GMP Regulations and

Monitoring

Agenda
GMP Particle Monitoring Requirements

Certification and Monitoring

EC GMP (changes?)
FDA Aseptic Guidelines
Global Organizations (WHO, PIC/S)

Pharmaceutical Process Monitoring

Monitoring locations
Sample point placement

Facility Monitoring Systems

Hardware and Software
Alarming, HMIs, Reports
Data Interpretation

GMP Particle Monitoring

Requirements

Varied Requirements
One common classification body
ISO14644-1 and ISO14644-2

Various regulatory bodies for monitoring

EC GMP Annex 1 Enforced by various European regulatory agencies
21-CFR-211/210 Enforced by the FDA
Asian requirements governing manufacture of pharmaceutical products

Local import requirements

USA only allows drugs manufactured to CFR-211 into US
Europe only allows drugs manufactured to EC GMP into EU

Certification vs. Monitoring

cGMP regulations require first Certification, then
Monitoring
Certification: Proving that cleanroom meets defined ISO
standard
Monitoring: Continued verification that cleanroom has not
shifted from normal conditions

cGMP = Current Good Manufacturing Practices

ISO 14644 Cleanroom Certification

Certification: Proving that cleanroom meets defined standard
Performed every 6 months 1 year (ISO14644-2)
To a specific procedure
Number of sample points ( floor area m2)
Location of sample points (equidistant & work height)
Specific volume (based on number of particles required)

20
VS
1,000
Cn,m
Confirms that the room can be used for a specific function

ISO 14644-1 Summary

ISO 14644 Certification Example

ISO 5 area (dimensions: 5 x 12 meters)

N L Area 5x12 60 7.74

N L 8 sampling point locations

EU ANNEX 1 Certification Limits

and Monitoring Requirements

EC Annex 1 Note (a)

Particle counter to be used

Continuous required in Grade A, recommended in B
Routine testing (define?) should use a volume of 1m3
for class A and B; preferably in C

Status of EU Annex 1
Current version published in May 2003 and adopted in
September 2003
Industry issued concerns regarding content of 2003
revisions
New draft release for comment issued November 2005
Close of public comment April 2006
Possible implementation in 2007??

NEW General Clause 4

The area should be monitored during operation in
order to control the particulate cleanliness of the
various grades. Replaced
Now is referred to as room certification

New limits defined

NEW Proposed Limits

AT REST
GRADE

IN OPERATION

Max Particle concentration > size

Microbiological

0.5um

5.0um

0.5um

5.0um

Air Sample
cfu/m^3

90mm settle
plate cfu/4hr

3 520

20

3 520

20

<1

<1

3 520

29

352 000

2 900

10

352 000

2 900

3 520 000

29 000

100

50

3 520 000

29 000

Not defined

Not defined

200

100

Clause 4 (cont.)
Minimum volume of 1m3 per location, to meet required
ISO14644-1 standard for particle counting probabilities.

20
VS
1,000
Cn,m
No sample tubing for certification
Class A is now essentially an ISO Class 4.8 based upon 5.0um
limit.

General Clause 5
Routinely monitor in operation
Monitoring locations
Formal risk analysis
Based upon results from certification

Grade A zone Continuous Monitoring

Some discussion regarding manifolds, providing validated
they will miss transient events

Grade B as Grade A but with reduced frequency

possible to now use manifolds.

General Clause 5 (cont.)

Systems
Independent counters
Manifolds

Frequency
All interventions and transient events must be captured and
alarms triggered if excursions from defined operating norms
occur

Monitoring sample size for auto system

Sample size is a function of the instrument flow rate
It is not required that the volume for certification be used

General Clause 6
Grade A & B
5.0um is a very important tool for early detection of failure
Occasional counts may be due to electronic noise from
particle counters, stray light, coincidence etc.

Consecutive or low levels of counts an indicator of

possible failure.
HVAC system
Filling equipment
Poor practices during machine set up and routine operation

FDA Guidelines (Sept 04)

Critical Areas:
Air in the immediate proximity of exposed sterilized containers/closures and
filling/closing operations would be of appropriate particle quality when it has no
more than 3520/m3 in a size range of 0.5 mm and larger when counted at
representative locations normally not more than 1 foot away from the work site,
within the airflow, and during filling/closing operations. This level of air
cleanliness is also known as Class 100 (ISO 5).
We recommend that measurements to confirm air cleanliness in critical areas be
taken at sites where there is most potential risk to the exposed sterilized product,
containers, and closures. The particle counting probe should be placed in an
orientation demonstrated to obtain a meaningful sample. Regular monitoring
should be performed during each production shift. We recommend conducting
nonviable particle monitoring with a remote counting system. These systems are
capable of collecting more comprehensive data and are generally less invasive
than portable particle counters.
(Section IV Buildings and Facilities)

FDA Guidelines

Supporting Clean Areas:

Supporting clean areas can have various classifications and functions. Many
support areas function as zones in which nonsterile components, formulated
products, in-process materials, equipment, and container/closures are prepared,
held, or transferred. These environments are soundly designed when they
minimize the level of particle contaminants in the final product and control the
microbiological content (bio-burden) of articles and components that are
subsequently sterilized.

The nature of the activities conducted in a supporting clean area determines its
classification. FDA recommends that the area immediately adjacent to the
aseptic processing line meet, at a minimum, Class 10,000 (ISO 7) standards
(see Table 1) under dynamic conditions. Manufacturers can also classify this
area as Class 1,000 (ISO 6) or maintain the entire aseptic filling room at Class
100 (ISO 5). An area classified at a Class 100,000 (ISO 8) air cleanliness level
is appropriate for less critical activities (e.g., equipment cleaning).

