PHARMACEUTICAL INSPECTION CONVENTION

PHARMACEUTICAL INSPECTION CO-OPERATION SCHEME

PI 025-2
25 September 2007

AIDE-MEMOIRE

INSPECTION OF MEDICINAL GASES

© PIC/S September 2007

Reproduction prohibited for commercial purposes.
Reproduction for internal use is authorised,
provided that the source is acknowledged.

Editor: PIC/S Secretariat

e-mail: [email protected]
web site: http://www.picscheme.org

PI 025-2 25 September 2007

 TABLE OF CONTENTS
Page

1. Document History............................................................................................ 1
2. Introduction ..................................................................................................... 1
3. Purpose........................................................................................................... 1
4. Scope.............................................................................................................. 2
5. Aide-Memoire.................................................................................................. 3
6. Addendum on the manufacture of medicinal gases at hospitals .................... 12
7. Revision History ............................................................................................ 14

1. DOCUMENT HISTORY

Adoption by Committee 30 May 2006

Entry into force 1 September 2006

2. INTRODUCTION

2.1 Manufacturing of medicinal gases is regulated by the PIC/S GMP Guide and
Annex 6. The last revision of Annex 6 was done in 2001 (entry into force:
September 2001). In 2003, the PIC/S Expert Circle on Medicinal Gases
established a Working Group in order to draft an Aide-Memoire on the
Inspection of Medicinal Gases.

2.2 As the industrial production of gases is commonly a highly automated,

continuous process, involving automated systems, emphasis must be put on
investigating this aspect during an inspection. It requires a detailed technical
knowledge, including insight of computerised systems (see specific PIC/S
guidance), from GMP inspectors.

2.3 The manufacture of medicinal gases is a process carried out in closed

equipment. However, the re-use of containers without adequate precautions
could lead to a contamination of the product by a wide variety of contaminants.

3. PURPOSE

This Aide-Memoire was prepared to enable the effective planning and

conducting of GMP inspections of manufacturing of medicinal gases, in
particular from the point of view of optimal use of limited inspection time and
from the point of view of optimal evaluation of GMP compliance.

PI 025-2 1 of 14 25 September 2007

4. SCOPE

This document describes three different types of manufacturing of medicinal

gases: air separation units, filling stations and manufacturing of medicinal gases
in hospitals which should be covered during inspections and which should be
evaluated from the point of view of GMP compliance. This document focuses
on the special needs for inspecting the manufacturing of medicinal gases.

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 Area of operation/Items Items Crucial questions Supporting documents

5. AIDE MEMOIRE

1. General
1.1
Manufacturing
API/bulk/manufacturing National legislation
authorisation (if any) at the hospital?
1.2
Site Master File (if any) PIC/S recommendation
1.3 Personnel
Organisation chart
Personnel? GMP Chapter 2

Defined responsibilities? GMP Annex 6: 2

Responsible persons?
1.4 Personnel
Qualification and
Are training needs GMP Chapter 2
training of personnel identified? GMP Annex 6: 2.2

Training records?

Is training effectiveness GMP 2.9
assessed?
1.5 Quality management
QA/QC systems
Complaints? GMP Chapter 1

CAPA?

Deviations?

Change control?

Self Inspection
Is there a procedure? GMP Chapter 1.2 and 9

Is there a schedule?
Contract manufacture.
Contracts
Is there any GMP Chapter 7
and analysis outsourcing, including
container testing,
transportation?

Accepting and auditing
policy?
Validation / Qualification
Qualification
Validation policy of the GMP Annex 15

(DQ,IQ,OQ,PQ) factory/hospital?

VMP
Are critical control GMP Annex 6: 5.1 and

points identified? Annex 11

Revalidation

Are critical processes

Computerised systems validated and critical

Risk analysis equipment qualified?

Process validation
Timetable if not
implemented and

Change Control
present validation
status?

Periodically system
review

GMP critical
Computerised systems
validation policy?
(controlling / monitoring)

Cylinder cleaning
validated? GMP Annex 6: 5.3.6
Validation
Analytical methods
Are analytical methods
appropriately validated?
Complaints and product
Complaints, recall
How often do customers GMP Chap. 8 and point
recall query empty 5.1.
containers?

How this deficiency is
classified?

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 Area of operation/Items Items Crucial questions Supporting documents

Premises
Preventative
Plant, process, GMP Chap. 3

maintenance of calibration system?
filter(s), compressor,
cooler and separation
column, storage
tank(s), pipelines
Container design
Containers suitable for
Valve specific for a
medicinal gases particular gas or mixture
of gases?

Risk of contamination in
the case of complete
emptying?

