Annex “Handbook of Good Manufacturing Practices for Medical Gases”  1 
G/TBT/N/COL/125  
Adopting the Handbook of Good Manufacturing Practices for Medical Gases and 
laying down other provisions  
THE MINISTER OF SOCIAL WELFARE,  
Availing himself of his statutory powers, especially those conferred by Article 173 of 
Law 100 of 1993 and implementing the provisions of Article 12 of Decree 677 of 
1995 and Article 2 of Decree 205 of 2003,  
WHEREAS  
Decree 677 of 1995 partially governing the system of records, quality control and the 
system of health monitoring for medicines, among other th ings, lays down in Article 
12 the requirement for pharmaceutical laboratories to implement and comply with 
good manufacturing practice.  
Article 9 of Decree 549 of 2001 prohibits the manufacture or importation of medicinal 
products from laboratories manufac turing them without a certificate of good 
manufacturing practice.  
Medical gases, as pharmaceutical preparations used in the prevention, diagnosis, 
treatment, relief or cure of illnesses or ailments and in inhalation therapies, 
anaesthesia, “in vivo” diagno sis or in the preservation and transport of organs, tissues 
and cells for medical practice, are classified as medicinal products.  
While medical gases are regarded as medicinal products, current regulations for 
medicinal products and the relevant inspection  handbook are not applicable to 
manufacturing facilities for them, as the manufacturing processes for medical gases 
are quite different from those used to produce medicinal products.  
The manufacture of medical gases is a specialised industrial process requ iring special 
design, production capacity, storage, distribution, maintenance and supply; there is 
therefore a need to define the special characteristics relating to their manufacture and 
quality control.  
On the basis of international standards on producti on and handling of medical gases, 
such as:  NFPA99 (National Fire Protection Association), ISO10083 (National 
Standard Oxygen Concentrators for Use with Medical Gas Pipeline System) of 1992, 
Report No 32 of the World Health Organization, this Ministry has d rafted this 
document as the technical annex on good manufacturing practice.  
In the light of the above,  
HEREBY DECIDES AS FOLLOWS:  
ARTICLE 1.  The handbook of good manufacturing practices for medical gases, 
contained in the technical annex that forms an inte gral part of this Resolution is 
hereby adopted. It shall be mandatory to comply with it and apply it in the processes 
of manufacture, quality control and marketing of medical gases by the industry and 
institutions providing health services.  Annex “Handbook of Good Manufacturing Practices for Medical Gases”  2 
ARTICLE 2.  Good  manufacturing practice and quality control in pharmaceutical 
processes relating to medical gases shall be applied under the technical direction of a 
pharmaceutical chemist legally entitled to carry out the profession.  
ARTICLE 3.  Invima may allow establish ments manufacturing medical gases up to 
one year after publication of this Resolution to comply with the new requirements for 
good manufacturing practice laid down the technical annex that forms an integral part 
of the Resolution.  
PARAGRAPH 1.  Establishmen t commencing their activities after the entry into force 
of this Resolution shall comply in full with the requirements set out in the technical 
annex that forms an integral part of this Resolution.  
PARAGRAPH 2.  The bodies referred to in Article 1 of this R esolution that do not 
comply shall be subject to the health safety measures and penalties laid down in 
Decree 677 of 1995.  
ARTICLE 4.  This Resolution shall apply from the date of its publication, shall 
derogate from Resolution 1672 of 2004 and amend Resolu tion 3862 of 2005 as 
appropriate.  Annex “Handbook of Good Manufacturing Practices for Medical Gases”  3 
TECHNICAL ANNEX  
HANDBOOK OF GOOD MANUFACTURING PRACTICES FOR MEDICAL GASES  
GLOSSARY  
MEDICAL COMPRESSED AIR. - Synthetic or natural mixture of gases, principally oxygen 
and nitrogen supplied from cylinders, bulk containers or medical air compressors.  
OPERATING ALARM. - Visual or audible alarm to indicate the need to adjust the supply or 
correct a malfunction.  
EMERGENCY ALARM. - Visual or audible alarm to indicate that the supply is outside 
normal operating limits.  
MANUAL OXYGE N ANALYSERS. - Oxygen analysers operating with the principles of 
electrochemical, galvanic, paramagnetic or polarographic fuel cell principles and which have 
to be calibrated using certified standards.  
RATED CAPACITY. - Flow that the oxygen concentrator syst em can maintain continuously 
without the secondary supply (if any) or reserve supply coming into operation.  
CYLINDER. - Vessel designed for gases at low or high pressure, compressed or liquefied.  
MEDICAL OXYGEN CONCENTRATOR. - System with compressors of air only, to produce 
oxygen -enriched air from ambient air, by means of molecular sieve apparatus.  
MOLECULAR SIEVE APPARATUS. - Apparatus to increase the concentration of oxygen in 
ambient air by absorbing nitrogen and other gaseous components.  
CONTAINERS. - Gene ric term denoting gas vessels.  
DISTRIBUTOR. - Someone who receives finished medicinal products, duly labelled, in large 
cryogenic vessels and/or high -pressure cylinders, and does not manipulate the product or the 
labelling in any way.  
VESSEL. - Cryogenic the rmos flask, tank or cylinder in contact with medical gas.   
Cryogenic vessels or Dewars are portable containers used to supply liquid products at low 
pressure and temperature.  Cryogenic vacuum flasks are stationary or movable vacuum -
insulated containers for  containing liquefied gas.  Tanker trucks can carry liquefied gas.  
PACKAGING OF MEDICAL GAS. - All the operations, including filling and labelling, that a 
bulk medical gas has to undergo to be converted into a finished product.  
CRYOGENIC VESSELS OR DEWARS. - Portable vessels used to store liquid products at 
low pressure and temperature, similar in design to thermos flasks insulated with a vacuum 
between the inner and outer parts.  
CRYOGENIC VESSELS FOR HOME USE. - Vessels designed to store liquid oxygen for 
home  care of patients.  
CONTROL EQUIPMENT. - Apparatus needed to keep control variables within the specified 
limits.  Annex “Handbook of Good Manufacturing Practices for Medical Gases”  4 
MEDICAL GAS MANUFACTURING PLANT. - A pharmaceutical plant that manufactures 
the product in both liquid or gas form and/or that fills liquid to liq uid, liquid to gas or gas to 
gas. 
MICROBIOLOGICAL FILTER. - Filter designed to retain micro -organisms.  
MEDICAL GAS. - Medicinal product consisting of one or more gaseous components suitable 
for coming into direct contact with the human organism, of known con centration and 
prepared in accordance with pharamacopoeic specifications.  Gases used in inhalation therapy, 
anaesthesia, in vivo  diagnosis or for preserving or transporting organs, tissues and cells for 
use in medical practice must comply with the specific ations for medical gases.  
BATCH. - Each cylinder, flask or cryogenic vessel filled individually or set of containers 
corresponding to the manufacture in a particular period in such a way that the end product is 
homogeneous.  In the case of gases packaged in manifolds, the batch consists of the containers 
filled uninterruptedly; and in each cryogenic tanker truck a batch consists of the mixture 
resulting from the residual product in the container plus the new product.  In the case of a 
continuous manufacturing process, the batch must correspond to a defined fraction of 
production over time, characterised by a homogenous product.  
MANIFOLD OR FILLING RACK. - Equipment used to fill one or more containers with gas 
simultaneously.  
MEDICAL OXYGEN OBTAINED BY LIQUEFYING  AIR. - The medicinal product in gas 
or liquid pharmaceutical form, distributed in cryogenic containers or compressed in high -
pressure containers.  
MEDICAL OXYGEN OBTAINED BY THE MOLECULAR SIEVE PROCESS. - oxygen in 
gaseous pharmaceutical form, obtained from oxygen concentrators.  
SOUND OR HAMMER TEST. - Prueba para determinar el grado de corrosión o daño interno 
de las paredes de un cilindro.  
HYDROSTATIC TEST. - Hydraulic test applied to high -pressure containers required in 
specifications for safety reasons to c heck that cylinders, pipes and tanks can be used at high 
pressure.  
DEW POINT.  The dew point or dew temperature  is the temperature at which the 
water vapour in the air begins to condense into dew, mist and, where the temperature 
is low enough, frost.  
CONTIN UOUS FILLING SEQUENCE. - Simple continuous filling, without interruptions or 
drops or stoppages in the systems during filling.  This process does not apply to the filling of 
high-pressure cylinders in a multiple filling manifold or rack.  
OXYGEN CONCENTRATOR SYSTEM. - Method for producing oxygen -enriched air from 
ambient air using air compressors and molecular sieves, known as pressure swing adsorption 
(PSA) systems.  
PIPING SYSTEM (FOR NON -FLAMMABLE MEDICAL GAS). - Central supply system 
with control equipment an d a system of piping extending to outlet terminals where non -
flammable medical gases are used.  
PIPED DISTRIBUTION SYSTEM. - The part of a piping system joining the supply source to 
the outlet terminals, including valves isolating the branches and additional  pressure regulators Annex “Handbook of Good Manufacturing Practices for Medical Gases”  5 
as required to reduce the pressure from the supply source in any part of the distribution 
system  
PRIMARY SUPPLY. - The part of the medical oxygen concentrator system feeding the 
distribution line.  
SECONDARY SUPPLY. - The part of the med ical oxygen concentrator system that 
automatically feeds the distribution line if the primary supply fails.  
RESERVE SUPPLY. - The part of the medical oxygen concentrator system that automatically 
feeds the distribution line if the primary and secondary supp lies fail.  
STATIONARY TANK. - A high -capacity stationary container for storing product in liquid 
form.  Located outside premises.  
NON -RETURN VALVE. - Mechanical device designed to prevent the return of gaseous 
fluids, ensuring that they move in one direction only.  
GENERAL CONSIDERATIONS  
A. Medical gases must be prepared by establishments whose manufacturing processes are 
periodically inspected by the competent authorities.  The Handbook of Good Manufacturing 
Practices for Medical Gases is to be applied as an in dispensable guide for satisfying the 
required conditions for the manufacture and marketing of medical gases, with a view to 
guaranteeing the user good quality, safe and effective products.  
B. Establishments manufacturing, filling, storing, distributing and  marketing medical gases 
must comply with current official standards on health and safety at the work place.  
1. QUALITY ASSURANCE  
1.1 Principle.  Quality Assurance is a wide ranging concept which covers all matters that 
individually or collectively influenc e the quality of a product.  It is the total sum of the 
organised arrangements made with the object of ensuring that medicinal products are of the 
quality required for their intended use.  
Quality Assurance therefore incorporates good manufacturing practice (GMP) plus other 
factors such as product design and development.  
1.2 A system of quality assurance appropriate for the manufacture of pharmaceutical products 
should ensure that:  
a) pharmaceutical products are designed and developed in a way that takes acco unt of 
the requirements of GMP;  
b) production and control operations are clearly specified in writing and good 
manufacturing practice adopted;  
c) managerial responsibilities are clearly specified in job descriptions;  
d) arrangements are made for the manufa cture, supply and use of the correct starting and 
packaging materials;  
e) all necessary controls on starting materials, intermediate products, and bulk products, 
and any other in -process controls, calibrations, and checks are carried out;  Annex “Handbook of Good Manufacturing Practices for Medical Gases”  6 
f) the finished p roduct is properly processed and checked, according to the defined 
procedures;  
g) pharmaceutical products are not sold or supplied before the qualified persons have 
certified that each production batch has been produced and controlled in accordance 
with th e requirements of the authorities responsible for marketing and any other 
regulations relevant to the production, control and release of pharmaceutical 
products;  
h) satisfactory arrangements exist to ensure, as far as possible, that the pharmaceutical 
products are stored by the manufacturer, distributed and subsequently handled so that 
quality is maintained throughout their shelf life;  
i) there is a procedure for self -inspection or internal quality audit which regularly 
appraises the effectiveness and appli cability of the quality assurance system.  
