1208-USp-STERILITY TESTING—VALIDATION OF ISOLATOR SYSTEMS

1208

STERILITY

TESTIN G

—

V

ALIDATION

OF

ISOLATOR

SYSTEMS

This chapter provides guidelines for the validation of

isolator systems

for

use

in

sterility

testing

of

compendial

articles

加工配制药物

.

[note

—

In

the

context

of

this

chapter,

―de contaminated‖

净化

refers

to

an

item

or

surface that has been subjected to a process that eliminates

消除

viable

存活的

bioburd en

微生物量

.]

Isolators

—

devices

that

create

controlled

environments

in

which

to

conduct

Pharmacopeial

sterility

tests

—

have

been

used

since

the

mid-1980s. An isolator is supplied with air through a

HEPA

or better air

filter

and

is

able

to

be

reproducibly

decontaminated.

Closed

isolators,

which are systems with no direct opening to the external environment, are

normally

used

for

sterility

testing,

although

open

isolators

which

allow

the

egress

出口，外出

of

materials

through

a

defined

opening

that

precludes

排除

the

entry

进入

of

contamination

by

means

of

air

overpressure

过

压

may

be

used.

Closed

isolators

use

only

decontaminated

interfaces

or

a

rapid-transfer

port

for

the

transfer

of

materials. Isolators are constructed of

flexible plastics

(such as polyvinyl

chloride), rigid plastics, glass, or stainless steel.

Isolator systems protect the test article and supplies from contamination

during

handling

by

essentially

eliminating

direct

contact

between

the

analyst and the test articles. All transfers of material into and out of the

isolator

are

accomplished

in

an

aseptic

无菌的，防腐剂

fashion

while

maintaining

complete

environmental

separation.

Aseptic

manipulations

within

the

isolator

are

made

with

half-suits,

which

are

flexible

components

of

the

isolator

wall

that

allow

the

operator

a

full

range

of

motion

within

the

isolator,

or

by

gloves

and

sleeves.

Operators

are

not

required to wear special clean-room clothing for conducting sterility tests

within isolators; standard laboratory clothing is adequate, although a pair

of sterile gloves is frequently worn under the isolator gloves as an added

precaution against contamination entering the isolator enclosure and for

hygiene

purposes.

The

interior

of

the

isolator

is

treated

with

sporicidal

chemicals that result in the elimination of all viable bioburden on exposed

surfaces.

ISOLATOR DESIGN AND CONSTRUCTION

构造

Air Handling Systems

An isolator used for sterility testing is equipped with microbial retentive

filters (HEPA filters or better are required).

At rest, the isolator meets the

particulate air-quality requirements

for an ISO Class 5 area as defined

in

ISO

14644-1

through

-3*

(see

Microbiological

Evaluation

of

Clean

Rooms and Other Controlled Environments 1116).

However, the isolator

need not meet Class 5 conditions during an operation that may generate

particulates,

and

no

requirements

for

air

velocity

速率，高速

or

air

exchange

rate

exist.

The

isolator

should

be

sealed

密封

well

enough

during decontamination that the dissemination

传播

of sporicidal

杀孢子

vapors or gases into the surrounding environment is kept to appropriately

low

levels.

When

direct

openings

to

the

outside

environment

exist,

constant air overpressure conditions maintain sterile conditions within the

isolator.

In

general,

both

open

and

closed

isolators

are

maintained

at

positive

pressure

relative

to

the

surrounding

environment,

and

overpressures of 20 Pa or more are typical. The user should never exceed

the

maximum

pressure

recommended

by

the

isolator

manufacturer.

Airflow within isolators used for sterility testing is either unidirectional or

turbulent.

Transfer Ports and Doors

Isolators may be attac

hed to a ―pass

-

through‖ decontaminator or transfer

isolator to enable the direct transfer of sterile media, sterile dilution fluids,

and

sterile

supplies

from

the

decontaminator

into

the

isolator

system.

Rapid transfer ports (RTPs) enable two isolators, i.e., the work station and

transfer isolator, to be connected to one another, so that supplies can be

moved

aseptically

from

one

isolator

to

another.