Possibility and methods
of cleaning?
1.6 Premises
Remote operation of
Are there controls to GMP 3.6
ASU prevent access by
unauthorised persons?

List of products
Separation of medical

technical/industrial GMP Annex 6: 3.1.1and
gases? 3.1.2

Air separation unit [oxygen (and nitrogen) only]

2. Air separation units GMP Annex 6: 5

Production
2.1
Batch definition
How do they define the GMP Annex 6: 5.2.7
batch? Criteria used to
define a batch?
2.2
Flow chart of the
Rational explanation on GMP Annex 15
process procedure?

Layout of the plant, line
Which are the critical
drawings points of the process?

Shutdown and start-up
Where and how
samples of products
and intermediates are
taken?

How do you clean and
purge?
2.3
Air Inlet
What is the quality of GMP Annex 6: 5.2.2
- Position the air?

- Is it regularly cleaned
Potential Contaminants GMP 4.11

near by?
- Sequence of filters
(dust, CO2, water,
hydrocarbons)
2.4
Filters & /Molecular
What type of filters do GMP Annex 6: 5.2.4
Sieves they use?
- Types
SOP for maintenance?
- Changing frequencies
How is (or is) really
- Proper installation integrity tested for these
filters?
- For sieves regeneration
- Pressure drop
- Integrity testing

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 Area of operation/Items Items Crucial questions Supporting documents

2.5
Air compressors
Type of compressor GMP Chap. 3

- Maintenance frequency and oil used?

- Change and
consumption of oil
If water could come in GMP Annex 6: 5.2.9
- Oil type used contact with medicinal
gas: microbiology?
- Check of bearings
- Air Cooled
- Water cooled (water
quality)
- Pressure
2.6
Separation column
Removal of GMP Chap. 3
- Proper design (valves, contaminants (e. g.
sensors) Argon?)
GMP Annex 6: 5.2
- Maintenance
Checking of important
parameters?
- Removal of (temperature, pressure)
contaminants
- Pressure
- Liquid levels
2.7
Storage tank GMP Chap. 3
- Design GMP Annex 6: 5.2
- Maintenance
- Tank pressure
- Filling level
2.8 Transport process for
Transport process for
Is there a qualification GMP Annex 15
bulk gases bulk gases report for mobile and GMP Annex 6: 3.2.1
stationary storage
• Bulk transport
tank?
• Filling and decantation

Are the mobile tank
procedure
and the storage tank
• Dedicated Mobile dedicated to medicinal
delivery tank gas?
• Storage tank
Identification of filling
points and methods for
prevention of incorrect
connections?

What is your bulk
concept in relation to
mobile tanks?
2.9 In Line Process E. g. In line gas analyzers
Records from dedicated
Monitoring in line process
monitoring equipment? GMP 5.48

Is there a critical
instrument list?

Are there procedures GMP 3.41
for calibration of critical
instruments such as
analyzers?

Have appropriate GMP Annex 6: 3.2.1
calibration tolerances
been applied?

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 Area of operation/Items Items Crucial questions Supporting documents

3. Air separation units GMP Annex 6: 6

Quality control
3.1 Specifications for finished Ph Eur
products
3.2 Quality control labs
Test method
Raw data? GMP Annex 15

Trend analysis
Suitability of the

Validation of analytical method?
methods
Has this equipment set

Tubing distance for up been validated?
sampling and purging
principles when
Is the point of
performing analysis measurement
sufficiently close to the

Calibration gases gas source to ensure

Standards steady state conditions

Microbiological during analyses?
contamination

Particles
Is there a certificate of

OOS analysis available for
the reference gases
used?

3.3
Release
How and who is GMP Annex 6: 2.1 and

responsible? 7.1

Verify products not
released!
4. Air separation units
The syntax of all these GMP Chap. 4
Documentation documents?
4.1
Master batch doc
4.2
Certificate of analysis
4.3
Relevant SOPs
4.4
Logbooks for
equipment

Filling station

5. Filling station
5.1 Supplier of the bulk
Bulk gases
Types of bulk gases? GMP Annex 6: 5.2.10

Agreements?

Requirements for
transport (contract,
dedicated) tanks?

Procedures for loading
and documentation?
5.2 Control of the incoming
Unloading procedure
Procedures for GMP Annex 6: 5.2.10/11
bulk
Definition of batch unloading and
documentation?

Requirements for
documentation
When?

Quality control (testing)
How are deliveries of

gases outside of normal

Release of bulk working hours handled?

Delivery documents
Presence of staff?

Who can unload?

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 Area of operation/Items Items Crucial questions Supporting documents

How hoses are

handled?

What controls are
required for unloading?

QC on delivery vessel
or on bulk tank?