1.3 The manufacturer must take responsibility for the quality of the medical gases, 
guaranteeing that they are fit for the intended purpose, satisfy the requirements for their 
marketing to be authorised and present  no risk to the patient.  The attainment of this quality 
objective is the responsibility of the managerial and administrative levels of manufacturing 
establishments.  To achieve this quality objective there must be a comprehensively designed 
and correctly im plemented system of quality assurance incorporating good manufacturing 
practice and thus quality control.  It should be fully documented and its effectiveness 
monitored.  All parts of the quality assurance system should be adequately resourced with 
competent  personnel, and suitable and sufficient premises, equipment and facilities.  
2. GOOD MANUFACTURING PRACTICES (GMP) FOR MEDICAL GASES  
2.1 Good manufacturing practice for medical gases is that part of quality assurance which 
ensures that products are consiste ntly produced and controlled to the quality standards 
appropriate to their intended use and as required by the marketing authorisation.  The principal 
aim of the rules governing GMP is to reduce the risks inherent in any pharmaceutical 
production that canno t be completely prevented by comprehensive control of the products.  
These risks are of two basic types: cross -contamination (notably by unforeseen contaminants) 
and mix -ups (owing to incorrect labelling of vessels).   
The basic requirements of GMP are that:  
a) all manufacturing processes are clearly defined, systematically reviewed in the light 
of experience and shown to be capable of consistently manufacturing pharmaceutical 
products of the required quality and complying with their specifications;  
b) critic al steps of manufacturing processes and significant changes to the process are 
validated;  
c) all necessary facilities are provided including:  
1) appropriately qualified and trained personnel;  
2) appropriate infrastructure and space;  
3) suitable equipment a nd services;  
4) correct materials, vessels and labels;  Annex “Handbook of Good Manufacturing Practices for Medical Gases”  7 
5) approved procedures and instructions;  
6) suitable storage and transport, and  
7) appropriate personnel, laboratories and equipment for carrying out controls during the 
production process, under the r esponsibility of production management;  
d) instructions and procedures are written in clear and unambiguous language, 
specifically applicable to the facilities provided;  
c) operators are trained to carry out procedures correctly;  
f) records are made, manua lly and/or by recording instruments, during manufacture 
which demonstrate that all the steps required by the defined procedures and 
instructions were in fact taken and that the quantity and quality of the product was as 
expected. Any significant deviations  are fully recorded and investigated;  
g) records of manufacture including distribution which enable the complete history of a 
batch to be traced, are retained in a comprehensible and accessible form;  
h) the storage and distribution of the products minimise s any risk to their quality;   
i) a system is available to recall any batch of product, from sale or supply;  
j) complaints about marketed products are examined, the causes of quality defects 
investigated and appropriate measures taken in respect of the defe ctive products and 
to prevent recurrence.  
3. QUALITY CONTROL  
3.1 Quality Control is that part of GMP which is concerned with  sampling, specifications and 
testing, and with the organisation, documentation and release procedures which ensure that 
the necessa ry and relevant tests are actually carried out and that materials are not released for 
use, nor products released for sale or supply, until their quality has been judged to be 
satisfactory.  Quality control is not restricted to laboratory operations, but mu st be applied in 
all decisions relating to product quality.  
3.2 Any holder of a manufacturing permit must have a quality -control section or department 
or person responsible for quality control if it is contracted out.  It is of fundamental importance 
for qu ality control to be independent of production.  The quality -control section or department 
must also be independent of other departments or sections and must be under the authority of 
a qualified and experienced person with access to one or more control labo ratories.  It must 
have sufficient resources to ensure that quality -control procedures can be carried out 
effectively and reliably.  The basic requirements of quality control are that:  
a) adequate facilities, trained personnel and approved procedures are ava ilable for 
sampling, inspecting and testing starting materials, packaging materials, intermediate, 
bulk, and finished products, and where appropriate for monitoring environmental 
conditions for GMP purposes;  
b) samples of starting materials, packaging mate rials, intermediate products, bulk 
products and finished products are taken by personnel and by methods approved by 
quality control;  
c) test methods are validated;  Annex “Handbook of Good Manufacturing Practices for Medical Gases”  8 
d) records are made, manually and/or by recording instruments, which demonstrate that 
all th e required sampling, inspecting and testing procedures were actually carried out. 
Any deviations are fully recorded and investigated;  
c) the finished products contain active ingredients complying with the qualitative and 
quantitative composition of the mar keting authorisation, are of the purity required, 
and are enclosed within their proper containers and correctly labelled;  
f) records are made of the results of inspection and that testing of materials, 
intermediate, bulk, and finished products is formally assessed against specification.  
Product assessment includes a review and evaluation of relevant production 
documentation and an assessment of deviations from specified procedures;  
g) no batch of product is released for sale or supply prior to certification  by a qualified 
person that it is in accordance with the requirements of the marketing authorisation.  
h) sufficient solid and liquid starting materials are kept to enable them to be examined in 
future if necessary.  This requirement does not apply to gaseou s starting materials nor 
to liquefied medical gases used as a starting material that are subsequently gasified, 
nor to finished products.  
3.3 The quality -control department or section or the person responsible for it should establish, 
validate and implemen t all quality control procedures, keep and store the reference samples of 
materials and products, ensure the correct labelling of containers of materials and products, 
ensure the monitoring of the stability of the active pharmaceutical ingredients, partici pate in 
the investigation of complaints related to the quality of the product, and take part in 
environmental monitoring.  All these operations should be carried out in accordance with 
written procedures and, where necessary, recorded.  
3.4 Finished product assessment should embrace all relevant factors, including production 
conditions, results of in -process testing, a review of manufacturing (including packaging) 
documentation, compliance with finished product specification and examination of the final 
finished pack.  
3.5 Quality control personnel should have access to production areas for sampling and 
investigation as appropriate.  
4. SANITATION AND HYGIENE  
All aspects of the manufacture of pharmaceutical products must be accompanied by a high 
level of sanitat ion and hygiene, covering production personnel, premises, equipment and 
apparatus, materials and containers, cleaning and disinfecting products and anything that 
might be a source of contamination of the product.  All possible sources of contamination 
must be removed by means of a comprehensive sanitation and hygiene programme.  
5. VALIDATION  
5.1 Validation studies are an essential part of GMP and should be conducted in accordance 
with predefined protocols.  A written report summarizing the results recorded an d the 
conclusions reached should be prepared and filed.  Processes and procedures should be 
established on the basis of the results of a validation study; they should be revalidated 
periodically to ensure that they are still appropriate for obtaining the de sired results.  Special 
attention should be paid to validating processing, testing and cleaning procedures.  Annex “Handbook of Good Manufacturing Practices for Medical Gases”  9 
5.2 Process validation.  Processes of critical importance must be validated prospectively and 
retrospectively.  
5.3 Whenever a preparation method or fo rmula is adopted, measures must be taken to 
demonstrate that they are suitable for the process usually used.  It must be demonstrated that 
the process defined, using the specified materials and equipment, results in a product of the 
required uniform quality . 
5.4 Any major change in the manufacturing process must be validated, including any change 
in equipment or materials that might affect the quality of the product and/or the 
reproducibility of the process.  
6. COMPLAINTS  
6.1 Principle.  All complaints and ot her information concerning potentially defective products 
must be reviewed carefully in accordance with written procedures.  
6.2 A person should be designated responsible for handling the complaints and deciding the 
measures to be taken together with suffic ient supporting staff to assist him.  If this person is 
not the qualified person, the latter should be made aware of any complaint, investigation or 
recall.  
6.3 There should be written procedures describing the action to be taken, including the need 
to cons ider a recall, in the case of a complaint concerning a possible product defect.  
6.4 Any complaint concerning a product defect should be recorded with all the original details 
and thoroughly investigated.  The person responsible for quality control should al ways be 
involved in the study of such problems.  
6.5 If a product defect is discovered or suspected in a batch, consideration should be given to 
checking other batches in order to determine whether they are also affected.  
6.6 Where necessary, there must be a follow -up, which may include recalling the product, 
when investigating and assessing the complaint.  
6.7 All the decisions and measures taken as a result of a complaint should be recorded and 
referenced to the corresponding batch records.  
6.8 Complaints r ecords should be reviewed regularly for any indication of specific or 
recurring problems requiring attention and possibly the recall of marketed products.  
6.9 The competent authorities should be informed if a manufacturer is considering action 
following fa ulty manufacture, product deterioration or any other serious quality problems 
with a product.  
7. PRODUCT RECALLS  
7.l Principle.  There must be a system for recalling a product from the market quickly and 
effectively where it is defective or is suspected of being defective.   
7.2 A person should be designated as responsible for execution and co -ordination of recalls 
and should be supported by sufficient staff to handle all the aspects of the recalls with the 
appropriate degree of urgency.  This person should be  independent of the sales and marketing 
organisation.  If this person is not the qualified person for product authorisation, the latter 
should be made aware of any recall operation.  Annex “Handbook of Good Manufacturing Practices for Medical Gases”  10 
7.3 There should be established written procedures, regularly checked and u pdated when 
necessary, for any recall activity.  Recall operations should be initiated promptly, at least with 
institutions providing health services.  
7.4 The competent authorities of all countries to which products may have been distributed 
should be infor med promptly if products are intended to be recalled because they are, or are 
suspected of being defective.  
7.5 In order for a product recall to be effective, the distribution records should be readily 
available to the person responsible for recalls, and s hould contain sufficient information on 
wholesalers and directly supplied customers, including – for exported products – the 
addressees of samples for clinical trials and medical samples.  
7.6 The progress of the recall process should be recorded and a fina l report issued, including a 
reconciliation between the delivered and recovered quantities of the products.  
7.7 The effectiveness of the arrangements for recalls should be reviewed and evaluated 
regularly.  
7.8 Recalled products should be identified and sto red separately in a secure area while 
awaiting a decision on their fate.  
8. CONTRACT MANUFACTURE AND ANALYSIS  
8.1 Principle.  Contract manufacture and analysis of medical gases must be correctly defined, 
agreed and controlled in order to avoid misunderstand ings which could result in a product or 
work of unsatisfactory quality.  There must be a written contract between the contract giver 
and the contract acceptor which clearly establishes the duties of each party.  
 The contract must clearly state the way in wh ich the qualified person releasing each batch of 
product for sale or issuing the analysis certificate exercises his full responsibility.  
8.2 General  
8.2.1 All arrangements for contract manufacture and analysis of medical gases, including any 
proposed chang es in technical or other arrangements, should be in accordance with the 
marketing authorisation for the product concerned  
8.2.2 There should be a written contract covering the manufacture and/or analysis of products 
and any technical arrangements made in c onnection with them.  
8.2.3 The contract must allow the contract giver to have the contract acceptor’s premises 
audited.  
8.2.4 If analysis takes place on a contract basis, the qualified person is responsible for 
granting final approval before the product is  released to go into circulation.  
8.3 The contract giver  
8.3.1 The contract giver is responsible for assessing the competence of the contract acceptor 
to carry out successfully the work or tests required and for ensuring by means of the contract 
that the p rinciples and guidelines of GMP as interpreted in this Handbook are followed.  
8.3.2 The contract giver should provide the contract acceptor with all the information 
necessary to carry out the contracted operations correctly in accordance with the marketing  
authorisation and any other legal requirements.  Annex “Handbook of Good Manufacturing Practices for Medical Gases”  11 
The contract giver should ensure that the contract acceptor is fully aware of any problems 
associated with the product or the work which might pose a hazard to his premises, 
equipment, personnel, other mate rials or other products.  
8.3.3 The contract giver should ensure that all processed products and materials delivered to 
him by the contract acceptor comply with their technical specifications or that the products 
have been released for marketing by a qualif ied person.  
8.4 The contract acceptor  
8.4.1 The contract acceptor must have adequate premises and equipment, knowledge and 
experience to carry out satisfactorily the work ordered by the contract giver.  Contract 
manufacture may be undertaken only by a manuf acturer who is the holder of a manufacturing 
authorisation.  
8.4.2 The contract acceptor should not pass to a third party any of the work entrusted to him 
under the contract without the contract giver’s prior evaluation and approval of the 
arrangements.  Arrangements made between the contract acceptor and any third party should 
ensure that the manufacturing and analytical information is made available in the same way as 
between the original contract giver and contract acceptor.  
