Environmental Monitoring

R Raghunandanan, Mumbai
Director ISPE India
26th February 2011

Agenda
Introduction

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Environment includes
All the factors impacting quality and

safety of pharmaceutical products

Facility

Utilities
Machines

Personnel
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Why environmental monitoring is

important
GMP requirement
Facilities are designed to protect products from
contamination or deterioration
Facility must operate to meet the design
criteria
Only routine monitoring can prove that
facilities are functioning as designed.

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Why environmental monitoring is

important
Regulatory Requirements, US FDA

Microbiological control of drug manufacturing

areas: Statutory requirement as per 21 CFR 211 as
stated in Sections 211.46, 211.56, and 211.113
211 CFR 211.46, Ventilation, air filtration, air
heating and cooling:
Adequate control over microorganisms, dust,
humidity and temperature.
Pre filters and particulate matter air filters for air
supplies to production areas
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Why environmental monitoring is

important
Regulatory Requirements

EM is a requirement of GMP as per WHO, MHRA,

MCC,TGA etc too.
Schedule M requirements
Sec 8.2.1. The licensee shall prevent mix-up and
cross-contamination of drug material and drug
product (from environmental dust) by proper airhandling system, pressure differential, segregation,
status labeling and cleaning. Proper records and
Standard Operating Procedures thereof shall be
maintained.

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Why environmental monitoring is

important
Schedule M requirement
All environmental parameters listed under para
3.1 to 3.10 shall be verified and established at
the time of installation and thereafter
monitored at periodic intervals. The
recommended frequencies of periodic
monitoring shall be as follows :-

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Why environmental monitoring is

important
Schedule M requirement - recommended frequencies
(a) Particulate monitoring in air 6 Monthly.
(b) HEPA filter integrity testing (smoke testing) Yearly
(c) Air change rates 6 Monthly.
(d) Air pressure differentials Daily.
(e) Temperature and humidity Daily
(f) Microbiological monitoring by settle plates and/or
swabs in aseptic areas - daily, and at decreased
frequency in other areas
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What impacts from environment

Product deterioration
Microbiological deterioration
Thermal deterioration
Humidity induced deterioration
Product contamination
Particulate contamination
Cross contamination
Increased bio-burden
Sterility failures
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Different environments
Product exposed areas
Aseptic preparation
Aseptic filling, blending
Preparatory areas
Solution preparation
Component preparation
General areas
Component washing
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What need to be monitored

Non-viable air monitoring (particulates)
Viable air monitoring (microbiological)
Surface monitoring (facility and equipment)
Personnel monitoring (garments & gloves)
Temperature and humidity
Pressure differentials (p)
Gases and other utilities (including water)
Disinfectants
Detergents and washing agents
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Different classes of environments

EU
Grade
A
B
C
D

ISO Class

Class

5
6
7
8

100
1000
10,000
100,000

US FED
STD
M 3.5
M 4.5
M 5.5
M 6.5

(US FED STD now replaced by ISO 14644-1 though

we frequently use the terminology Class 100 etc.)
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Available standards and guidance

EU Annex 1, 2008
USP 32, General Chapter <1116>
ISO 14644
Schedule M of D&C Act and Rules of India
Guidance for industry, US FDA Sterile Drug
Products produced by Aseptic Processing-Sept
2004
21 CFR Part 211.42
21 CFR Part 211.46
(and others)
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Available standards and guidance

It is important to remember that
All standards are not exactly identical
Manufacturer to follow the market
requirements as a minimum
You are free to have tighter in-house
standards

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Area particulates (non-viable) EU Annex 1

Maximum no of particles per cubic meter

At rest

In Operation

Grade

0.5
micron

5.0
micron

0.5
micron

5.0
micron

3520

20

3520

20

3520

29

352,000

2900

352,000

2900

3,520,000 29,000

3,520,000 29,000

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Not
defined

Not
defined
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At rest and In Operation

At rest
Air flow is ON
Equipment installed but not in use
No personnel in the area
In Operation
Air flow is ON
Equipment in operation (sometimes
simulated)
Specified no. of personnel in the area
Define these for each clean room
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Microbiological monitoring standards

(EU Annex 1)
Limits for microbial contamination

Grade

Air sample
Cfu/m3

Settle plate
Cfu/4 Hrs

Contact
plate
Cfu/plate

Glove
print
Cfu/glove

<1

<1

<1

<1

10

100

50

25

--

200

100

50

--

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Define Your Monitoring philosophy

