Pic gmp 2021.pdf annexes

PHARMACEUTICAL INSPECTION CONVENTION
PHARMACEUTICAL INSPECTION CO-OPERATION SCHEME
PE 009-15 (Annexes) 1 May 2021
PE 009-15 (Annexes)
1 May 2021
GUIDE TO GOOD MANUFACTURING
PRACTICE FOR MEDICINAL PRODUCTS
ANNEXES
© PIC/S 2021
Reproduction prohibited for commercial purposes.
Reproduction for internal use is authorised,
provided that the source is acknowledged.
Editor: PIC/S Secretariat
14 rue du Roveray
CH-1207 Geneva
e-mail: info@picscheme.org
web site: http://www.picscheme.org

Table of contents
PE 009-15 (Annexes) -i- 1 May 2021
ANNEXES
Annex 1 (Manufacture of sterile medicinal products) 1
Principle 1
General 1
Clean room and clean air device classification 2
Clean room and clean air device monitoring 3
Isolator technology 5
Blow/fill/seal technology 6
Terminally sterilised products 6
Aseptic preparation 7
Personnel 7
Premises 8
Equipment 10
Sanitation 10
Processing 10
Sterilisation 13
Sterilisation by heat 13
Moist heat 14
Dry heat 14
Sterilisation by radiation 14
Sterilisation with ethylene oxide 15
Filtration of medicinal products which cannot be sterilised in their final container 16
Finishing of sterile products 16
Quality control 17
Annex 2A
(Manufacture of advanced therapy medicinal products for human use) 19
Scope 19
Principle 23
Part A: General guidance 24
Supplimentary provisions to PIC/S GMP Guide Part I 25
Chapter 1 Pharmaceutical quality system 25
Chapter 2 Personnel 25
Chapter 3 Premises and equipment 26
Chapter 4 Documentation 30
Chapter 5 Production 31
Chapter 6 Quality control 42
Chapter 7 Outsourced activities 47
Chapter 8 Complaints and product recall 48
Part B: Specific guidance on selected product types 49
Common glossary to Annex 2A and 2B 52
Annex 2B
(Manufacture of biological medicinal substances and products for human use) 59
Scope 59
Principle 61
Part A: General guidance 63
Personnel 63
Premises and equipment 63
Animals 66
Documentation 67

Table of contents
PE 009-15 (Annexes) -ii- 1 May 2021
Production 67
Starting and raw materials 68
Seed lot and cell bank system 70
Operating principles 71
Quality control 73
Part B: Specific guidance on selected product types 74
Annex 3 (Manufacture of radiopharmaceuticals) 79
Principle 79
Introduction 79
Quality assurance 80
Personnel 81
Documentation 82
Production 82
Quality control 83
Reference and retention samples 85
Distribution 85
Glossary 85
Annex 4
(Manufacture of veterinary medicinal products other than immunologicals) 86
Manufacture of premixes for medicated feeding stuffs 86
The manufacture of ectoparasiticides 87
The manufacture of veterinary medicinal products containing penicillins 87
Retention of samples 87
Sterile veterinary medicinal products 87
Annex 5 (Manufacture of immunological veterinary medical products) 88
Principle 88
Personnel 88
Premises 89
Equipment 92
Animals and animal houses 93
Disinfection Waste disposal 93
Production 94
Starting materials 94
Quality control 97
Annex 6 (Manufacture of medicinal gases) 98
Principle 98
Manufacture of active substance gases 98
Manufacture of medicinal gases 99
Personnel 99
Documentation 101
Production 102
Quality control 105
Transportation of packaged gases 106
Glossary 107

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PE 009-15 (Annexes) -iii- 1 May 2021
Annex 7 (Manufacture of herbal medicinal products) 109
Principle 109
Premises 111
Storage areas 111
Production area 111
Equipment 111
Documentation 111
Specifications for starting materials 111
Processing instructions 113
Quality Control 113
Annex 8 (Sampling of starting and packaging materials) 114
Principle 114
Personnel 114
Starting materials 114
Packaging material 115
Annex 9 (Manufacture of liquids, creams and ointments) 116
Principle 116
Production 116
Annex 10
(Manufacture of pressurised metered dose aerosol preparations for inhalation) 118
Principle 118
General 118
Production and quality control 119
Annex 11 (Computerised systems) 120
Principle 120
General 120
Risk management 120
Personnel 120
Suppliers and service providers 120
Project phase 121
Validation 121
Operational phase 122
Data 122
Accuracy checks 122
Data storage 122
Printouts 122
Audit trails 122
Change and configuration management 122
Periodic evaluation 122
Security 123
Incident management 123
Electronic signature 123
Batch release 123
Business continuity 123
Archiving 124
Glossary 124