8.4.3 The contract acceptor sho uld refrain from any activity which may adversely affect the 
quality of the product manufactured and/or analysed for the contract giver.  
8. 5 The contract  
8.5.1 A contract should be drawn up between the contract giver and the contract acceptor 
which specif ies their respective responsibilities relating to the manufacture and control of the 
product. All arrangements for manufacture and analysis must be in accordance with the 
marketing authorisation and agreed by both parties.  
8.5.2 The contract should specify  the way in which the qualified person releasing the product 
for sale ensures that each batch has been manufactured and checked for compliance with the 
requirements of marketing authorisation.  
8.5.3 The contract should describe clearly who is responsible f or purchasing materials, testing 
and releasing materials, undertaking production and quality controls, including in -process 
controls, and who has responsibility for sampling and analysis.  In the case of contract 
analysis, the contract should state whether or not the contract acceptor should take samples at 
the premises of the manufacturer.  
8.5.4 Manufacturing, analytical and distribution records, and reference samples should be 
kept by, or be available to, the contract giver.  Any records relevant to assessi ng the quality of 
a product in the event of complaints or a suspected defect must be accessible and specified in 
the defect/recall procedures of the contract giver.  
8.5.5 The contract should describe the handling of starting materials and bulk, intermediat e 
and finished products in the event of their being rejected.  The processing of information must 
also be described where the analysis conducted indicates that the product analysed must be 
rejected.  
9. SELF -INSPECTION AND QUALITY AUDITS  
9.1 Principle.  The p urpose of self -inspection is to assess the manufacturer’s compliance with 
GMP in all aspects of production and quality control.  The self -inspection programme must be Annex “Handbook of Good Manufacturing Practices for Medical Gases”  12 
designed to detect any non -compliance with GMP and recommend any necessary corrective 
meas ures.  Self-inspection should be carried out regularly, and may also be carried out on 
special occasions, such as when a medical gas is recalled or repeatedly rejected, or when the 
official health authorities announce an inspection.  The group responsible fo r self -inspection 
should include persons able to assess compliance with GMP in an objective manner.  All 
recommendations for corrective measures must be implemented.  The self -inspection 
procedure must be documented, and an effective monitoring programme set  up. 
9.2 Self -inspection points  
9.2.1 Written instructions for self -inspection must be drafted to establish minimum standards 
and uniform requirements covering at least the following:  
a) Personnel  
b) Premises, including those for personnel  
c) Maintenance o f buildings and equipment  
d) Storage of starting materials and finished products  
e) Equipment  
f) Production, and controls during processing  
g) Quality control  
h) Documentation  
i) Sanitation and hygiene  
j) Validation and revalidation programmes  
k) Calibrati on of measuring instruments or systems  
l) Procedures for recalling products from the market  
m) Handling of complaints  
n) Control of labelling  
o) Results of previous self -inspections and corrective measures adopted  
9.3 Self -inspection team  
9.3.1 A self -inspection team must be designated of local experts in their respective fields and 
familiar with GMP.  The team may consist of persons from within the body or institution or 
outside it.  
9.4 Self -inspection frequency  
9.4.1 The frequency of self -inspection will d epend on the needs of each body or institution . 
9.5 Self -inspection report  
9.5.1 Once the self -inspection is completed a report must be drafted on it, including:  Annex “Handbook of Good Manufacturing Practices for Medical Gases”  13 
a) Self-inspection results,  
b) Assessment and conclusions, and  
c) Recommended corrective measu res. 
9.6 Monitoring  
9.6.1 The administration of the body or institution should assess both self -inspection and the 
necessary corrective measures.  
9.7 Quality audit  
9.7.1 Self -inspection may be complemented by a quality audit, consisting of an examination 
and assessment of all or part of the quality system, with the specific aim of improving it.  The 
quality audit may be carried out by independent specialists from outside the body, specialist 
institutions or working teams specifically designated by the same b ody to that end.  The audit 
may also extend to suppliers and contract acceptors.  
9.8 Audit of suppliers  
9.8.1 The quality -control department or section and other relevant sections are responsible for 
approving suppliers that can be entrusted with the respon sibility for supplying starting and 
packaged materials that satisfy the specifications laid down.  
9.8.2 Before a supplier is approved and included in the specifications, it must be assessed, 
taking account of the supplier’s background and the nature of the  materials required.  If an 
audit is necessary, it should include an assessment of the supplier’s capability to comply with 
GMP standards.  
10. PERSONNEL  
10.1 Principle.  The establishment and maintenance of a satisfactory system of quality 
assurance and the correct manufacture of medicinal products relies upon people.  For this 
reason there must be sufficient qualified personnel to carry out all the tasks which are the 
responsibility of the manufacturer.  Individual responsibilities should be clearly understood  by 
everyone involved and recorded.  All personnel should be aware of the principles of good 
manufacturing practice that affect them.  
10.2 General  
10.2.1 The manufacturer should have an adequate number of personnel with the necessary 
qualifications in the p rocesses in use.  The responsibilities placed on any one individual should 
not be so extensive as to present any risk to quality.  
10.2.2 The manufacturer must draw up an organisation chart and a specific job description for 
each employee.  Moreover, all empl oyees should have adequate authority to carry out their 
duties and responsibilities.  
Duties may be delegated provided they are delegated to suitable persons.  Duties should be 
assigned to specific personnel and there should be no gaps or overlaps in their 
responsibilities.   
10.2.3 All personnel must know the principles governing GMP relating to their job, and 
receive initial and in -service training as required by their job, with special emphasis on Annex “Handbook of Good Manufacturing Practices for Medical Gases”  14 
hygiene -related aspects.  Personnel must be motivated to comp ly with appropriate quality 
standards.  
10.2.4 The necessary measures must be adopted to prevent unauthorised persons entering 
production, storage and quality -control areas.  Personnel not working in such areas must not 
use them as through -routes to other ar eas. 
10.3 Key personnel  
10.3.1 Key personnel include the technical director, a professionally qualified pharmaceutical 
chemist, the head of production, the head of quality control, and qualified person(s) who 
should be full -time personnel.  The heads of pro duction and quality control must be 
independent from each other.  In very large institutions, some of his functions may be 
delegated, but not his responsibility.  
10.3.2 The heads of quality assurance, production and quality control must be professionally 
qualified and demonstrably suitable for carrying out the duties assigned by the body or 
institution; in any case, each product batch must be released under the responsibility of a 
professional pharmaceutical chemist.  
10.3.3 The heads of Production and Qualit y Control generally have some shared, or jointly 
exercised, responsibilities relating to quality.   
These may include:  
a) the authorisation of written procedures and other documents, including amendments;  
b) the monitoring and control of the manufacturing e nvironment;  
c) plant hygiene;  
d) process validation and calibration of the analysis instruments;  
e) training, covering the principles and application of quality assurance;  
f) the approval and monitoring of suppliers of materials;  
g) the approval and monito ring of contract manufacturers;  
h) the designation and monitoring of storage conditions for materials and products;  
i) the keeping of records;  
j) the monitoring of compliance with GMP requirements;  
k) the inspection, investigation and taking of samples, in  order to monitor factors that 
may influence product quality.  
10.3.4 The head of the production department generally has the following responsibilities:  
a) to ensure that products are produced and stored according to the appropriate 
documentation in order to obtain the required quality;  
to approve the instructions relating to production operations, including in -process controls, 
and to ensure their strict implementation;  Annex “Handbook of Good Manufacturing Practices for Medical Gases”  15 
c) to ensure that the production records are evaluated and signed by an authorised 
person before they are sent to the quality -control department;  
d) to check the maintenance of his department, premises and equipment;  
e) to ensure that the appropriate checks are carried out of processing and calibrations of 
the control equipment, and that suc h checks are recorded and that the reports are 
available;  
f) ensuring that initial and continuing training of the production personnel is carried out, 
and adapted according to needs.  
10.3.5 The head of the quality -control department generally has the follo wing responsibilities:  
a) to approve or reject starting materials, packaging materials, and intermediate, bulk 
and finished products;  
b) to evaluate batch records;  
c) to ensure that all the necessary testing is carried out;  
d) to approve specifications, sa mpling instructions, test methods and other quality -
control procedures;  
e) to approve and monitor any contract analysis;  
f) to check the maintenance of his department, premises and equipment;  
g) to ensure that the appropriate validations are carried out, i ncluding of the analysis 
processes and control equipment;  
h) to ensure that initial and continuing training of the personnel is carried out and 
adapted according to needs.  
Other duties of the quality -control department are described in section 3.2.  
10.4 Tr aining  
10.4.1 The manufacturer should provide training on the basis of a written programme for all 
the personnel whose duties take them into production areas or into control laboratories 
(including the technical, maintenance and cleaning personnel), and fo r other personnel whose 
activities could affect the quality of the product.  
10.4.2 Besides the basic training on the theory and practice of GMP, newly recruited 
personnel should receive training appropriate to the duties assigned to them. Continuing 
traini ng should also be given, and its practical effectiveness should be periodically assessed. 
Training programmes should be available, approved by either the head of production or the 
head of quality control, as appropriate. Training records should be kept.  
10.4.3 Personnel working in areas where contamination is a hazard, e.g. clean areas or areas 
where highly active, toxic or sensitising materials are handled, should be given specific 
training.  
10.4.4 The concept of quality assurance and all the measures capa ble of improving its 
understanding and implementation should be fully discussed during the training sessions.  Annex “Handbook of Good Manufacturing Practices for Medical Gases”  16 
10.4.5 Visitors or untrained personnel should, preferably, not be taken into the production and 
quality control areas.  
 If this is unavoidable, th ey should be given information in advance, particularly about 
personal hygiene and the prescribed protective clothing.  
10.5 Personal hygiene  
10.5.1 All personnel should receive medical examination upon recruitment and throughout 
their employment.  
10. 5.2 A ll personnel must receive training in the practice of personal hygiene.  All persons 
involved in the manufacturing process must observe a high level of personal hygiene.  In 
particular, personnel should be instructed to use the hand -washing facilities before  entering 
production areas.  This obligation must be displayed on signs and instructions must be 
complied with.   
10.5.3 No person showing signs of illness or having open lesions, to the extent that they 
might affect product quality, should be allowed to han dle starting, packaged or processed 
materials, or pharmaceutical products until the condition is considered to be cured.  
10.5.4 All employees must be urged to inform their supervisor immediately of any conditions 
(regarding premises, equipment or personnel ) that they consider might have an adverse effect 
on the products.  
10.5.5 Smoking, eating, drinking or chewing, or the keeping of plants, food, drinks, smoking 
materials or medicinal products should be prohibited in production, laboratory and storage 
areas , or in any other area where such activities might have an adverse effect on product 
quality.  
10.5.6 The procedures relating to personal hygiene, including the use of protective clothing, 
apply to anyone entering production areas, whether they are permanen t or temporary 
employees, contractors, visitors, administrators or inspectors.  
11. PREMISES  
11.1 Principle.  Premises must be located, designed, constructed, adapted and maintained to 
suit the operations to be carried out.  Their layout and design must aim t o minimise the risk of 
errors and permit effective cleaning and maintenance in order to avoid cross -contamination, 
build up of dust or dirt and, in general, any adverse effect on the quality of products.  Since 
medical gases are generally manufactured in cl osed equipment, premises must be designed 
and constructed to facilitate proper sanitation.  Premises for manufacturing oxygen and non -
synthetic medical air must be located in an environment offering minimal contamination from 
the air used as a starting mate rial. 
11.2 General  
11.2.1 Areas used for production, packaging, secondary packaging, control, storage and 
distribution of medical gases must be properly designed so as to guarantee orderly location of 
equipment and materials; they must be identified, demar cated and be spacious enough for the 
processes taking place there.  