Reduction of risk to patients
High confidence levels of sterility assurance
A systematic and risk based approach of
monitoring
Investigation linked to Corrective and
Preventive Actions
Make assessments through trending the
results
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Carry out risk assessment

Carry out a risk assessment based on
Type of product manufactured
Type and age of facility
Type and age of machinery
Extent and type of containment used
Document the rationale based on the risk
assessment
Periodically review the rationale and update
monitoring levels
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Essentials of monitoring
programme
Should be capable of detecting an adverse
drift in a timely manner
This only will facilitate meaningful and
effective corrective actions
The programme should be facility specific
The manufacturer should develop, initiate,
implement and document a monitoring
program meeting these essentials
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SOP for environmental monitoring (i)

Detailed SOP for EM is one of the first steps and the
SOP to include

Reference to risk assessment

Responsibilities of various functions
Locations of monitoring (drawing etc.),
document rationale
Sampling and testing methods, sample sizes
Specific sampling equipment and
techniques
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SOP for environmental monitoring (ii)

Detailed SOP for EM to include
Frequency and time of sampling
Alert and action levels
Documentation and periodic reviews
Trending of results
Notification to all concerned during
excursions
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Need for trained personnel

Personnel involved in EM should
Be adequately qualified
Be experienced and trained
Know the local regulatory requirements
Know how to handle excursions
Have investigational skills

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Area monitoring non-viable

Particulates monitoring required for all clean
rooms
During qualification
As part of routine review
Particulates equal to or greater than 0.5m
and 5.0m must be quantified
Samples must be at least one cubic meter in
volume (see ISO 14644-1)
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Grade A monitoring - non-viable

Continuous monitoring of particulates in Grade
A zones during preparation and operation
Continuous monitoring of particulates in Grade
B is recommended
Point of fill monitored within 30 cm during
operation
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Grade A monitoring - non-viable

Where particles are generated during operation
use simulated conditions (e.g. powder filling)
Rationale for simulated conditions should be
justified and documented

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Area monitoring viable

SOP to include additional details for
Media requirements, growth promotion tests
Need for neutralizers if any
Incubation requirements (time & temp)
Identification of organisms recovered
Precautions to avoid contamination during
and after monitoring (e.g.: use of contact
plates)
Monitoring for anaerobic organisms at
defined intervals
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Surface monitoring (i)

Surface monitoring involves sampling various
surfaces for microbiological quality
Product contact surfaces, floors, walls, and
equipment should be tested on a regular basis
Contact plates and/or swabs are the choice

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Surface monitoring (ii)

Contact plates for smooth and easy to sample
surfaces
Swabs for difficult to sample surfaces
Helpful to assess
Cleaning efficacy
Contamination potentials
Recovery studies need to be done

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Personnel monitoring (i)

Personnel significantly affect the quality of the
environment
Maintain contamination-free gloves and gowns
throughout operations
Monitoring of each operator's gloves and
garments at exit
When exceed established levels or show an
adverse trend, carry out investigation
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Personnel monitoring (ii)

Follow-up actions shall include
Increased sampling
Increased observation of aseptic behavior
Retraining
Gowning re-qualification
Shifting the individual to other operations

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Personnel monitoring (iii)

Trends from daily monitoring of personnel can
provide important information indicating possible
routes of contamination

Adequacy of personnel practices and training

shall be routinely reviewed

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Temperature & humidity levels

Define product specific requirements
When exceeded assess impact on product
quality and patient safety
Understand regulatory requirements
Employ automated monitoring techniques
where possible
Alarms and notifications when limits are
exceeded
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Setting alert and action levels

This is driven by
Product specific requirements
Regulatory requirements

Market requirements (customer market)

Findings during initial qualification

Arising out of trend analysis

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Trend analysis
Monitoring trends provide assurance
That facility is under control
That practices are acceptable
Trends change when changes are made to
facility or practices
Trends help updating alert and action levels
and also frequencies
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Dealing with excursions

Notification to all concerned
Investigation to commence
Root cause identification
Interview personnel involved
Impact assessment on various batches
Remedial actions
Corrective and preventive actions

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Corrective & Preventive Actions

CAPA should be agreed and documented
Changes may be required to
Facility, HVAC system
Equipment, containment, barrier systems
Ways of working
Training to personnel
CAPA should be progressed and closed

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EM and batch release

EM data should be reviewed before release of
batches of sterile products
Any excursions must be investigated and actions
completed before batch release
Batches prior to and post to the excursions
should also be included in the investigations

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Remember
A well-designed facility without
proper environmental monitoring
is nothing more than
an ill-designed facility

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Questions

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