Table of contents
PE 009-15 (Annexes) -iv- 1 May 2021
Annex 12 (Use of ionising radiation in the manufacture of medicinal products) 125
Introduction 125
Responsibilities 125
Dosimetry 126
Validation of the process 126
Commissioning of the plant 127
General 127
Gamma irradiators 127
Electron beam irradiators 128
Premises 129
Processing 129
Gamma irradiators 130
Electron beam irradiators 130
Documentation 131
Microbiological monitoring 131
Annex 13 (Manufacture of investigational medicinal products) 132
Principle 132
Glossary 133
Quality management 135
Personnel 135
Documentation 136
Specifications and instructions 136
Order 136
Product specification file 136
Manufacturing formulae and processing instructions 137
Packaging instructions 137
Processing, testing and packaging batch records 137
Production 137
Packaging materials 137
Manufacturing operations 138
Principles applicable to comparator product 138
Blinding operations 138
Randomisation code 139
Packaging 139
Labelling 139
Quality control 141
Release of batches 142
Shipping 144
Complaints 144
Recalls and returns 144
Recalls 144
Returns 145
Destruction 145
Annex 14
(Manufacture of medicinal products derived from human blood or plasma) 147
Glossary 147
Scope 149
Principles 149
Quality management 151
Traceability and post collection measures 152

Table of contents
PE 009-15 (Annexes) -v- 1 May 2021
Manufacturing 154
Quality control 156
Release of intermediate and finished products 157
Retention of plasma pool samples 157
Disposal of waste 157
Addendum 157
Annex 15 (Qualification and validation) 161
Principle 161
General 161
Organising and Planning for Qualification and Validation 161
Documentation, including VMP 162
Qualification Stages for Equipment, Facilities and Systems 163
Re-qualification 165
Process Validation 165
Verification of Transportation 169
Validation of Packaging 170
Qualification of Utilities 170
Validation of Test Methods 170
Cleaning Validation 171
Change Control 172
Glossary 173
Annex 16 [Qualified person and batch release] 176
Annex 17 (Real Time Release Testing and Parametric Release) 177
Principle 177
Scope 177
Real Time Release Testing (RTRT) 177
Parametric Release and Sterilisation 179
Glossary 181
Annex 18 [GMP Guide for active pharmaceutical ingredients]** 183
Annex 19 (Reference and retention samples) 184
Scope 184
Principle 184
Duration of storage 185
Size of reference and retention samples 185
Storage conditions 186
Written agreements 186
Reference samples – General points 186
Retention samples – General points 187
Reference and retention samples for parallel imported
/ parallel distributed products 187
 This Annex is specific to the EU GMP Guide and has not been adopted by PIC/S.
** The EU first adopted the ICH GMP Guide on APIs as Annex 18 to the EU GMP
Guide while PIC/S adopted it as a stand-alone GMP Guide (PE 007). The Guide has
now been adopted as Part II of the PIC/S GMP Guide (see PE 009 (Part II)).

Table of contents
PE 009-15 (Annexes) -vi- 1 May 2021
Reference and retention samples in the case of closedown of a
manufacturer 187
Annex 20 (Quality risk management)*** 189
Foreword and scope of application 189
Introduction 189
Scope 191
Principles of quality risk management 191
General quality risk management process 191
Responsibilities 192
Initiating a quality risk management process 193
Risk assessment 193
Risk control 194
Risk communication 195
Risk review 195
Risk management methodology 195
Integration of quality risk management into industry and regulatory operations 196
Definitions 197
References 199
Appendix I: Risk Management Methods and Tools 200
Basic Risk Management Facilitation Methods 200
Failure Mode Effects Analysis (FMEA) 200
Potential Areas of Use(s) 200
Failure Mode, Effects and Criticality Analysis (FMECA) 200
Fault Tree Analysis (FTA) 201
Hazard Analysis and Critical Control Points (HACCP) 201
Hazard Operability Analysis (HAZOP) 202
Preliminary Hazard Analysis (PHA) 202
Risk Ranking and Filtering 203
Supporting Statistical Tools 203
Appendix II: Potential Applications For Quality Risk Management 204
Quality Risk Management as Part of Integrated Quality Management 204
Quality Risk Management as Part of Regulatory Operations 205
Quality Risk Management as Part of Development 206
Quality Risk Management for Facilities, Equipment and Utilities 206
Quality Risk Management as Part of Materials Management 207
Quality Risk Management as Part of Production 208
Quality Risk Management as Part of Laboratory Control and Stability Studies 209
Quality Risk Management as Part of Packaging and Labelling 209
GLOSSARY 210
*** This Annex is voluntary.