11.2.2 For the purposes of this section, the manufacturing areas of a medical gas 
manufacturing plant shall include the following:  production, filling, secondary packaging, 
quality control,  quality assurance, storage and maintenance.   Annex “Handbook of Good Manufacturing Practices for Medical Gases”  17 
11.2.3 Piping carrying fluids that might be a hazard for the production process must run 
outside the production area.  In any case all production piping must:  
a) be identified by means of an internationally reco gnised code (colour and direction of 
flow) or the applicable national standards;  
b) allow external cleaning and maintenance.  For medical gases phosphorus deoxidised 
copper piping and/or materials approved or referred to in international standards must 
be used: NFPA99 (National Fire Protection Association) in the current version and 
ISO10083 (National Standard Oxygen Concentrators for Use with Medical Gas 
Pipeline System) in the current version.  Pipes must be rigid or flexible depending on 
where they are ins talled, in accordance with the standard codes and of the dimensions 
given on the drawings.  
11.2.4 The installation of cryogenic storage tanks and distribution manifolds must be 
approved in line with specific procedures.   
Electrical cables and hoses forming  part of equipment should generally be positioned so as to 
avoid obstructing operators’ working space.  
Premises should be carefully maintained, ensuring that repair and maintenance operations do 
not present any hazard to the quality of products.  They shoul d be properly cleaned in 
accordance with detailed written procedures.  
11.2.5 The electricity supply and lighting, temperature, humidity and ventilation should be 
such that they do not adversely affect, directly or indirectly, either the medical gases durin g 
their manufacture and storage, or the accurate functioning of equipment.  
11.2.6 Premises should be designed and equipped so as to afford maximum protection against 
the entry of insects or other animals.  
11.3 Ancillary areas  
11.3.1 Rest and refreshment ro oms should be separate from other areas.  
11.3.2 Facilities for changing clothes, and for washing and toilet purposes should be easily 
accessible and appropriate for the number of users.  Toilets should not directly communicate 
directly with production or st orage areas.  
11.3.3 Maintenance workshops should as far as possible be separated from production areas.  
Whenever parts and tools are stored in the production area, they should be kept in rooms or 
lockers reserved for that use.  
11.4 Storage areas  
11.4.1 Ar eas must be identified.  Storage areas must be arranged so that medical and industrial 
gases can be segregated.  
11.4.2 During storage, cylinders must be protected from external damage.  Protection should 
be of a level that includes storage under cover, prote ction of cylinder packaging facilities and 
even protection of individual cylinders.  
11.4.3 Cylinders must not be exposed to an ambient temperature exceeding 52ºC.  Annex “Handbook of Good Manufacturing Practices for Medical Gases”  18 
11.4.4 Storage areas should be of sufficient capacity for their intended purpose; they must b e 
clean, well ventilated and free of flammable materials, to avoid mix -ups or risks of 
contamination and to allow orderly rotation of stock.  
11.4.5 There must be a means to ensure that storage areas are free from insects, rodents or 
other external agents.   
11.4.6 Floors, walls and roofs must be of a material that is robust, easily cleaned and 
maintained in good condition.  
11.4.7 There must be written procedures laying down the conditions for storing starting 
materials and finished products.  
11.4.8 The follo wing storage areas or zones must be duly demarcated:  
a) starting materials;  
b) inputs and packaging materials;  
c) sorting of empty vessels;  
d) empty vessels for filling;  
e) full vessels in quarantine;  
f) approved finished products.  
11.5 Weighing areas (may  be part of the storage or production areas)   
11.5.1 Starting materials are generally weighed and their yield estimated on that basis in 
special weighing areas, with special dust control systems, for example.  
11.6 Production area  
11.6.1 In order to minimis e the risk of a medical hazard due to cross -contamination, dedicated 
and self contained facilities must be available for the production of medical gases, except for 
obtaining oxygen and nitrogen by liquefying air.  
11.6.2 Premises should preferably be laid out in such a way as to allow the production to take 
place in areas connected in a logical order corresponding to the sequence of the operations 
and to the requisite cleanliness levels.  
11.6.3 The adequacy of the working and in -process storage space should  permit the orderly 
and logical positioning of equipment and materials so as to minimise the risk of confusion 
between different medicinal products or their components, to avoid cross -contamination and 
to minimise the risk of omission or wrong application of any of the manufacturing or control 
steps.  
11.6.4 Premises for the packaging of medical gases should be specifically designed and laid 
out so as to avoid mix -ups or cross -contamination.  
11.6.5 Production areas should be well lit, particularly where visu al on -line controls are 
carried out.  
11.7 Quality control area  Annex “Handbook of Good Manufacturing Practices for Medical Gases”  19 
11.7.1 Quality -control laboratories should be separated from production areas.  
11.7.2 Control laboratories should be designed to suit the operations to be carried out in them.  
There should be a  specific place for storing reference standards.  
11.7.3 Appropriate construction materials should be used in the design of the laboratory.  It 
must also be properly ventilated and designed to avoid the formation of harmful vapours.  
12. EQUIPMENT  
12.1 Princi ple. Equipment should be designed, built, adapted, located and maintained to suit 
its intended purpose.  Equipment must be designed and located so as to minimise the risk of 
errors, and so that it can be efficiently cleaned and maintained, so as to avoid cr oss-
contamination, dust and dirt, and in general anything that might adversely affect product 
quality.   
12.2 Equipment should be installed in such a way as to minimise any risk of error or 
contamination.  
12.3 Fixed pipework should be clearly labelled to in dicate the contents and, where possible, 
the direction of flow.  
12.4 All pipework and other service fittings should be clearly marked and, in the case of gases 
and liquids, special care must be taken to use connections or adaptors that cannot be 
interchang ed. 
12.5 Balances and measuring equipment of an appropriate range and precision should be 
available for production and control operations and calibrated in accordance with a fixed 
timetable.  
12.6 Manufacturing equipment should be designed, located and main tained to suit its intended 
purpose.  
12.7 Manufacturing equipment should be designed so that it can be easily and thoroughly 
cleaned on the basis of a fixed timetable.  
12.8 The control laboratory equipment and instruments must be appropriate for the planne d 
analysis procedures.  
12.9 Production equipment should not present any hazard to the products.  The parts of the 
production equipment that come into contact with the product must not be reactive, additive 
or absorptive to such an extent that as to affect t he product quality.  
12.10 Defective equipment should, if possible, be removed from production and quality 
control areas, or at least be clearly labelled as defective.  
12.11 There should be no removable connections between pipes containing different gases.  
12.12 Filling manifolds or racks, flasks, tanker trucks and cylinders shall be fitted with 
standard filling connector types for the various medical gases, so as to avoid confusion.  
12.13 The connectors of the valves on filling racks shall be specific to ea ch type of gas, to 
prevent them being switched over.  
12.14 The technical specifications of the connection valves for the various medical gases 
must be documented and made available to personnel in the required areas.  Annex “Handbook of Good Manufacturing Practices for Medical Gases”  20 
12.15 Non -return valves used to prevent  returns of foreign material, contamination or 
interchanges of products within production and distribution systems must be checked before 
and during use, controls and servicing being recorded.  Such valves must undergo validation 
studies to ensure that they  continue to comply with the required specifications.  
12.16 Hydrostatic tests must be carried out on supply lines, piping and connections, and their 
sealing must be checked periodically.  
13. MATERIALS  
13.1 General  
13.1.1 All materials entering the factory must be quarantined immediately after acceptance or 
processing, until they are released for use or distribution.  
13.1.2 All materials and products must be stored under appropriate conditions laid down by 
the manufacturer, and in an order enabling batches t o be separated and stocks rotated in 
accordance with the first -in first -out rule.  
13.2 Starting materials  
13.2.1 The purchase of starting materials is an important operation which should involve 
suitable qualified staff who are familiar with the products a nd suppliers.  
13.2.2 Starting materials should be purchased only from approved suppliers named in the 
relevant specification and, where possible, directly from the producer.  It is recommended that 
the specifications established by the manufacturer for the starting materials be discussed with 
the suppliers.  It is advisable for all aspects of the production and control of the starting 
material in question, including handling, labelling and packaging requirements, as well as 
complaints and rejection procedures  to be discussed with the manufacturer and the supplier.  
13.2.3 For each delivery, the containers should be checked for integrity of package and seal 
and for correspondence between the delivery note and the supplier’s labels.  
13.2.4 All materials received must be checked to ensure that they tally with the order.  
Containers must be cleaned where necessary and the relevant data must be included on the 
labels.  
13.2.5 Any damage to containers or other problems that might adversely affect product 
quality must be  recorded and notified to the quality -control department for investigation.  
13.2.6 If one material delivery is made up of different batches, each batch must be considered 
as separate for sampling, testing and release.  
13.2.7 Starting materials in the stora ge area should be appropriately labelled.  Labels should 
bear at least the following information:  
a) the designated name of the product and reference code where applicable;  
b) any batch number(s) assigned by the supplier, and the batch number(s) assigned by  
the manufacturer on receipt;  
c) where appropriate, the status of the contents (e.g. in quarantine, on test, released, 
rejected, returned, or recalled);  
d) where appropriate, an expiry date or a date beyond which retesting is necessary.  Annex “Handbook of Good Manufacturing Practices for Medical Gases”  21 
13.2.8 When fully c omputerised storage systems are used, all the above information need not 
necessarily be in a legible form on the label.  
13.2.9 There should be appropriate procedures or measures to assure the identity of the 
contents of each container of starting material.  Bulk containers from which samples have 
been drawn should also be identified.  
13.2.10 Only starting materials which have been released by the Quality Control Department 
and which are within their shelf life should be used.  
13.2.11 Starting materials shoul d only be dispensed by designated persons, following a 
written procedure, to ensure that the correct materials are accurately weighed or measured 
into clean and properly labelled containers.  
13.2.12 Each dispensed material and its weight or volume should b e checked and the check 
recorded.  
13.2.13 Materials dispensed for each batch of end product should be kept together and 
conspicuously labelled as such.   
13.3 Packaging materials  
13.3.1 The purchase, handling and control of printed packaging materials shall  be accorded 
attention similar to that given to starting materials.  
13.3.2. Particular attention should be paid to printed packaging materials.  
They should be stored in adequately secure conditions such as to exclude unauthorised access.  
Cut labels and oth er loose printed materials should be stored and transported in separate 
closed containers so as to avoid mix -ups. Packaging materials should be issued for use only 
by authorised personnel following an approved and documented procedure.  
13.3.3 Each delivery  or batch of printed or primary packaging material should be given a 
specific reference number or identification mark.  
13.3.4 Outdated or obsolete primary packaging material or printed packaging material should 
be destroyed and this disposal recorded.  
13.3.5 All products and packaging materials to be used should be checked on delivery to the 
packaging department for quantity, identity and conformity with the packaging instructions.  
13.3.6 Containers should be cleaned in accordance with established procedure s to prevent any 
contamination or entry of impurities.  
13.3.7 Vessels for medical gases must have technical specifications indicating their 
references.  
13.3.8 The colour code laid down by the current pharmacological standards must be used to 
identify medic al gas vessels.  
13.3.9 Each cylinder must undergo an external inspection, observing dents, arc burns, 
impacts, presence of oil, grease or other signs of external damage, including fire or heat 
damage that might make the cylinder unfit or unsafe for use.  This inspection must take place 
at the stage of sorting empty cylinders and inspected cylinders must be recorded as approved 
or rejected.  Cylinders rejected after filling for use may be passed through the process again.  Annex “Handbook of Good Manufacturing Practices for Medical Gases”  22 
13.3.10 For oxygen and medical air, an  odour test must be conducted to detect the presence of 
any unusual smell.  If any uncharacteristic smell is detected, the cylinder must be sent for 
maintenance.  
13.3.11 Every maintenance operation on a cylinder must be recorded.  
13.3.12 A sonic test must b e conducted to indicate any internal corrosion in cylinders.  This 
procedure may not be used on aluminium or other cylinders made of unsuitable materials.   
13.3.13 There should be procedures for testing medical gas cylinders under hydrostatic 
pressure and f or checking that they have undergone a recent test before use.  Records must be 
kept of such checks.  