Aseptic

connections

between two isolators or an isolator and an RTP-equipped container can

be

made

in

unclassified

environments

using

RTPs.

The

nonsterile

surfaces

of

the

RTP

are

connected

using

locking

rings

or

flanges.

A

compressed gasket assembly provides an airtight seal, thereby preventing

the ingress of microorganisms.

When

the

two

RTP

flanges

are

linked

to

form

an

airtight

passage,

a

narrow band of gasket remains that could harbor microbial contamination.

This exposed gasket should be routinely disinfected immediately after the

connection is made, and before materials are transferred through the RTP.

Good

aseptic

technique

is

used

when

transferring

materials

and

care

is

taken not to touch the gasket with the materials being transferred or with

the gloved hands.

Preventive

maintenance

and

lubrication of

the gasket

assemblies on the

flanges

is

performed

according

to

the

RTP

manufacturer's

recommendations.

The

RTP

gaskets

are

changed

at

the

recommended

frequency

and

periodically

checked

for

damage,

because

cut

or

torn

gaskets cannot make a truly airtight seal.

Selection of a Location for the Isolator

Isolators

for

sterility

testing

need

not

be

installed

in

a

classified

clean

room,

but

it

is

important

to

place

the

isolator

in

an

area

that

provides

limited

access

to

nonessential

staff.

The

appropriate

location

provides

adequate space around the isolator for moving transfer isolators, staging

of materials, and general maintenance. No environmental monitoring of

the surrounding room is required.

Temperature

and

humidity

control

in

the

room

is

important

to

operator

safety

and

comfort

and

is

critical

for

the

effective

utilization

of

certain

decontamination

technologies.

Uniform

temperature

conditions

in

the

room are desirable when temperature-sensitive decontamination methods

are employed. Care should be taken in locating the isolator so that cold

spots

are

avoided

that

might

result

in

excessive

condensation

when

condensing vapors are used for decontamination.

V

ALIDATION OF THE ISOLATOR SYSTEM

The isolator system must be validated before its use in sterility testing as

part of a batch release procedure. To verify that the isolator system and all

associated equipment are suitable for sterility tests, validation studies are

performed

in

three

phases:

installation

qualification

(IQ),

operational

qualification

(OQ),

and

performance

qualification

(PQ).

The

following

sections

contain

points

to

consider

in

the

validation

of

isolator

systems

for sterility testing. The assignment of test functions to a particular phase

of the validation program (i.e., IQ, OQ, and PQ) is not critical, as long as

proper function of the isolator is demonstrated and documented before its

use in compendial Assays.

Installation Qualification (IQ)

The IQ phase includes a detailed description of the physical aspects of the

system, such as the dimensions, internal configuration, and materials of

construction. The unit layout is diagrammed with interfaces and transfer

systems

clearly

and

dimensionally

indicated.

Compliance

with

design

specifications

for

utility

services,

such

as

air

supply,

vacuum,

external

exhaust,

and

temperature

and

humidity

control,

is

verified.

Other

equipment used with the isolator system is also described in detail; if any

revisions

to

design

specifications

are

made,

these

are

included.

Equipment manuals and copies are catalogued and stored where they can

be

retrieved

and

reviewed.

Compliance

of

drawings

to

design

specifications

is verified.

All drawings

and process

and instrumentation

diagrams are catalogued, stored, and are retrievable.

All documentation is reviewed to verify that it precisely reflects the key

attributes

of

the

installed

system.

This

establishes

a

general

benchmark

for

the

isolator

system's

compliance

with

design

specifications

and

installation requirements.

Potential process-control or equipment problems that could cause system

failure

during

operation

are

identified

and

documented

during

failure-mode

analysis

and

hazard

analysis.

The

system

is

modified,

if

necessary,

to

minimize

the

risk

of

failure,

and

critical

control

point

methods are established.

The

results

of

the

IQ

are

summarized

in

an

Installation

Qualification

Report. The following documentation is suggested.

Equipment

—

The

equipment

is

listed

with

its

relevant

design

specifications.