Annex 1 Manufacture of sterile medicinal products
PE 009-15 (Annexes) -1- 1 May 2021
ANNEX 1
MANUFACTURE OF STERILE MEDICINAL PRODUCTS
PRINCIPLE
The manufacture of sterile products is subject to special requirements in order to
minimise risks of microbiological contamination, and of particulate and pyrogen
contamination. Much depends on the skill, training and attitudes of the personnel
involved. Quality Assurance is particularly important, and this type of manufacture
must strictly follow carefully established and validated methods of preparation
and procedure. Sole reliance for sterility or other quality aspects must not be
placed on any terminal process or finished product test.
Note: This guidance does not lay down detailed methods for determining the
microbiological and particulate cleanliness of air, surfaces, etc. Reference
should be made to other documents such as the EN/ISO Standards.
GENERAL
1. The manufacture of sterile products should be carried out in clean areas entry to
which should be through airlocks for personnel and/or for equipment and
materials. Clean areas should be maintained to an appropriate cleanliness
standard and supplied with air which has passed through filters of an appropriate
efficiency.
2. The various operations of component preparation, product preparation and filling
should be carried out in separate areas within the clean area. Manufacturing
operations are divided into two categories; firstly those where the product is
terminally sterilised, and secondly those which are conducted aseptically at some
or all stages.
3. Clean areas for the manufacture of sterile products are classified according to
the required characteristics of the environment. Each manufacturing operation
requires an appropriate environmental cleanliness level in the operational state
in order to minimise the risks of particulate or microbial contamination of the
product or materials being handled.
In order to meet “in operation” conditions these areas should be designed to
reach certain specified air-cleanliness levels in the “at rest” occupancy state. The
“at rest” state is the condition where the installation is installed and operating,
complete with production equipment but with no operating personnel present.
The “in operation” state is the condition where the installation is functioning in the
defined operating mode with the specified number of personnel working.
The “in operation” and “at rest” states should be defined for each clean room or
suite of clean rooms.

PE 009-15 (Annexes) -2- 1 May 2021
For the manufacture of sterile medicinal products 4 grades can be distinguished.
Grade A: The local zone for high risk operations, e.g. filling zone, stopper bowls,
open ampoules and vials, making aseptic connections. Normally such conditions
are provided by a laminar air flow work station. Laminar air flow systems should
provide a homogeneous air speed in a range of 0.36 – 0.54 m/s (guidance value)
at the working position in open clean room applications. The maintenance of
laminarity should be demonstrated and validated.
A uni-directional air flow and lower velocities may be used in closed isolators and
glove boxes.
Grade B: For aseptic preparation and filling, this is the background environment
for the grade A zone.
Grade C and D: Clean areas for carrying out less critical stages in the
manufacture of sterile products
CLEAN ROOM AND CLEAN AIR DEVICE CLASSIFICATION
4. Clean rooms and clean air devices should be classified in accordance with EN
ISO 14644-1. Classification should be clearly differentiated from operational
process environmental monitoring. The maximum permitted airborne particle
concentration for each grade is given in the following table:
Grade Maximum permitted number of particles/m³
equal to or greater than the tabulated size
At rest In operation
0.5m 5.0m 0.5m 5.0m
A 3,520 20 3,520 20
B 3,520 29 352,000 2,900
C 352,000 2,900 3,520,000 29,000
D 3,520,000 29,000 not defined not defined
5. For classification purposes in Grade A zones, a minimum sample volume of 1m³
should be taken per sample location. For Grade A the airborne particle
classification is ISO 4.8 dictated by the limit for particles ≥5.0 μm. For Grade B
(at rest) the airborne particle classification is ISO 5 for both considered particle
sizes. For Grade C (at rest & in operation) the airborne particle classification is
ISO 7 and ISO 8 respectively. For Grade D (at rest) the airborne particle
classification is ISO 8. For classification purposes EN/ISO 14644-1 methodology
defines both the minimum number of sample locations and the sample size based
on the class limit of the largest considered particle size and the method of
evaluation of the data collected.
6. Portable particle counters with a short length of sample tubing should be used for
classification purposes because of the relatively higher rate of precipitation of