13.3.14 Valves for cylinders must be specific for each type of gas and they must be 
guaranteed free of particles, oil or grease.  The procedure for inspectin g valves must be 
documented, indicating the reference used; the inspection must also include:  
a) a check for damaged screw threads on the valve or the top of the shank;  
b) a check of the condition of the valve collar and shank to ascertain that they are no t 
bent or otherwise damaged;  
c) a check for visible signs of damage or corrosion in the valve or visible signs of heat 
or fire damage;  
d) a check that the valve is of the correct type for the medical gas to be filled.  
13.3.15 Specifications must be drawn u p for the following inspections on flasks used for 
medical gases before filling:  
a) External inspection of the container to detect external damage.  
b) Inspection of all inlet and outlet connections.  
c) The correct connections for each type of gas must be p ermanently welded on so as to 
avoid unauthorised changes of connector.  
d) Adaptor couplings may not be used on connections.  
e) Basic inspection of the content reference measuring system.  
f) Inspecting marking of vessels:  labels to identify the gas, permane nt marks with the 
name of the gas filling.  All vessels must bear the name of the gas close to the inlet 
and outlet connections.  
g) Labels must be of washable material, secure and easily legible.  
h) All damaged labels must be removed.  
i) Cryogenic vessels f or medical gases must be fitted with non -return valves or devices 
in the gas outlet line before the external connection, or failing that at the closest 
possible point to the connection between the vessel and the piping system on the side 
of the client’s di stribution network, to ensure that the gas is not contaminated by the 
client’s processes.  Annex “Handbook of Good Manufacturing Practices for Medical Gases”  23 
13.3.16 All accessories for cylinders of oxygen or other oxidising gases must be kept free 
from grease or oil.  
13.3.17 Cylinder valves may be removed or repaired by t he gas filler only.  
13.3.18 All cylinders must be stamped in bas relief with the following:  name of the cylinder 
owner; maximum service or test pressure; the tare weight of the cylinder in the case of 
liquefied gases; volume in litres of water; date of lat est hydrostatic test, giving month, year 
and logo of hydrostatic testing laboratory; technical manufacturing standard of the cylinder 
and identifying serial number of the cylinder.  Cylinder identifying marks or numbers must not 
be removed or altered.  
All n ew cylinders must have the marks indicated in this handbook.  If a cylinder in use does 
not have all this information, the missing information, apart from the manufacturing standard, 
must be added at the next hydrostatic test.  
13.3.19 Compressed gases must not be stored underground.  
13.4 Intermediate and bulk products  
13.4.1 Intermediate and bulk products must be kept in conditions that observe the product’s 
quality and safety specifications.  
13.4.2 Upon receipt, intermediate products and bulk products purch ased as such must be 
handled as if they were starting materials.  
13. 5 Finished products  
13.5.1 Finished products should be held in quarantine until their final release, after which 
they should be stored as usable stock under conditions established by the manufacturer.  
13.6 Rejected materials  
13.6.1 Rejected materials and products should be clearly marked as such and stored 
separately in restricted areas.  They should either be returned to the suppliers or, where 
appropriate, destroyed.  Whatever action is ta ken should be approved and recorded by the 
qualified person.  
13.7 Recalled products  
13.7.1 Recalled products must be identified and stored in a separate secure area until it is 
decided what to do with them.  This decision must be taken as quickly as possibl e. 
13.8 Returned products  
13.8.1 Products returned from the market must be destroyed.  
13.9 Reagents  
13.9.1 All reagents must be recorded upon receipt or preparation.  
13.9.2 Reagents made in the laboratory must be prepared in accordance with written 
procedu res and must be properly labelled.  The label must indicate the concentration, 
normalisation factor, storage time, due date for renormalisation and storage conditions.  The 
label must be signed and dated by the person preparing the reagent.  Annex “Handbook of Good Manufacturing Practices for Medical Gases”  24 
13.10 Reference s tandards  
13.10.1 Reference standards may be available in the form of official reference standards.  
Reference standards prepared by the manufacturer must be analysed, authorised and stored as 
official reference standards.  They must also be kept in a secure area under the responsibility 
of a specially designated person.  
13.10.2 Official reference standards must be used only for the purpose described in the 
relevant monograph.  
13.10.3 To ensure normalisation of secondary or working standards, appropriate tests  and 
controls must be carried out at regular intervals.  Any secondary or reference standard 
prepared in the same factory must be based on official reference standards, where available.   
13.10.4 All reference standards must be stored and used in a way that does not affect their 
quality.  
13.11 Waste materials  
13.11.1 The necessary measures must be taken to store waste materials for disposal 
appropriately and safely.  Toxic substances and flammable materials must be stored in 
properly designed, separate and sea led containers in accordance with the relevant standards in 
force.  
13.11.2 Waste materials must not be allowed to accumulate but must be collected in 
appropriate containers for transfer to collection points outside the buildings and disposal in a 
harmless and sanitary manner at regular and frequent intervals.  
13.12 Miscellaneous  
13.12.1 Insecticides, fumigating agents and sanitation materials must not be allowed to 
contaminate equipment, starting materials, packaging materials, processing materials or 
finished products.  
13.12.2 Vessels, the associated valves, starting materials and marks, must safeguard the 
identity, safety, efficacy and purity of medical gases, and must accordingly be inspected 
before use.  In particular the vessels for this type of medicina l products are used more than 
once.  
14. DOCUMENTATION  
14.1 Principle.  Good documentation is an essential part of the quality assurance system and 
must therefore by related to all aspects of GMP.  It aims to define the specifications of all 
manufacturing and  inspection materials and methods, ensure that all personnel involved in 
manufacturing know what to do and when, ensure that all qualified persons have all the 
information needed to decide on the sales authorisation of a batch of medicinal products, and 
provide the auditors with the necessary means to investigate the history of a batch suspected 
of having some defect.  The design and use of a document depend on the manufacturer.  
14.2 General  
14.2.1 All documents must be designed, edited and distributed with care.  They must comply 
with the relevant requirements set out in the manufacturing and marketing authorisations.  Annex “Handbook of Good Manufacturing Practices for Medical Gases”  25 
14.2.2 Documents must be approved, signed and dated by the qualified persons.  No document 
may be altered without authorisation.   
14.2.3 Documen ts must not contain any ambiguous expressions:  
the title, nature and purpose must be expressed clearly.  They must be drafted in an orderly 
fashion and be easy to check.  Copies must be clear and legible.  Working documents 
reproduced from the originals must not contain any errors due to the reproduction process.  
14.2.4 Documents must be regularly reviewed and kept up to date.  
If a document is altered, a system must be set up to prevent accidental use of documents prior 
to that alteration.  
14.2.5 Where data ha s to be entered in a document, they must be clear, legible and indelible.  
There must be sufficient space to enter all the data required.  
14.2.6 If a document is amended, the change must be signed and dated, and it must be 
possible to read the original info rmation that was changed.  Where appropriate, the reason for 
the change must be given.  
14.2.7 A record must be kept of all action taken and completed, providing information on all 
important activities relating to the manufacture of pharmaceutical products.   
All records, including those relating to standard operating procedures, must be kept for at 
least one year after the expiry date of the finished product.  
14.2.8 Data may be recorded by means of electronic data -processing systems, or using 
photographic sys tems or other reliable means.  The master formulas and detailed standard 
operating procedures for the system must be available and the accuracy of the records must be 
checked.  If the documentation is handled using data -processing methods, only qualified 
persons may enter new data into the computer or alter existing data, and a record of 
alterations and deletions must be kept; a key or other means of restricting access to the system 
must be implemented and the entry of important data must be checked independe ntly. 
Records of electronically filed batches must be protected by means of a backup copy on 
magnetic tape, microfilm, printouts or other means.  It is especially important that the relevant 
data is easily accessible for as long as it is kept.  
14.3 Required  documents  
14.3.1 Labels  
14.3.1.1 Labels affixed to containers, equipment or installations must be clear and 
unambiguous and prepared in accordance with the format laid down by the company or 
institution.  Labels should use colour, as well as words, to indi cate the status of the product 
(e.g. in quarantine, accepted, rejected).  
14.3.1.2 all finished pharmaceutical products must be identified by labels, as required by 
current health regulations, and contain at least the following information:  
a) Name of pharm aceutical product;  
b) List of active ingredients (with their respective international common names, if any), 
indicating the quantity of each, and a declaration of the net contents, such as the 
number of pharmaceutical units, weight or volume;  Annex “Handbook of Good Manufacturing Practices for Medical Gases”  26 
c) Manufactur er’s batch number;  
d) Expiry date, not in coded form;  
e) Any necessary special storage or handling conditions;  
f) Instructions for use and any necessary warnings or precautions; and  
g) Name and address of the manufacturer, company, institution or person re sponsible for 
placing the product on the market.  
14.3.1.3 For reference standards, the attached label or document must indicate the 
concentration, manufacturing date, expiry date, date on which the seal is first opened and 
storage conditions, where appropr iate. 
14. 4 Test specifications and procedures  
14.4.1 The test procedures described in the documents must be tested in the context of the 
available facilities before they are adopted for the relevant tests.  
14.4.2 Duly authorised and dated specifications m ust be drawn up, including tests of identity, 
content, purity and quality, for both starting and packaged materials and finished products; 
where appropriate, specifications will also be drawn up for intermediate and bulk products.  
14.4.3 Each specification  must be approved and maintained by the quality -control unit.  
14.4.4 The specifications for medical gases must be periodically reviewed in line with new 
editions of the official pharmacopoeias in the country.  
14.4.5 The quality -control laboratory must have  the official pharmacopoeias in the country, 
reference standards and spectra and other reference materials as required.  
14.5 Specifications for starting materials and packaging  
14.5.1 The specifications for starting materials, packaging or printed packagin g materials 
must contain a description of the materials, including:  
a) Name (common international name, if any) and internal reference code;  
b) Reference, if any, to a monograph of the pharmacopoeia; and  
c) Quality and quantity standards, with acceptance l imits.  
Depending on practices in the company or institution, other data may be added to the 
specifications, such as:  
d) Data referring to the supplier and original producer of the materials;  
e) A sample of the printed materials;  
f) Sampling and testing ins tructions, or a reference to those procedures.  
g) Storage conditions and precautions to be taken;  
h) Maximum permitted storage time before a new examination.  Annex “Handbook of Good Manufacturing Practices for Medical Gases”  27 
Packaging materials must comply with the officially approved specifications, and it is 
important f or such materials to be compatible with the pharmaceutical product they contain.  
Materials must be examined to check that they do not contain defects in their identifying 
marks that might affect product integrity or quality.  
14.5.2 The documents describing  the test procedure should indicate the required frequency for 
reassessing each of the starting materials, as required by its stability.  
14.6 Specifications for intermediate and bulk products   
When using intermediate or bulk products, their specifications or the data enabling the final 
product to be assessed must be available.  These specifications must be similar to the 
specifications for starting materials or for finished products, as appropriate.  
14.7 Specifications for finished products  
The specification s for finished products must include at least the following information:  
a) Name of product and reference code, if any;  
b) Name(s) of active ingredient(s) (and common international name(s), if any);  
c) Master formula or reference to the master formula;  
d) Description of pharmaceutical form and details of vessel;  
e) Sampling and testing instructions, or a reference to those procedures;  
f) Quality and quantity standards, with acceptability standards.  
g) Storage conditions and precautions where applicable.  
h) Service life.  
14.8 Filling instructions  
14.8.1 Appropriate procedures and controls must be established to ensure that vessels have 
been filled correctly in terms of quantity and quality..  
14.8.2 The residual gas in cylinders returned for filling must be e liminated using “purging and 
venting” or “evacuation” methods.  A cylinder may not be filled until it is guaranteed that all 
gas remaining from a previous filling has been evacuated.  
14.8.3 All operations for transferring medical gases from an initial prima ry store must be 
carried out in accordance with written procedures designed to prevent any contamination.  
