product Efficacy
Product Safety
Product Security
(product secured
from all errors)

Patient Protection (GMP)

Focus on
Qualification, validation,
Quality
quality control, monitoring
(Combined & stability study
Guides)
Conduct bioequivalence
Control contamination,
Safety
(Combined) impurity, degradation prod
Security Protect product from
(Single
errors e.g. mix-up,
Guide)
mislabeling, etc.
Functions

GMP Tracking
GMP Goals GMP Approach

GMP in Detail (PIC/S Part I)

Hardware//Premise/Equipment
Quality
(facility flows, Manufacturing
Lifecycle
approach [initial Environment, process core, etc.)
Humanware//Personnel
(validation),
Safety
ongoing
Software//Quality
(monitoring) Management/Production/QC/Co
change control] mplaint & Recall/Self Inspection
Security
Paperware//Documentation
Efficacy: R&D phase
4

Manufacturing Environment (Background)

Process background e.g. aseptic area,

production area, storage area, QC lab (micro)
Process barrier e.g. LAF, dispensing booth

HVAC/Cleanroom Validation and Environmental

Monitoring Reference Hierarchy

Qualification and Validation Phases

URS: User Requirement Specification

DQ: Design Qualification
IQ: Installation Qualification
OQ: Operational Qualification
PQ: Performance Qualification
MQ: Maintenance Qualification

PIC/S: Environmental Monitoring

Shared Responsibility between Production
& QC Heads: Monitoring and control of the
manufacturing environment
For Environmental Monitoring, there should
be written policies (QM), procedures (SOP),
and the associated records of actions taken
or conclusions reached
Where required, QC documentation should
include Environmental Monitoring data

The Most Applicable Guideline: WHO

In the WHO Guideline

Classification and Environmental Monitoring

(EM) of Cleanrooms and Laminar Flow
Workstations, the elements include:
Airborne particle (non-viable count)
Microbial count (airborne viable count,
surface-borne)
Alert and action limits for Environmental
Monitoring

Alert and action limits should be set by the

manufacturers for their benefit

10

Environmental Monitoring Management

Environmental Monitoring Policy is defined

in Quality Manual (+ Continuous Improvement)

Environmental Monitoring Program (with detail

related to 5W1H Who, What/Which, Where,
When, How) is issued and implemented

SOPs for How are prepared, approved, and

issued

In the SOPs, the How to includes type of data

determination, construction of Control Chart (CC),
plotting the data on CC, and establishing alert
(mean2SD) and action (mean3SD) limits
11

List of Key Parameters in EM

Airborne particle count (non-viable) (sterile)
Continuous monitoring (aseptic filtration &
filling/stoppering)

Microbial count (viable)

Airborne (active & passive methods) & surfaceborne count (sterile)
Airborne passive method settle plate (nonsterile)

Air differential pressure (sterile & non-sterile)

Room temperature (sterile & non-sterile)
Relative humidity (sterile & non-sterile)

12

Cleanroom

Class 10,000 cleanroom

Class 100 cleanroom
13

Cleanroom and Clean Air Device

Classification
Grade

Maximum permitted number of particles/m3 equal

to or greater than the tabulated (particle) size
At Rest
In Operation
0.5 m

5.0 m

0.5 m

5.0 m

3,520

20

3,520

20

3,520

29

352,000

2,900

352,000

2,900

3,520,000

29,000

3,520,000

29,000 Not defined Not defined

14

Airborne Microbial Limits

Grade

Glove
Contact
> 0.5 um
Air
Settle
Print 5
particles/m3 Sample Plates Plates
fingers
(cfu/m3) diam. 90 diam. 55
(cfu/glove)
mm
mm
(cfu/4hrs) (cfu/plate)

3,520

<1

<1

<1

<1

3,520

10

352,000

100

50

25

3,520,000

200

100

50

15

16

17

Process Barriers vs. Backgrounds

Process Cores
Filling, stoppering, capping,
filtration, staging (sterile items)
Storage of sterile bulk for filling
Storage of sterilized components
Compounding (with active comp.)
prior to sterile filtration
Washing prior to heat sterilization
UDAF: Unidirectional Airflow

Process
Barriers

Process
Backgrounds

UDAF (A)