PE 009-15 (Annexes) -3- 1 May 2021
particles ≥5.0μm in remote sampling systems with long lengths of tubing.
Isokinetic sample heads should be used in unidirectional airflow systems.
7. “In operation” classification may be demonstrated during normal operations,
simulated operations or during media fills as worst-case simulation is required for
this. EN ISO 14644-2 provides information on testing to demonstrate continued
compliance with the assigned cleanliness classifications.
CLEAN ROOM AND CLEAN AIR DEVICE MONITORING
8. Clean rooms and clean air devices should be routinely monitored in operation
and the monitoring locations based on a formal risk analysis study and the results
obtained during the classification of rooms and/or clean air devices.
9. For Grade A zones, particle monitoring should be undertaken for the full duration
of critical processing, including equipment assembly, except where justified by
contaminants in the process that would damage the particle counter or present a
hazard, e.g. live organisms and radiological hazards. In such cases monitoring
during routine equipment set up operations should be undertaken prior to
exposure to the risk. Monitoring during simulated operations should also be
performed. The Grade A zone should be monitored at such a frequency and with
suitable sample size that all interventions, transient events and any system
deterioration would be captured and alarms triggered if alert limits are exceeded.
It is accepted that it may not always be possible to demonstrate low levels of ≥5.0
μm particles at the point of fill when filling is in progress, due to the generation of
particles or droplets from the product itself.
10. It is recommended that a similar system be used for Grade B zones although the
sample frequency may be decreased. The importance of the particle monitoring
system should be determined by the effectiveness of the segregation between
the adjacent Grade A and B zones. The Grade B zone should be monitored at
such a frequency and with suitable sample size that changes in levels of
contamination and any system deterioration would be captured and alarms
triggered if alert limits are exceeded.
11. Airborne particle monitoring systems may consist of independent particle
counters; a network of sequentially accessed sampling points connected by
manifold to a single particle counter; or a combination of the two. The system
selected must be appropriate for the particle size considered. Where remote
sampling systems are used, the length of tubing and the radii of any bends in the
tubing must be considered in the context of particle losses in the tubing. The
selection of the monitoring system should take account of any risk presented by
the materials used in the manufacturing operation, for example those involving
live organisms or radiopharmaceuticals.
12. The sample sizes taken for monitoring purposes using automated systems will
usually be a function of the sampling rate of the system used. It is not necessary
for the sample volume to be the same as that used for formal classification of
clean rooms and clean air devices.

PE 009-15 (Annexes) -4- 1 May 2021
13. In Grade A and B zones, the monitoring of the ≥5.0 μm particle concentration
count takes on a particular significance as it is an important diagnostic tool for
early detection of failure. The occasional indication of ≥5.0 μm particle counts
may be false counts due to electronic noise, stray light, coincidence, etc.
However consecutive or regular counting of low levels is an indicator of a possible
contamination event and should be investigated. Such events may indicate early
failure of the HVAC system, filling equipment failure or may also be diagnostic of
poor practices during machine set-up and routine operation.
14. The particle limits given in the table for the “at rest” state should be achieved after
a short “clean up” period of 15-20 minutes (guidance value) in an unmanned state
after completion of operations.
15. The monitoring of Grade C and D areas in operation should be performed in
accordance with the principles of quality risk management. The requirements and
alert/action limits will depend on the nature of the operations carried out, but the
recommended “clean up period” should be attained.
16. Other characteristics such as temperature and relative humidity depend on the
product and nature of the operations carried out. These parameters should not
interfere with the defined cleanliness standard.
17. Examples of operations to be carried out in the various grades are given in the
table below (see also paragraphs 28 to 35):
Grade
Examples of operations for terminally sterilised products
(see para. 28-30)
A Filling of products, when unusually at risk
C Preparation of solutions, when unusually at risk. Filling of
products
D Preparation of solutions and components for subsequent filling
Grade
Examples of operations for aseptic preparations
(see para. 31-35)
A Aseptic preparation and filling
C Preparation of solutions to be filtered
D Handling of components after washing
18. Where aseptic operations are performed monitoring should be frequent using
methods such as settle plates, volumetric air and surface sampling (e.g. swabs
and contact plates). Sampling methods used in operation should not interfere with
zone protection. Results from monitoring should be considered when reviewing
batch documentation for finished product release. Surfaces and personnel should
be monitored after critical operations.
Additional microbiological monitoring is also required outside production
operations, e.g. after validation of systems, cleaning and sanitisation.