14.8.4 Industrial oxygen and medical oxygen may be filled at the same rime from the same 
filling line, in identified systems, provided that the follow ing conditions are satisfied:  
a) The starting material complies with the quality specifications for medical use.  
b) Suitable cylinders for medical use only are used.   
c) The supply line for the industrial oxygen filling department is fitted with a non -return 
valve.  Annex “Handbook of Good Manufacturing Practices for Medical Gases”  28 
14.8.5 Medical oxygen cylinders must be filled in accordance with a written procedure, 
including at least the following operations:   
a) Evacuate the gas remaining in the cylinder by evacuation, using a suction pump 
capable of creating a vacuum in side the cylinder of inches of mercury at sea level 
(150 millibars absolute pressure) or using a purge and vent procedure, before filling 
the cylinder.  
b) Check the compression temperature of each cylinder in the batch during filling.  
c) Test the cylinders  for leaks.  
d) Check the final filling pressure and keep a record of this process.  
14.8.6 The data in the filling records must allow the significant aspects of the filling 
operations to be monitored and identified at any point in the process, and must incl ude at least 
the following data:  
a) Trade name.  
b) Date and time of filling operations.  
c) Inspection records for high -pressure cylinders and cryogenic containers.  
d) Reference of the filling station and equipment used.  
e) Name of gas and batch number assi gned.  
f) Operations carried out before filling.  
g) Serial number and size and quantity of cylinders to be filled.  
h) Records of filling temperature and pressure.  
i) Initials of the operators for each significant stage.  
j) Records of quality -control tests.  
k) For analysis equipment the date of the latest calibration, the reference gas 
specification and calibration results must be recorded.  
l) Sample of the label with the batch number printed on it.  
m) Any deviations occurring must be documented and authorise d by the person 
responsible.  
n) Conformity indications, with the date and signature of the supervisor responsible for 
the filling operation.  
14.8.7 Each container must be marked with a label identifying the product in accordance with 
the current provisions  for medicinal products, including the following additional information:  
a) For medical oxygen produced by liquefaction the process used must be indicated on 
the label.  
b) handling instructions, precautions and warnings;  Annex “Handbook of Good Manufacturing Practices for Medical Gases”  29 
c) safety pictograms;  
d) United Nat ions international product identification number;  
e) an additional label firmly and securely affixed to a visible part of the recipient must 
indicate the batch number, date of manufacture and expiry date of the product.  
14.8.8 Identification labels need no t be removed if they are in good condition and match the 
product to be filled.  Only those for earlier batch numbers need be removed.  Labels may not 
be superimposed.  
14.8.9 Outlet connections from valves of vessels must be fitted with a security seal 
guaran teeing the integrity of the contents.  
14.9 Record of processing of batches  
14.9.1 A record of the process must be kept for each manufacturing batch.  The method for 
drawing up such records must be designed to avoid transcription errors.  
14.9.2 Before beginn ing a processing operation a check must be carried out to ensure that the 
equipment and premises are free of products, documents or materials from the previous 
process that are no longer required for the process about to begin, and that the equipment is 
clean and ready for use.  This check must be recorded.  
14.9.3 Once medical gas processing is complete the record must be signed and dated by the 
person responsible.  During the process and when each activity is carried out, the following 
data must be recorded:  
a) Name of product.  
b) Number of batch being manufactured.  
c) Dates and times when the main intermediate stages begin, and when production is 
completed.  
d) name of the person responsible for each stage of production;  
e) initials of the operator of differe nt significant steps of production and, where 
appropriate, of the person who checked each of these operations (e.g. weighing);  
f) the batch number and/or analytical control number as well as the quantities of each 
starting material actually weighed;  
g) any relevant processing operation or event and equipment used;  
h) a record of the in -process controls and the initials of the person(s) carrying them out, 
and the results obtained;  
i) the product yield obtained at different and pertinent stages of manufact ure, with 
comments or explanations of any significant deviation from the expected yield;  
j) notes on special problems including details, with signed authorisation for any 
deviation from the specifications.  
14.10 Batch Packaging Records  Annex “Handbook of Good Manufacturing Practices for Medical Gases”  30 
14.10.1 A packaging record should be kept for each batch or part batch processed. It should 
be based on the relevant parts of the packaging instructions and the method of preparation of 
such records should be designed to avoid transcription errors.  
14.10.2 Before any packagin g operation begins, there should be checks that the equipment 
and work station are clear of previous products, documents or materials not required for the 
planned packaging operations, and that equipment is clean and suitable for use. These checks 
must be recorded.  
14.10.3 The following information should be entered at the time each action is taken, clearly 
identifying the person responsible by means of a signature or stamp:  
a) name of product, batch number and the quantity of bulk product to be packed, as well 
as the batch number and the expected quantity of finished product, the actual quantity 
obtained and the reconciliation or yield;  
b) the date(s) and times of the packaging operations;  
c) the name of the responsible person carrying out the packaging op eration;  
d) the initials of the operators of the different significant steps;  
e) records of checks for identity and conformity with the packaging instructions 
including the results of in -process controls;  
f) details of the packaging operations carried ou t, including references to equipment and 
the packaging lines used and, where appropriate, instructions for leaving the product 
unpackaged, or a record of the return of products for which packaging was not 
completed to the storage area;  
g) whenever possible , samples of printed packaging materials used, including specimens 
of the batch coding, expiry dating and any additional overprinting;  
h) notes on any special problems or unusual events including details, with details of any 
deviation from the packaging i nstructions and the signed authorisation of the person 
responsible;  
i) the quantities and reference number or identification of all printed packaging 
materials and bulk product issued, used, destroyed or returned to stock and the 
quantities of obtained pro duct, in order to provide for an adequate reconciliation.  
14.11 Procedures and (standard) records  
14.11.1 There should be written procedures and standard records for the receipt of each 
delivery of each starting and primary and printed packaging material.  
14.11.2 The records of the receipts should include at least the following information:  
a) the name of the material on the delivery note and the containers;  
b) the "in -house" name and code of material (if different from a);  
c) date of receipt;  
d) supplier’ s name and, if possible, manufacturer’s name;  Annex “Handbook of Good Manufacturing Practices for Medical Gases”  31 
e) manufacturer’s batch or reference number;  
f) total quantity, and number of containers received;  
g) the batch number assigned after receipt;  
h) any relevant comment.  
14.11.3 There should be standard writt en operating procedures for the internal labelling, 
quarantine and storage of starting materials, packaging materials and other materials, as 
appropriate.  
14.11.4 There should be standard written operating procedures for each instrument and piece 
of equipm ent. 
14.11.5 There should be standard written procedures for sampling, which include the 
person(s) authorised to take samples.  
14.11.6 Sampling instructions should include at least the following information:  
a) sampling methods and plan;  
b) equipment to be  used;  
c) precautions to be observed to avoid contamination of the material or any deterioration 
in its quality;  
d) the amount to be taken;  
e) instructions for subdividing the sample;  
f) type of containers to be used for taking samples, indicating the leve l of disinfection or 
cleaning required.  
14.11.7 In order to ensure that each batch of intermediate, bulk or finished product is 
identified with a specific batch number, there should be a standard operating procedure 
including a batch numbering system.  
14.11.8 The standard operating procedure for batch numbering must be designed to ensure 
that numbers are not duplicated.  
14.11.9 The numbers assigned to batches must be recorded immediately, in a journal of 
operations, including the assignment date, product id entity and batch size.  
14.11.10 There should be written procedures for the analyses of materials and products at the 
various stages of manufacture, describing the methods and equipment used, recording the 
tests conducted.  
14.11.11 The records of the analys es should include at least the following information:  
a) name of material or product and pharmaceutical form, if any;  
b) batch number and name of manufacturer and/or supplier, if any;  
c) references to relevant analysis specifications and procedures;  Annex “Handbook of Good Manufacturing Practices for Medical Gases”  32 
d) analysis results, including observations and calculations, and reference to the 
specifications (limits);  
e) analysis dates;  
f) initials of the persons conducting the analyses;  
g) initials of persons checking the analyses and calculations, if any;  
h) clear ind ication of authorisation or rejection (or any other measure relating to the 
condition of the material or product) and the date and signature of the person 
responsible.  
14.11.12 There should be written procedures for authorising and rejecting materials and 
products, especially the procedure for authorising the sale of a finished product by an 
qualified person.  
14.11.13 Records must be kept of the distribution of each batch of a product, to facilitate the 
recall of the batch if necessary.  
14.11.14 There must be standard operating procedures and records for action taken, and 
conclusions on the following aspects, where relevant:  
a) assembly and checking of equipment;  
b) analysis apparatus and its calibration;  
c) maintenance, cleaning and sanitation;  
d) status of  personnel, including suitability, training, clothing and hygiene;  
e) animal and inspect control;  
f) complaints;  
g) recall of products from the market;  
h) returns.  
14.11.15 Journals must be kept of operations with important and essential equipment, 
correct ly recording the following:  checks, calibrations, maintenance, cleaning or repairs, 
including dates and the identity of persons carrying out these operations.  
14.11.16 Proper chronological records must be kept of the use of the important and essential 
equipment and the areas in which the products were processed.  
14.11.17 There should be mandatory written procedures for assigning responsibility for 
sanitation, describing in detail cleaning timetables, methods, equipment and materials to be 
used, and the inst allations to be cleaned.  
15. Good manufacturing practice  
15.1 Principle.  Production operations must follow clearly defined procedures in order to 
obtain products of the requisite quality and be in accordance with the relevant manufacturing 
and marketing au thorisations.  Annex “Handbook of Good Manufacturing Practices for Medical Gases”  33 
15.2 General  
15.2.1 All handling of materials and products, such as quarantine, sampling, storage,  
labelling, dispensing, processing, packaging and distribution should be done in accordance  
with written procedures or instructions and, where n ecessary, recorded . 
15.2.2 Any deviation from instructions or procedures should be avoided as far as possible.  If a 
deviation occurs, it should be approved in writing by the competent person, with the 
involvement of the quality control department or sectio n when appropriate.   
15.2.3 Checks on yields, and reconciliation of quantities, should be carried out as necessary to 
ensure that there are no discrepancies outside acceptable limits.  
15.2.4 Access to production premises should be restricted to authorised personnel.  
15.2.5 Normally, the production of non -medicinal products should be avoided in areas and 
with the equipment destined for the production of medicinal products.  
15.2.6 Controls during processing should not present any risk to product quality, and should 
accordingly be carried out as far as possible in the production area.  
15. 3 Production  
15.3.1 Automated operations controlled by a computerised system with associated software 
should be validated retrospectively, such as the computerised system used  to control the 
variables of pressure, temperature and product purity.  Such systems should be validated 
retrospectively or prospectively.  
15.3.2 The manufacturing process should be designed to avoid the risk of cross -contamination 
where different gases are  manufactured at the same time in the same area.  All products must 
be identified, indicating the stage, name of the gas and batch number being processed.  
15.3.3 Production areas must be sufficiently and properly ventilated.  
15.3.4 There should be written p rocedures and corresponding records describing each stage of 
the manufacturing, filling and labelling processes.  
15.3.5 Each operation should be signed by the person responsible for carrying it out and 
endorsed by the head of section.  
15.3.6 Any deviation detected during manufacture should be notified to the section head so 
that appropriate corrective measures can be taken.  
15.3.7 For each batch manufactured, the name of the product, volume or weight, batch 
number and processing date must be identified by m eans of labels or other means.  
15.4 Prevention of Cross -Contamination and Bacterial Contamination during Production  
15.4.1 When dry materials are used in production, special precautions should be taken to 
prevent the generation and dissemination of dust.  
15.4.2 Contamination of a starting material or of a product by another starting material or 
product must be avoided.  This risk of accidental cross -contamination arises from the 
uncontrolled release of dust, gases, vapours, sprays or organisms from materials  and products 
in process, from residues on equipment, insects entering the premises and contaminants from 
operators’ clothing and skin, etc.  The significance of this risk varies with the type of Annex “Handbook of Good Manufacturing Practices for Medical Gases”  34 
contaminant and of product being contaminated.  Products in wh ich contamination is likely to 
be most significant are those administered in large doses and/or over a long time.  
15.4.3 Cross -contamination should be avoided by at least the following technical and 
organisational measures:  
a) production in segregated are as; 
b) using appropriate clothing inside areas where products are processed;  
c) using cleaning and decontamination procedures of known effectiveness, as ineffective 
cleaning of equipment is a common source of cross -contamination;  
d) testing for residues i n containers and vessels.  
e) use of cleaning -status labels on equipment.  