FDA GMP

Particle Monitoring Limits by Class:

TABLE 1- Air Classifications

a- All classifications based on data measured in vicinity of exposed materials during periods of activity.
b- ISO 14644-1 designations provide uniform particle concentration values for cleanrooms in multiple
industries. An ISO 5 particle concentration is equal to Class 100 and approximately equals EU Grade A.
c- Values represent recommended levels of environmental quality. You may find it appropriate to establish
alternate microbiological action levels due to the nature of the operation or method of analysis.
d- The additional use of settling plates is optional.
e- Samples from Class 100 (ISO 5) environments should normally yield no microbiological contaminants.

Global Perspective
World Health Organisation (WHO)
Limits for 0.5 m and 5.0 m
Old EC GMP limits

Global Perspective
Pharmaceutical Inspection Co-operation Scheme (PIC/S)
New guidance from September 2003
Central body made of European, US, Japan, Australia, Canada, and other
sponsor nations
Single method for Good Manufacturing Practices (GMP) inspection
protocols
Particles monitored at 0.5 and 5.0 m

Requirements Summary
Annex 1, increase from 0 counts at 5.0um to 1/m3 done in an effort to
increase statistical confidence of real counts. For room certification,
monitoring has shown that this is difficult to control.
No more than 2-3 counts/m3 should be observed during continuous monitoring.
Samples should be taken at least every 1 to 2 minutes.

Requires a volume of 1m3 to ensure statistical significance of data for

PORTABLE sampling.
Large particles of major concern, 10-20um most likely to be viable.
Bill Whyte, 11um mean size of viable
Lundquist & Reinmuller, mean size is 10-20um

Continuous monitoring preferred in critical areas by both EC GMP and

FDA guidelines.
Portable monitoring or Manifolds in support areas.

Pharmaceutical Process
Monitoring

GMP Classifications
Supporting Areas

Pharma Cleanroom

Sampling Locations for ISO Certification

Monitoring to GMP Standards

Portable (Intermittent) Particle Counters

Monitoring to GMP Standards

Dedicated (Continuous) Particle Sensors

Filling Line
Monitoring

Vial filling line

Monitor point-of-fill & other

critical locations (accumulator,
capping, etc)

Tubing: Stainless or Bev-a-line

Filling Line Monitoring

Measure not directly
above critical point
Starve of air
Create turbulence

Measure to one side,

close to critical location
Within 12 of critical
point (FDA guideline)

Post fill pre freeze dryer

Monitoring post-fill position
Vials are now semi-capped
(open) but within fill line
envelope
Monitoring proves control
of zone

Suitable location:
Close to conveyor,
inside clean zone

Isolator
Isolator access is more difficult
Install ports to plumb transport
tubing inside
Bulkhead, tri-clover fittings are
common

Mount sensors below or at side

of isolator

Combined Viable/Nonviable
Monitoring

Glove box
Background Wall
(Grade B area)
Half-suit isolator

Sample Placement - Summary

Analyze workflow patterns when choosing sample points.
Isokinetic sampling in unidirectional flow zones.
Commonly, many sample points are located too high, near air
filters - mostly counting zeros.
No room air system can assure high product quality if the
process tools or workers are contaminating the product.
Sample point rules:
At work level.
Inside process equipment.
Where product/glassware is exposed.
At critical points (risk analysis).
Risk to final product quality.

Facility Monitoring
Systems

Particle Monitoring Hardware

Continuous point-of-use sensors

Portable counters

(critical areas)

(support/background areas)

Facility Monitoring Software

Alarm Notification
During alarm conditions
operators need to be notified.
Various alarm configurations
Alarm lamp
Light tower + Siren
Paging / email

Essential for feedback to

comply with PAT meaning

Cleanroom HMI Stations

Operator interface in the cleanroom
View the source of alarms
Alarm acknowledgement
Change operating modes

Desired installation requirements

Flush-mount (no cleanroom space taken)
Membrane keyboard or touchscreen
Stainless steel, NEMA enclosure

System Reports
To support the release of a batch, hardcopy printed reports
provide evidence that the environmental conditions for
aseptic fill have been maintained.
Standard report types required by Regulatory inspectors:
Exception Reports
Time Plot reports for duration of batch
Statistics
Max, Min, Ave, Std Dev, % Alarm, %Conformance

Alarm Events

Batch Reports
Events Report
Statistical Report
Trend Report

High Transient Event Requires further investigation

Intervention Reports
Particle counting
Time order
Clear representation if out
of tolerance parameter at
any time

Particle Data Interpretation

Cyclic Data
Activity patterns
Manufacturing shifts
Work flow

Process signature
Recipe flow
Sequencing

95% UCL
(apx.2 x SD)
Operational
Average

Particle Data Interpretation

Periodic Data
Activity patterns
5.0 um monitoring

continuous

Frequent

N:m = 3:10
Where t= 1 min

Data Interpretation Guidance

For 0.5um particles
Assign a 95% confidence limit of actual events during production
The sample test should be performed during media fills to ensure that
operators are following SOP for normal operations.
Limits found may be less than the Class limit for operational classification.

For 5.0um particles

Single events need to be tracked e.g., a number of events per unit time
Frequency estimated at no more than 3 events in any 10 minutes (n:m =
3:10) to create an action limit, and potentially any 2:10 for an alert.
Actual operations will determine action limits.
Also based upon viable contamination limits, either during production or
during media fills, to determine worst case scenario for testing.

Summary
GMP Particle Monitoring Requirements

Certification and Monitoring

EC GMP (changes?)
FDA Aseptic Guidelines
Global Organizations (WHO, PIC/S)

Pharmaceutical Process Monitoring

Monitoring locations
Sample point placement

Facility Monitoring Systems

Hardware and Software
Alarming, HMIs, Reports
Data Interpretation