PE 009-15 (Annexes) -5- 1 May 2021
19. Recommended limits for microbiological monitoring of clean areas during
operation:
Recommended limits for microbial contamination (a)
Grade Air sample
cfu/m³
Settle plates
(diam. 90 mm),
cfu/4 hours (b)
Contact plates
(diam. 55 mm),
cfu/plate
Glove print
5 fingers
cfu/glove
A < 1 < 1 < 1 < 1
B 10 5 5 5
C 100 50 25 -
D 200 100 50 -
Notes: (a)
These are average values.
(b)
Individual settle plates may be exposed for less than 4 hours.
20. Appropriate alert and action limits should be set for the results of particulate and
microbiological monitoring. If these limits are exceeded operating procedures
should prescribe corrective action.
ISOLATOR TECHNOLOGY
21. The utilisation of isolator technology to minimise human interventions in
processing areas may result in a significant decrease in the risk of microbiological
contamination of aseptically manufactured products from the environment. There
are many possible designs of isolators and transfer devices. The isolator and the
background environment should be designed so that the required air quality for
the respective zones can be realised. Isolators are constructed of various
materials more or less prone to puncture and leakage. Transfer devices may vary
from a single door to double door designs to fully sealed systems incorporating
sterilisation mechanisms.
22. The transfer of materials into and out of the unit is one of the greatest potential
sources of contamination. In general the area inside the isolator is the local zone
for high risk manipulations, although it is recognised that laminar air flow may not
exist in the working zone of all such devices.
23. The air classification required for the background environment depends on the
design of the isolator and its application. It should be controlled and for aseptic
processing it should be at least grade D.
24. Isolators should be introduced only after appropriate validation. Validation should
take into account all critical factors of isolator technology, for example the quality
of the air inside and outside (background) the isolator, sanitisation of the isolator,
the transfer process and isolator integrity.

PE 009-15 (Annexes) -6- 1 May 2021
25. Monitoring should be carried out routinely and should include frequent leak
testing of the isolator and glove/sleeve system.
BLOW/FILL/SEAL TECHNOLOGY
26. Blow/fill/seal units are purpose built machines in which, in one continuous
operation, containers are formed from a thermoplastic granulate, filled and then
sealed, all by the one automatic machine. Blow/fill/seal equipment used for
aseptic production which is fitted with an effective grade A air shower may be
installed in at least a grade C environment, provided that grade A/B clothing is
used. The environment should comply with the viable and non viable limits at rest
and the viable limit only when in operation. Blow/fill/seal equipment used for the
production of products which are terminally sterilised should be installed in at
least a grade D environment.
27. Because of this special technology particular attention should be paid to, at least
the following:
• equipment design and qualification
• validation and reproducibility of cleaning-in-place and sterilisation-in-
place
• background clean room environment in which the equipment is located
• operator training and clothing
• interventions in the critical zone of the equipment including any aseptic
assembly prior to the commencement of filling.
TERMINALLY STERILISED PRODUCTS
28. Preparation of components and most products should be done in at least a grade
D environment in order to give low risk of microbial and particulate contamination,
suitable for filtration and sterilisation. Where the product is at a high or unusual
risk of microbial contamination, (for example, because the product actively
supports microbial growth or must be held for a long period before sterilisation or
is necessarily processed not mainly in closed vessels), then preparation should
be carried out in a grade C environment.
29. Filling of products for terminal sterilisation should be carried out in at least a grade
C environment.
30. Where the product is at unusual risk of contamination from the environment, for
example because the filling operation is slow or the containers are wide-necked
or are necessarily exposed for more than a few seconds before sealing, the filling
should be done in a grade A zone with at least a grade C background. Preparation
and filling of ointments, creams, suspensions and emulsions should generally be
carried out in a grade C environment before terminal sterilisation.