C of A?

Delivery points
protected when not in
use?
5.3 Cylinders
Ownership and types of
Who owns the cylinders GMP Annex 6: 5.3
cylinders and the valves?

Who releases the
containers for the
filling?

Valves; type – including
pressure retention
valves?

Traceability of valves -
batch number of valves/
changing
documentation?

Receiving and
How are cylinders
preparation handled upon receipt?

Are the cylinders
returned by the
customer checked for
open valves to avoid
the risk of
contamination during
storage and
transportation?

Receiving of empty
cylinders: new/ used
ones/ return after
maintenance?

External appearance?

Valves: open or not?

Do you check the
residual pressure?

Procedure with/ without
residual pressure?

Are there internal visual
inspection followed by
cleaning with validated
methods in the case of
cylinders without
residual pressure?

Do the additional
measures for empty
cylinders make sure
that there is no
contamination with
water or other
contaminants?

How are the cylinders

Maintenance
prepared? (connected,

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 Area of operation/Items Items Crucial questions Supporting documents

relabelled, evacuation,
purging)

When and where are
old labels removed?

Washing?

Who is responsible for
their maintenance?

Maintenance records?

What requirements for
maintenance
(hydrostatic test,
pressure testing,
painting, rust, valves)?

Frequency and how
managed?

Maintenance
outsourced?

Hydrostatic pressure
test : quality of the
water used

Internal inspection?

Storage
New cylinders (or
cylinders coming from
hydrostatic pressure
test): who is responsible
for internal inspection?
When and how?

How are cylinders re-
commissioned after
maintenance?

Specification for
Storage of empty and
cylinders and valves filled cylinders (storage,
protection, quarantine)

Are returned cylinders,
prepared cylinders and
full cylinders adequately
segregated?

Specification for
cylinders and valves?
Specifications for the
quality of inner surface
(rust, corrosion,
roughness)?

Cleaning validation
Is there a validation
report?

Is there an adequate
risk analysis taking into
account all impurities
probable in the case of
returning cylinders with
open valves / without
residual pressure (e.g.
rust, dust, residuals of
liquid contamination)?

Valves
Is there an adequate GMP Annex 6: 7.4
protection against
contamination during

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 Area of operation/Items Items Crucial questions Supporting documents

transport?

Are valves gas specific? GMP Annex 6: 5.3.3

Tamper evident seals?

Maintenance of valves:
method, frequency and
documentation?

Traceability
Is there a system to GMP Annex 6: 5.3.3
secure traceability of
cylinders, valves, gases
and filling?
5.4 Premises and equipment
Layout, suitability
Is design suitable for
medicinal gases?

Industrial/medicinal GMP Annex 6: 3.1.1 and
separation? 3.2.4

Access to the filling
area and storage area?

Measures for the
prevention of the
connection of wrong GMP Annex 6: 3.2.2
containers?

Segregation of the
different gases,
cylinders, and of gases GMP Annex 6: 3.1.3
at different stages of
processing?

How are the areas
GMP Annex 6: 3.1.3
marked? Identification?

Pipelines; where,
dedicated, back-flow GMP Annex 6: 3.2.4
valves (to QC, mixing)

Contamination labelling?

Maintenance
(evaporators, tanks, GMP 3.34
flow-meters, pressure
indicators, alarms,
balances, pumps)?

Calibration of
GMP Annex 6: 3.2.1
equipment?

Adequate measures to
prevent contamination
of the manifold/ filing
line?

Control of cleaning and
purging of filling
equipment and GMP Annex 6: 5.3.4
pipelines including
checks for absence of
contaminants?
Records?

How do you avoid
contamination of the
manifold / filling line
with the content of
cylinders which have
been returned for
refilling?

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 Area of operation/Items Items Crucial questions Supporting documents

5.5 Filling process Filling
How is a batch defined? GMP Annex 6: 5.3

Is there a line clearance GMP 5.45
before starting filling?

How is filling controlled
(weight, flow/time,
pressure, feel with
hand)?

If fill controlled by
pressure is settle
pressure measured?

How are mixed gases
filled?

Mixing procedure for
mixed gases (validation,
rolling/tumbling)?

What in process
controls are there
(especially mixed
gases)?

For multi-cylinder
manifolds – how do you
ensure every cylinder is
filled?

Sealing procedure
(tamper evidence)?

Labelling/ content of
label/ reconciliation/
instruction for use?

How are batch labels
prepared and applied?

How are cylinder
bundles, homecare,
mobile containers filled?
Traceability
How do you check
leakage?