15.4.4 Measures to prevent cross -contamination and their effectiveness should be checked 
periodically.  This check should be made according to set procedures.  
15. 5 Processing operatio ns: intermediate and bulk products  
15.5.1 Before any processing operation is started, steps should be taken to ensure that the 
work area and equipment are clean and free from any product residues, labels, starting 
materials or documents or other products n ot required for the current operation.  
15.5.2 Any necessary in -process controls and environmental controls should be carried out 
and recorded.  
15.5.3 Measures should be adopted to indicate any faults occurring in equipment or services 
such as supplies of w ater, gas and electricity to equipment.  
15.5.4 Any significant deviation from the expected yield should be recorded and investigated.  
15.5.5 Checks should be carried out to ensure that pipelines and other pieces of equipment 
used for the transportation of products from one area to another are connected in a correct 
manner.  
15.5.6 Measuring, weighing, recording and control equipment and instruments must be 
maintained and calibrated at predetermined intervals and a record of these operations must be 
kept.  To ensure that instruments are working satisfactorily, they should be checked every day 
or before they are used for analysis.  The dates must be clearly indicated on which 
maintenance and calibration work is carried out and the date on which recalibration is 
required.  
15.5.7 Maintenance and repair work must not put product quality at risk.  
15.6 Packaging operations  
15.6.1 When setting up a programme for the packaging operations, particular attention should 
be given to minimising the risk of cross -contamination,  mix -ups or substitutions.  Different 
products should not be packaged in close proximity unless there is physical segregation or 
electronic supervision.  
15.6.2 Before packaging operations are begun, steps should be taken to ensure that the work 
area, packag ing lines and other equipment are clean and free from any products, materials or Annex “Handbook of Good Manufacturing Practices for Medical Gases”  35 
documents previously used, if these are not required for the current operation.  The line -
clearance should be performed and recorded according to an appropriate check -list. 
15.6.3 The name and batch number of the product being handled should be displayed at each 
packaging station or line.  
15.6.4 Normally, filling and sealing should be followed as quickly as possible by labelling.  If 
it is not the case, appropriate procedures sho uld be applied to ensure that no mix -ups or 
mislabelling occur.  
15.6.5 The correct performance of any printing operation (for example code numbers, expiry 
dates) to be done separately or in the course of the packaging should be checked and 
recorded.  Attent ion should be paid to printing by hand which should be re -checked at regular 
intervals.  
15.6.6 Special care should be taken when using cut -labels and when over -printing is carried 
out off -line. 
15.6.7 Printed and embossed information on packaging material s should be distinct and 
resistant to fading or erasing.  
15.6.8 On -line control of the product during packaging should include at least checking the 
following:  
a) general appearance of the packages;  
b) quantity of packages;  
c) whether the correct products and packaging materials are used;  
d) whether printing is correct and  
e) correct functioning of line monitors.  
15.6.9 Any significant or unusual discrepancy observed during reconciliation of the amount 
of bulk product and printed packaging materials and th e number of units produced should be 
investigated and satisfactorily accounted for before release.  
15.6.10 Upon completion of a packaging operation, any unused batch -coded packaging 
materials should be destroyed and the destruction recorded.  A documented p rocedure should 
be followed if uncoded printed materials are returned to stock.  
16. Good quality -control practice  
16.1 General  
Quality control involves sampling, specifications and tests, as well as the organisational, 
documentation and authorisation proce dures that ensure that all the relevant tests are carried 
out and that the use of materials or the dispensing of products for sale or supply are not 
authorised without establishing that they are of satisfactory quality.  Quality control is not 
restricted to  laboratory operations, but must be applied in all decisions relating to product 
quality.  It is of fundamental importance for quality control to be independent of production.  
16.2 Quality control.  Annex “Handbook of Good Manufacturing Practices for Medical Gases”  36 
16.2.1 Medical gases must comply with the specifications of  the official pharmacopoeias in 
the country.  
16.2.2 Quality control should be checked against the specifications laid down.  
16.2.3 Bulk gas used as a starting material should be approved and released before use in a 
filling operation.  
16.2.4 An analysis ce rtificate should be issued and kept for each load of product and each 
delivery of medical gas should be backed up by an analysis certificate.  
16.2.5 The content of each and every cryogenic tanker truck used to transport liquefied 
medical gases should be an alysed in terms of identity and purity before filling.  An appropriate 
certificate should be issued for that analysis.  
16.2.6 During direct filling from a cryogenic tanker truck into stationary tanks, the product 
need not be analysed provided that the batch  is accompanied by an appropriate analysis 
certificate issued by the manufacturer.  
16.2.7 Gases used as standards for calibrating or adjusting analysis equipment must be 
properly identified and should have their respective analysis certificate in accordanc e with the 
relevant specifications.  
16.2.8 All rejected products must be destroyed in accordance with written procedures and in 
safe environmental conditions.  This activity should be recorded and approved by the qualified 
person.  
16.2.9 All vessels of medi cal gases returned to the manufacturer without their security seal 
must be identified as rejected products and the product must be disposed of in accordance 
with the established procedures, depending on the type of medical gas.  
16.2.10 Upon entering the pl ant, all inputs must have an analysis certificate, and quality 
controls should be carried out as required to check the specifications.  The acceptance 
procedure must be documented and recorded.  
16.2.11. In the case of a single medical gas filled into cylind ers one at a time by individual 
filling operations or by filling manifolds, at least one cylinder of each uninterrupted filling 
cycle should be tested for identity and assay.  
16.2.12. Where the finished product is a mixture of two different gases in a cyli nder, at least 
one gas from each cylinder should be tested for identity and quantity, and the other gas in at 
least one cylinder of each filling cycle should be tested for identity and the level of impurities 
in the product.  
16.2.13 Where the finished prod uct is a mixture of three different gases, two gases from each 
cylinder should be tested for identity and quantity, and the third gas in at least one cylinder of 
each filling cycle should be tested for identity and the level of impurities in the product.  
16.2.14 When gases are mixed in -line before filling, continuous analysis of the mixture being 
filled is required.  
16.2.15. The contents of cryogenic containers of liquefied gas should be analysed, including a 
quantification of the impurities.  Annex “Handbook of Good Manufacturing Practices for Medical Gases”  37 
16.2.16 There should be stability studies to determine the shelf life of medicinal gases and 
specific procedures for assigning a shelf life to each batch.  
16.3. Control of starting materials and intermediate, bulk and finished products   
16.3.1 All tests must comply with  the instructions in the written procedure for each material 
or product.  The result should be checked by the supervisor before the material or product is 
released or rejected.  
16.3.2 Samples must be representative of batches of material collected in accord ance with an 
appropriate written procedure.  
16.3.3 Sampling must be carried out in such a way as to avoid contamination or other 
problems that might have an adverse effect on product quality.  
16.3.4 During sampling special care should be taken to avoid con tamination or mix -ups of the 
materials being sampled.  All sampling equipment and utensils that come into contact with the 
materials should be clean.  It is likely that special precautions will need to be taken with some 
exceptionally hazardous or potent mat erials.  
16.3.5 Equipment used in sampling must be cleaned before and after each use and must be 
stored separately from other laboratory equipment.  
16.3.6 Each sampling container must be labelled to indicate:  
a) the name of the material being sampled;  
b) the batch number;  
c) the number of the container from which the sample was taken;  
d) the signature of the person taking the sample;  
e) the sampling date.  
16.4 Test requirements  
16.4.1 Starting materials and packaging  
Before authorising the use of starting ma terials or packaging, the head of quality control must 
make sure that it has been checked that the materials meet the specifications regarding 
identity, activity, purity and other quality indicators.  
16.4.2 A sample must be taken for analysis from each con tainer of starting material.  
16.4.3 Each batch of printed packaging materials must be examined after receipt.  
16.4.4 Instead of a test carried out by the manufacturer, an analysis certificate provided by the 
supplier may be accepted, provided that the manu facturer can ascertain the reliability of that 
analysis, by periodically checking the results of tests carried out by the supplier and an on -
the-spot audit of the supplier’s capacity.  Certificates must be originals; photocopies are 
acceptable only if duly authenticated.  Certificates must contain at least the following 
information:  
a) identity of the supplier, signature of the competent official and declaration of 
suitability of the supplier;  Annex “Handbook of Good Manufacturing Practices for Medical Gases”  38 
b) name and batch number of the material submitted for testing;  
c) specifications and methods used;  
d) test results and date.  
16.5 In -process control  
Records must be kept of in -process controls, which will be part of batch records.  
16.6 Finished products  
16.6.1. Before each batch of pharmaceutical products is released, t he person responsible 
should check that each batch complies with the specifications for finished products.  
16.6.2 Products that do not comply with the relevant specifications or quality criteria must be 
rejected.   
16.7 Examination of production records  
16.7.1 Production and control records should be examined; if a batch does not comply with 
the specifications, it must undergo a full investigation.  Where necessary, this investigation 
should be extended to other batches of the same product and any other produ cts that might be 
linked to the defect or discrepancy.  The investigation should be recorded in writing, including 
the conclusions and follow -up. 
16.8 Stability studies  
16.8.1 The quality -control department should carry out an assessment of finished 
pharmac eutical products and, where necessary, of the packaging and packing materials and 
intermediate products.  
16.8.2 The quality -control department should lay down expiry dates and specifications for 
shelf lives, on the basis of stability tests relating to stor age conditions.  
16.8.3 A permanent programme should be prepared in writing and implemented for 
determining stability, including at least the following:  
a) full description of the medicinal product under study.  
b) complete test parameters and methods descri bing all the assays of activity, purity and 
physical properties, and documentary evidence that the tests indicate stability;  
c) requirement to include a sufficient number of batches;  
d) timetable of tests for each medicinal product;  
e) requirement for samp les for stability studies to be filled in the same containers as for 
marketing the product;  
f) requirement to keep appropriate samples;  
g) summary of all data obtained, including assessments and conclusions of the study.  
16.8.4 Stability should be determin ed before marketing and also after any significant 
information on processes, equipment, packaging materials, etc.  Annex “Handbook of Good Manufacturing Practices for Medical Gases”  39 
17. DISTRIBUTION  
17.1. Cylinder distribution trucks should have separate spaces set aside for medical and 
industrial -grade gases; confusion sh ould also be avoided between full and empty vessels.  
17.2. Liquefied medical gas and industrial gas may be transported in the same tanker truck.  If 
combined deliveries are made for both medical and industrial use, the transport vehicle should 
be fitted wit h a non -return system to guarantee the quality of the product inside at all times.  
17.3. There must be a written procedure for changing products where a tanker truck used for 
transporting a particular medical gas is fitted out for transporting another medi cal gas.  This 
activity should be recorded.  
17.4. Transport conditions must be such as to ensure that the manufacturer’s product release 
specifications are complied with.  
17.5. Vehicles used to distribute medical gases must require with the identification a nd 
adaptation requirements laid down in the relevant current regulations.  
18. PRODUCTION OF MEDICAL OXYGEN ON SITE USING THE MOLECULAR 
SIEVE PROCESS  
General considerations:  Besides the precautions described above applicable to oxygen 
generator plants, acco unt should be taken of the following:  Generator plants must be under 
the responsibility of a technical director who is a professional pharmaceutical chemist and is 
familiar with the generation process, the handling of cylinders and preventive and correctiv e 
maintenance of the plant and the control of medical oxygen gas produced by separating 
medical air by adsorption.  
All the personnel should be familiar with practices for manufacturing and controlling medical 
oxygen produced by this process and aware of th e critical aspects involved.  
Medical oxygen gas obtained using this process should comply with the required technical 
quality specifications in the pharmacopoeias officially approved in the country.  
18.1 The supply of oxygen using the molecular sieve proce ss should comply with special 
constraints regarding safety and reserves to ensure a fail -safe configuration.  