PE 009-15 (Annexes) -7- 1 May 2021
ASEPTIC PREPARATION
31. Components after washing should be handled in at least a grade D environment.
Handling of sterile starting materials and components, unless subjected to
sterilisation or filtration through a micro-organism-retaining filter later in the
process, should be done in a grade A environment with grade B background.
32. Preparation of solutions which are to be sterile filtered during the process should
be done in a grade C environment; if not filtered, the preparation of materials and
products should be done in a grade A environment with a grade B background.
33. Handling and filling of aseptically prepared products should be done in a grade A
environment with a grade B background.
34. Prior to the completion of stoppering, transfer of partially closed containers, as
used in freeze drying, should be done either in a grade A environment with grade
B background or in sealed transfer trays in a grade B environment.
35. Preparation and filling of sterile ointments, creams, suspensions and emulsions
should be done in a grade A environment, with a grade B background, when the
product is exposed and is not subsequently filtered.
PERSONNEL
36. Only the minimum number of personnel required should be present in clean
areas; this is particularly important during aseptic processing. Inspections and
controls should be conducted outside the clean areas as far as possible.
37. All personnel (including those concerned with cleaning and maintenance)
employed in such areas should receive regular training in disciplines relevant to
the correct manufacture of sterile products. This training should include reference
to hygiene and to the basic elements of microbiology. When outside staff who
have not received such training (e.g. building or maintenance contractors) need
to be brought in, particular care should be taken over their instruction and
supervision.
38. Staff who have been engaged in the processing of animal tissue materials or of
cultures of micro-organisms other than those used in the current manufacturing
process should not enter sterile-product areas unless rigorous and clearly defined
entry procedures have been followed.
39. High standards of personal hygiene and cleanliness are essential. Personnel
involved in the manufacture of sterile preparations should be instructed to report
any condition which may cause the shedding of abnormal numbers or types of
contaminants; periodic health checks for such conditions are desirable. Actions
to be taken about personnel who could be introducing undue microbiological
hazard should be decided by a designated competent person.
40. Wristwatches, make-up and jewellery should not be worn in clean areas.

PE 009-15 (Annexes) -8- 1 May 2021
41. Changing and washing should follow a written procedure designed to minimise
contamination of clean area clothing or carry-through of contaminants to the
clean areas.
42. The clothing and its quality should be appropriate for the process and the grade
of the working area. It should be worn in such a way as to protect the product
from contamination.
43. The description of clothing required for each grade is given below:
• Grade D: Hair and, where relevant, beard should be covered. A general
protective suit and appropriate shoes or overshoes should be worn.
Appropriate measures should be taken to avoid any contamination
coming from outside the clean area.
• Grade C: Hair and where relevant beard and moustache should be
covered. A single or two-piece trouser suit, gathered at the wrists and with
high neck and appropriate shoes or overshoes should be worn. They
should shed virtually no fibres or particulate matter.
• Grade A/B: Headgear should totally enclose hair and, where relevant,
beard and moustache; it should be tucked into the neck of the suit; a face
mask should be worn to prevent the shedding of droplets. Appropriate
sterilised, non-powdered rubber or plastic gloves and sterilised or
disinfected footwear should be worn. Trouser-legs should be tucked
inside the footwear and garment sleeves into the gloves. The protective
clothing should shed virtually no fibres or particulate matter and retain
particles shed by the body.
44. Outdoor clothing should not be brought into changing rooms leading to grade B
and C rooms. For every worker in a grade A/B area, clean sterile (sterilised or
adequately sanitised) protective garments should be provided at each work
session. Gloves should be regularly disinfected during operations. Masks and
gloves should be changed at least for every working session.
45. Clean area clothing should be cleaned and handled in such a way that it does not
gather additional contaminants which can later be shed. These operations should
follow written procedures. Separate laundry facilities for such clothing are
desirable. Inappropriate treatment of clothing will damage fibres and may
increase the risk of shedding of particles.
PREMISES
46. In clean areas, all exposed surfaces should be smooth, impervious and unbroken
in order to minimise the shedding or accumulation of particles or micro-organisms
and to permit the repeated application of cleaning agents, and disinfectants
where used.
47. To reduce accumulation of dust and to facilitate cleaning there should be no
uncleanable recesses and a minimum of projecting ledges, shelves, cupboards
and equipment. Doors should be designed to avoid those uncleanable recesses;
sliding doors may be undesirable for this reason.