Batch documentation GMP Annex 6: 4.1
(what, when, how, by
whom), gas batch,
cylinders?
5.6 Quality control
Testing of bulk gas
At what points are GMP Annex 6: 6
samples withdrawn i.e.
from the tanker prior to
delivery into the storage
tank?

Specs?

What is the extent of
testing performed?

Is bulk gas released
before filling into the
cylinders?

Testing of final product
What is the sample size

(sampling plan) for filled
cylinders?

Test methods

How is testing done and
by whom?

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 Area of operation/Items Items Crucial questions Supporting documents

Specifications?

Documentation and
evaluation of results
(sign.)?

Methods validated?

Instruments
(calibration)?

Calibration gases
(certificates,
procedure)?

Quarantine (physical,
administrative)
OOS?

Release
Are filled cylinders
quarantined before
release?

Who is authorised to
release?

Procedure (who and
how)?

Are there appropriate
alert and action limits
set to see process
deviations on time (e.g.
for water content)?
5.7 Distribution
Do distribution records GMP Annex 6, 7
provide traceability?

Are cylinders
adequately protected
during transport?

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 Area of
Items Questions to consider
operation/Items

6. ADDENDUM ON THE MANUFACTURE OF MEDICINAL GASES AT HOSPITALS

6.
6.1 Responsibility
Organisation chart, job descriptions
Who is responsible for the manufacturing

Contracts? Manufacturing licences and the distribution of medicinal gases in
the hospital?

Responsibility of the pharmacy
6.2 Premises and
Location management
Who has access? How is access control
Equipment / Production organized?

Drawings, List of equipment?

Is production equipment released for use
in manufacturing of medicinal gases
(qualification report)?
6.3 Maintenance
Maintenance
How are the intervals for preventive

Documentation maintenance determined?

Outsourcing policy, acceptance (e.g.
leakage tests)?

How are measuring devices calibrated?
6.4 Inspection of the system
Daily inspection e.g. pressure
control and other critical
parameters / areas
6.5 Cleaning measures
Premises and equipment
For pipelines and storage tanks normally
cleaning is not necessary; if there are
any critical cleaning measures, they
have to be validated)

Storage areas (cylinders) clean and tidy?
6.6 Medicinal (compressed)
Air inlet
Source, contamination, filtration?
Air
Are there specifications for the porosity
and material of the filter?

Compressor room condition
Hygiene, temperature, ventilation, clean

and tidy?

Pipeline system
Are pipelines colour coded; is the coding

Pressure and temperature standardized in a written procedure?

Is there a SOP for purging of pipelines?

Filters
Are design, size and sequence of the
filters suitable?

Pre, final, frequency of change,
saturation, integrity?

How are filters maintained (frequency of
change, records)?

Contamination
Is there a risk of contamination e.g. from

the exhaust of the vacuum system of the
hospital (often also situated in the
compressor room)?

Oil, water, other gases (as specified in
the European Pharmacopoeia)?

Receiver vessels
Material, condensation?

Dryer
Alarm system, water traps?

Online monitoring of dew point (water
content)?

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 Area of
Items Questions to consider
operation/Items

Are adsorption dryers used?

Pipelines
Material, condition, welds and as plan?

Back-up system
Is there a back-up system?

Capacity
Is the capacity of the system sufficient?
6.7 Medicinal Oxygen

Storage tank / evaporator unit
Owner?

History of equipment?

Back-up
Is there a back-up system?

Delivery
Dedicated mobile tank?

CoA given by the supplier when
delivered?

Filling procedure
SOP, personnel of the hospital should be
present, delivery has to be released
before filling

Release of the medicinal product
Who is responsible for the release after
refilling of the storage tank?

Non-return valve
There should be a validated method of
backflow prevention in the line supplying
the hospital to prevent contamination of
the storage tank / evaporator unit.
6.8 Quality Control

Test methods

Specification
Specification should be based on the
European Pharmacopoeia

Validation of methods
Especially, in the case of air, for the
testing of oil (e.g. method has to be
specific for the oil used for lubrication of
the compressors)

Testing
Identity, at least every delivery of raw
materials, together with a qualified
certificate of the supplier (if liquid oxygen
is not delivered as a medicinal product)?

Impurity (regular testing of the finished
product, e.g. twice a year if the
equipment is qualified and regular
maintenance is accomplished)?

Content (e.g. once a year in the case of
oxygen)?

Are samples of the finished products
taken at the end of the pipeline?

Bioburden (e.g. twice a year
microbiological testing of the medicinal
3
air, limit 10 cfu/m );

Particles?

OOS?

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 7. REVISION HISTORY

Version
Date Reasons for revision
number
25 September 2007 PI 025-2 Change in the Editor’s co-ordinates

*******

PI 025-2 14 of 14 25 September 2007