UDAF
UDAF

C
C

N/A

UDAF

18

Non-Viable Particle Count

Follow PIC/S Annex 1, WHO TRS # 961, and
ISO 14644 series, NEBB, ISPE (HVAC)
Equipment: airborne particle counter 0.1 or 1
ft3/min, particle size range: 0.3 25 m (GMP
codes 0.5 and 5 m)
Sample locations: NL = A0.5 (NL = number of
location; round up if decimal, A = area in m2)
19

Minimum Air Sample Volume

and Sampling Time
Grade

At Rest
5.0 m MASV

In Operation
MAST 5.0 m MASV

1,000 L 36 min

20

MAST

20

1,000 L 36 min

29

690 L

25 min

2,900

7L

1 min

2,900

7L

1 min

29,000

2L

1 min

29,000

2L

1 min

MASV: Minimum Air Sample Volume, MAST: Minimum Air

Sampling Time, Air Sampling Rate: 1 CFM
20

Environmental Monitoring:
Airborne Particle Counter (Non-viable Count)

Use of remote systems

recommended in laminar flow areas
21

Environmental Monitoring:
Microbial Air Sampler (Active Method; Viable Count)

22

Environmental Monitoring:
Settle Plate (Passive Method; Viable Count)

23

Two Types of Data Involved

Variable Data: data obtained by measurement
Normal data e.g. room temperature, %RH, air
differential pressure
Non-normal data e.g. sample statistics (SD, RSD,
CpK, AV, except for sample mean)

Attribute Data: data obtained by counting

Normal data e.g. average of particle count data
(UCL for cleanroom air particle count)
Non-normal data e.g. individual particle or
microbial count

24

From A Normal Distribution

In a Process:
(mu) = Process Mean
(Process Average)
s (sigma) = Process
Standard Deviation

In a Population:
(mu) = Population Mean
s (sigma) = Population
Standard Deviation
68.27%
95.45%
99.73%
-3s

-2s

-1s

+1s

+2s

+3s
25

Control Charts
(Normal & Non-normal Distributions)
USL
UCL

+3s

CL

About 99.73% of Distribution of Process Data*

LCL

-3s

LSL
USL & LSL = Upper & Lower Specification Limits
UCL & LCL = Upper & Lower Control Levels
CL = Center Line or Central Line
* In fact Product-in-Process Data

26

c Chart
(Microbial Alert Limits in Cleanroom)

UCL
CL
At least 99.73% of Poisson Distribution (Micro Count)
LCL

UCL & LCL = Upper & Lower Control Levels

CL = Center Line or Central Line
27

Establishing Alert and Action Limits

(Normal Data; Mean2SD, Mean3SD)

28

Establishing Alert and Action Limits

(Normal Data; Mean2SD, Mean3SD)

29

Combined Control Chart

(Room Temp (C) and Relative Humidity (%) Data)

30

Establishing Alert Limits

(Microbial Data; Alert Limit = Mean+4SD)

31

Establishing Action Limits

(Microbial Data; Action Limit = Mean+6SD)

32

EM Microbial Data Evaluation:

In-Trend and Out-of-Trend (OOT) Data

Alert and action limits should be set for each

sample site
Individual sample results should be evaluated
against the action and alert limits

33

Establishing Alert and Action Limits

(Particle Count Data; Mean2SD, Mean3SD)
In grade A: Continuous particle count is a full
degree of environmental monitoring of nonviable count
Detection of 0.5 and 5.0 m is the target
responsibility of the real time continuous counter
Trend analysis using control chart is usually made
to the count of 0.5 m size
Mean2SD and mean3SD are applied

34

Is CpK Necessary for EM Data?

CpK is most suitable for product characteristic
data, so it is no use using CpK in evaluating
the EM data

35

Conclusion
Like the other programs or functions, the
Lifecycle Approach is applied to EM program
Initial data are collected and used for calculation
of the UCL & LCL (mean3SD) for Control Chart
mean2SD is used as Alert Limits while
mean3SD is the Action Limits
mean4SD is used as Alert Limits for microbial
count while mean6SD is the Action Limits

Ongoing or routine EM data are evaluated using

the Control Chart and Alert/Action Limits
Continuous improvement and shift & drift are
monitored

36