The

IQ

verifies

that

equipment

meeting

the

appropriate

design specifications was received and that it was installed according to

the manufacturer's requirements.

Construction

Materials

—

The

construction

materials

of

critical

system

components are checked for compliance with design specifications. The

compatibility

of

the

intended

decontamination

method

with

the

construction materials is verified.

Instruments

—

System instruments are listed with their calibration status.

Utility Specifications

—

All utilities required for operation

—

as defined in

the

operating

manuals

and

process

and

instrumentation

diagrams

—

are

checked for availability and compliance with design specifications. Any

connection

between

utility

systems

and

the

isolator

system

is

inspected

and conformance of these connections to specifications is verified.

Filter Certification

—

HEPA filters and other microbial retentive filters are

tested and certified; copies of test results and certificates are included in

the IQ

summary.

Purchase orders are

reviewed

and conformance

of the

air filtration system to specifications is verified.

Computer Software

—

All computer software associated with the isolator

system is listed with its name, size, and file revision number. The master

computer disks are checked for proper labeling and stored securely.

Operational Qualification (OQ)

The OQ phase verifies that the isolator system operates in conformance to

functional specifications.

Operational

Performance

Check

—

This

test

verifies

that

all

alert

and

alarm functions comply with their functional specifications. The system's

ability to comply with all set points and adjustable parameters is verified.

Isolator

Integrity

Check

—

The

integrity

of

the

isolator

is

maintained

during all normal operating conditions. A leak test is performed to verify

the

compliance

with

the

manufacturer's

functional

specifications

and

to

ensure

safety

prior

to

charging

the

isolator

with

a

decontaminating

sporicidal

chemical.

To

safeguard

against

adventitious

contamination,

isolators

are

operated

at

a

suitable

positive

pressure

during

normal

operation. Validation studies must show that the air pressure set point can

be maintained and controlled during operation.

Decontamination

Cycle

Verification

—

A

decontamination

cycle

that

is

the

function

of

the

decontamination

equipment

in

concert

with

the

isolator(s) is verified.

Different

decontamination

methods

can

be

used

to

eliminate

bioburden

from isolator systems and supplies. Among the chemicals that have been

used

to

treat

isolators

are

peracetic

acid,

chlorine

dioxide,

ozone,

and

hydrogen

peroxide;

each

has

different

requirements

for

exposure

conditions

and

process

control.

It

is

critical

to

comply

with

the

manufacturer's operational requirements for the selected decontamination

method

and

to

describe

them

in

the

functional

specifications.

The

temperature inside the isolator is also important, particularly for hydrogen

peroxide

vapor

decontamination,

where

it

is

critical

to

maintain

the

concentration

relative

to

the

condensation

point.

Some

sterilization

chemicals,

such

as

chlorine

dioxide

and

ozone,

require

the

addition

of

moisture to the isolator prior to decontamination. When elevated relative

humidity is required, the ability to control it must be verified during OQ.

It

is

also

important

to

verify

the

concentration

and

distribution

of

the

decontaminating chemical.

When applied in gaseous or vapor form, the

distribution

may

be

evaluated

using

chemical

indicators,

spectroscopic

methods, or electronic sensors.

Gas and vapor decontamination methods may require fans in the isolator

to

distribute

the

chemical

evenly.

The

location

and

orientation

of

these

fans are adjusted to ensure optimum air distribution. If the isolator utilizes

a recirculating unidirectional airflow system, distribution fans may not be

required, but

this should

be

evaluated on

a

case-by-case

basis.

Because

shelving

units,

equipment,

glove-and-sleeve

assemblies,

and

half-suits

have an impact on distribution patterns, distribution checks are done with

the

isolator

fully

loaded

with

equipment

and

supplies,

and

the

setup

of

these units is defined and documented.

Many

installations

use

smaller

transfer

isolators

as

portable

surface

decontamination

units.

In

these

transfer

isolators,

test

articles

and

supplies

are

treated

chemically

to

eliminate

bioburden

before

transfer

through

an

RTP

into

the

testing

isolator.

Its

loading

configuration

is

defined, and configuration drawings are reviewed and verified during the