Medical oxygen gas produced by separating medical air using the molecular sieve process 
should be generated in a closed circuit specially construct ed for the purpose.  In this system 
for obtaining medical oxygen gas by separating air using the molecular sieve process, gas 
must have a shelf life that guarantees the uniformity of the batch and be released before it 
expires.  
18.2 The oxygen concentration  system and the oxygen produced must comply with good 
manufacturing practice for operation, quality standards, availability, purity and control of 
impurities, described herein.  
18.3 Oxygen concentrator systems are ensured a constant supply by the installat ion of a 
primary system that includes a PSA system and a reserve supply system that should be 
designed for automatic operation.  
18.4 Each primary PSA system must comprise at least the following:  
a) a compressor;  Annex “Handbook of Good Manufacturing Practices for Medical Gases”  40 
b) molecular sieve apparatus;  
c) storage tan ks; 
d) two oxygen analyser, and  
e) appropriate safety devices.  
The information used to design and select the PSA system must be entered into its logbook.  
The institution must guarantee a constant supply of medical gas.  
18.5 Notwithstanding sections 18.3 an d 18.4 a PSA system may comprise primary, secondary 
and reserve supply systems.  The secondary system must be configured the same way as the 
primary system described above.  
In this case each compressor must have a connection to enable it to supply another m olecular 
sieve should its own molecular sieve fail.  
Regardless of whether the institution has one or two PSA systems, it must guarantee a 
constant supply of medical oxygen.  
For existing institutions, the primary supply must be designed to supply at least t wice the 
average oxygen demand for the immediately previous year.  
For new institutions the primary supply must be designed in line with consumptions of 
existing institutions of similar sizes.  
18.6 The components of the oxygen concentrator systems, includin g any component 
connected to molecular sieve apparatus in contact with oxygen -enriched air, must be 
compatible with 99% oxygen V/V under all operating conditions and be free of oil, grease 
and solid particles.  
18.7 After the molecular sieve apparatus a 0.3  micron, 99% efficient coalescent filter should 
be installed to ensure that the gaseous product complies with the requirements for particles in 
the specifications.  
18.8 The storage volume for the reserve supply should allow for at least 48 hours of average  
demand and the reserve should come on stream immediately in the event of a fault in the 
system under optimum working conditions.  In any case the institution should guarantee the 
supply of medical gas.  
18.9 Should the primary oxygen concentrator supply sys tem fail, the reserve supply system 
should come on stream automatically.  The reserve supply system should comprise pressure 
vessels, such as cylinders, cryogenic flasks or tanks, filled with medical oxygen produced by 
a molecular sieve process or liquefyin g air.  
18.10 A non -return valve should be fitted in the supply line to the oxygen concentrator 
system.  The reserve supply system should discharge gas to the distribution system, after the 
non-return valve.   
18.11 The oxygen concentrator system should have a dual pressure -regulation system 
providing a stable nominal pressure of 50 psig and with pressure -relief valves designed to 
open at 75 psig.  
18.12 The control and monitoring system should include an oxygen analyser to continuously 
monitor and record the m edical oxygen concentration in a way that cannot be modified.  This Annex “Handbook of Good Manufacturing Practices for Medical Gases”  41 
device should incorporate compensation for temperature and variations in barometric pressure 
to ensure an accuracy of ±0.1% of the average value under all operating conditions.  
18.13 The ox ygen concentrator system should have microbiological filters appropriate to the 
operating parameters, so as to ensure the microbiological quality of the gas at the outlet of the 
concentrator system.  
18.14 The control and monitoring system should automatica lly change the PSA supply to the 
reserve supply in the event of a pressure or concentration failure.  
18.15 There should be a second independent oxygen analyser to continuously monitor 
and record the final concentration of the medical oxygen produced in a p ermanent, 
automatic and non -modifiable way.  This device should incorporate compensation for 
temperature and variations in barometric pressure to ensure an accuracy of ±0.1% of 
the average value under all operating conditions.   
18.16 The reserve system shou ld be used only when the main supply system fails.  A 
single network may not be supplied from the main supply and the reserve 
simultaneously.  
Whatever the source of its reserve system, the institution is responsible for safe use of 
medical oxygen.  
18.17 Whe re the independent oxygen analyser detects that the purity of the oxygen -enriched 
air from the oxygen concentrator is lower than specified, it must immediately cut off the 
supply to enable the reserve system to supply the product.  
18.18 Alarms:  Whatever th e configuration of the oxygen concentrator system, there must be 
operating and emergency warning devices such as visual and auditory alarms to indicate:   
a) switch from primary to secondary supply;  
b) reserve supply in operation;  
c) secondary reserve syste m in operation;  
d) activation of fault monitoring devices built into the system;  
e) reserve supply falling below 50% of nominal pressure;  
f) oxygen concentration falling below specified value;  
g) low pressure in the oxygen distribution system (45 psig).  
18.19 If the oxygen concentrator system has equipment to fill the reserve system, it should 
comply with the specifications and the requirements laid down herein for the filling of 
medical gases.  
18.20 The reserve filling system should have an over -pressure r elief valve.  
18.21 The high -pressure manifold should be designed to withstand 1.5 times the maximum 
supply pressure and must be fitted with a relief valve set to operate at 130% of the maximum 
working pressure with a capacity equivalent to the discharge of  the full output of the 
compressor or compressors of the oxygen concentrator system.  Annex “Handbook of Good Manufacturing Practices for Medical Gases”  42 
18.22 The medical oxygen manufacturer must have the following information:  
a) nominal capacity of the plant expressed in litres per minute, corrected for standard 
temperat ure and pressure (0 ºC, 101.3 kPa);  
b) instructions for installation, operation and maintenance;  
c) pressure, temperature and humidity ranges of inlet air and  
d) ambient temperature conditions for which the plant is designed.  
18.23 The manufacturer should have a certificate from the supplier to the effect that the 
oxygen concentrator system can operate continuously for at least seventy -two (72) hours in 
compliance with the design and operating specifications when required.  
18.24 The gas produced by the oxyg en concentrator system should comply with the 
specifications laid down in the current official pharmacopoeias.  
18.25 The plant should be installed in ventilated and hygienic premises for its exclusive use . 
The oxygen concentrator system must be located whe re the air source is free of toxic 
or flammable gases such as engine exhaust, fuel storage vents, discharges from 
surgical vacuum systems, particular material or odours of any kind of contaminants 
that might jeopardise the process or the medicinal product.  The air intake must be 
located outdoors, above roof level, at least three metres (10 feet) from any door, 
window, gas discharge, other intake or opening of the building; and at least six metres 
(20 feet) above ground level.  
The gas remaining from the prod uction of oxygen by molecular sieve should be 
discharged by means of a vent pipe to the atmosphere outside the production 
premises.  
Marking:  however the medical gas is obtained, the institution’s tanks or cylinders 
must be marked in accordance with the pro visions of this decision.  
ON-SITE PRODUCTION OF MEDICAL AIR BY COMPRESSOR  
19.1 Apart from the rules applicable to it medical air produced by this method must 
comply with the following requirements, depending on the areas to be certified.  
19.1.1 Medical air  must comply with the conditions and specifications set out in the 
current official pharmacopoeias in the country and air quality must be continuously 
monitored and permanently recorded downstream of the final line regulators and 
upstream of the network.  The air -quality parameters to be continuously monitored and 
permanently recorded are as follows:  
(1) Dew point.  The dew point at the system pressure should be monitored and when it 
exceeds the minimum design operating temperature it must trigger a local ala rm and 
all the master alarms.   
(2) Carbon monoxide.  The CO level should be monitored and when it exceeds 10 ppm 
it should trigger a local alarm.   Annex “Handbook of Good Manufacturing Practices for Medical Gases”  43 
(3) If a dew point or carbon monoxide monitor loses power the individual monitor 
signal should be triggered on  all the master panels.  
19.1.2 Medical air compressors must be designed to prevent contaminants or liquids 
being introduced into the network, using one of the following methods:  
(1) elimination of oil in any part of the compressor (such as liquid -ring comp ressors 
and permanently -sealed bearings);  
(2) reciprocating compressors having a separation between the section containing oil 
and the compression chamber consisting of at least two seals forming an area open to 
the atmosphere allowing:  
(a) direct visual a nd unobstructed inspection of the interconnecting shaft through the 
vent and inspection holes of a size not less than 1.5 shaft diameters.  
(b) plant operators to check proper operation of seals by direct visual inspection of the 
shaft through that opening,  without dismantling the compressor (such as extended -
head compressors, with an atmospheric vent between the compression chamber and 
the crankcase).  
(3) rotary compressors with an oil -free chamber allowing the following:  
(a) separation between each lubrica ted section and the compression chamber, by 
means of at least one atmospheric vented seal on each side, and with the vent closest 
to the lubricated section fitted with gravity drainage to the atmosphere.  
(b) unobstructed view of the atmospheric vent(s) clo sest to each lubricated section, 
accessible for inspection without dismantling the compressor;  
(c) entry of the rotary shaft to each compression chamber at a point where the 
pressure is high than atmospheric pressure;  
(d) plant operators to check proper op eration of the seals by direct visual inspection of 
the atmospheric vents.  
19.1.3 Medical air compressors should take their air from a clean air source located 
out of the way of engine exhausts, fuel storage vents, discharges from surgical 
vacuum systems, particulate material or odour of any kind.  The compressor air intake 
must be located outdoors, above roof level, at least three metres (10 feet) from any 
door, window, gas discharge, other intake or opening of the building; and at least six 
metres (20 feet ) above ground level.  
19. 2 Description of the system and installation  
19.2.1 Two or more compressors should be installed, designed for alternating or simultaneous 
operation as required.  
19.2.2 Each compressor should have an off switch and a starter with o verload protection.  
19.2.3 Compressor systems shall be fitted with an automatic control for alternating operation 
of the units, distributing consumption between them.  There should be an automatic system for Annex “Handbook of Good Manufacturing Practices for Medical Gases”  44 
bringing additional compressor units into operati on when the unit in service cannot maintain 
sufficient pressure.  
19.2.4 Compressor systems should have coalescent filters with an element to indicate 
when they are saturated to enable their working life to be established and a carbon 
filter, and bacteriolo gical filters suited to the operating parameters.  
19.2.5 Medical air compression systems should be equipped with filters located near the inlet 
air suction point, after coolers, receiver tanks and in -line filters for proper separation of 
particles and oil.  
19.2.6 Drying systems should be at least duplicated; during normal operation only one dryer 
should remain open to air flow while the other is regenerating or on standby.  
19.2.7 When post -coolers are required, they should be duplicated.  
19.2.8 Line -end fil ters should be duplicated, with appropriate valves to enable uninterrupted 
service.  
19.2.9 Medical -air compressors used to supply ambient air should not be used to supply air 
for other purposes.  
19.2.10 Air systems must be able to satisfy demand calculated  even with the largest 
compressor unit out of action.  
19.3 Technical direction and quality control  
19.3.1 Where the process of obtaining medical gases by means of the molecular air filtration 
method and medical air by on -site compressor is carried out by a  health service provider, the 
function of technical director may be carried out by the pharmaceutical chemist responsible 
for that institution’s pharmaceutical service.  
19.3.2 Quality control of medical air and medical gases produced in a health service pr ovider 
may be carried out in that institution’s quality -control section or department, unless it is 
contracted out.  
20. Other provisions  
20.1 Vessels and pipes used for generating and conveying medical gases in hospital 
installations should be made of the materials specified in this standard; this should be 
checked by the competent authority.  
Where the institution prepares the medical gas, the check referred to in this section is 
part of good manufacturing practice certification.  
20.2 Vessels and pipes used  for generating and conveying medical gases in hospital 
installations should be made of the materials specified in this standard; this should be 
checked by the competent authority.  
Where the institution prepares the medical gas, the check referred to in th is section is 
part of good manufacturing practice certification.  
20.3 Pharmacovigilance programme:  Annex “Handbook of Good Manufacturing Practices for Medical Gases”  45 
In accordance with the provisions of the current regulations, medical gases are 
medicinal products and are therefore covered by the institutional pharmacovig ilance 
programme pursuant to Resolution 1403 of 2007, or any regulation supplementing, 
amending or replacing it.