PE 009-15 (Annexes) -9- 1 May 2021
48. False ceilings should be sealed to prevent contamination from the space above
them.
49. Pipes and ducts and other utilities should be installed so that they do not create
recesses, unsealed openings and surfaces which are difficult to clean.
50. Sinks and drains should be prohibited in grade A/B areas used for aseptic
manufacture. In other areas air breaks should be fitted between the machine or
sink and the drains. Floor drains in lower grade clean rooms should be fitted with
traps or water seals to prevent backflow.
51. Changing rooms should be designed as airlocks and used to provide physical
separation of the different stages of changing and so minimise microbial and
particulate contamination of protective clothing. They should be flushed
effectively with filtered air. The final stage of the changing room should, in the at-
rest state, be the same grade as the area into which it leads. The use of separate
changing rooms for entering and leaving clean areas is sometimes desirable. In
general hand washing facilities should be provided only in the first stage of the
changing rooms.
52. Both airlock doors should not be opened simultaneously. An interlocking system
or a visual and/or audible warning system should be operated to prevent the
opening of more than one door at a time.
53. A filtered air supply should maintain a positive pressure and an air flow relative
to surrounding areas of a lower grade under all operational conditions and should
flush the area effectively. Adjacent rooms of different grades should have a
pressure differential of 10-15 pascals (guidance values). Particular attention
should be paid to the protection of the zone of greatest risk, that is, the immediate
environment to which a product and cleaned components which contact the
product are exposed. The various recommendations regarding air supplies and
pressure differentials may need to be modified where it becomes necessary to
contain some materials, e.g. pathogenic, highly toxic, radioactive or live viral or
bacterial materials or products. Decontamination of facilities and treatment of air
leaving a clean area may be necessary for some operations.
54. It should be demonstrated that air-flow patterns do not present a contamination
risk, e.g. care should be taken to ensure that air flows do not distribute particles
from a particlegenerating person, operation or machine to a zone of higher
product risk.
55. A warning system should be provided to indicate failure in the air supply.
Indicators of pressure differences should be fitted between areas where these
differences are important. These pressure differences should be recorded
regularly or otherwise documented.

PE 009-15 (Annexes) -10- 1 May 2021
EQUIPMENT
56. A conveyor belt should not pass through a partition between a grade A or B area
and a processing area of lower air cleanliness, unless the belt itself is continually
sterilised (e.g. in a sterilising tunnel).
57. As far as practicable equipment, fittings and services should be designed and
installed so that operations, maintenance and repairs can be carried out outside
the clean area. If sterilisation is required, it should be carried out, wherever
possible, after complete reassembly.
58. When equipment maintenance has been carried out within the clean area, the
area should be cleaned, disinfected and/or sterilised where appropriate, before
processing recommences if the required standards of cleanliness and/or asepsis
have not been maintained during the work.
59. Water treatment plants and distribution systems should be designed, constructed
and maintained so as to ensure a reliable source of water of an appropriate
quality. They should not be operated beyond their designed capacity. Water for
injections should be produced, stored and distributed in a manner which prevents
microbial growth, for example by constant circulation at a temperature above
70°C.
60. All equipment such as sterilisers, air handling and filtration systems, air vent and
gas filters, water treatment, generation, storage and distribution systems should
be subject to validation and planned maintenance; their return to use should be
approved.
SANITATION
61. The sanitation of clean areas is particularly important. They should be cleaned
thoroughly in accordance with a written programme. Where disinfectants are
used, more than one type should be employed. Monitoring should be undertaken
regularly in order to detect the development of resistant strains.
62. Disinfectants and detergents should be monitored for microbial contamination;
dilutions should be kept in previously cleaned containers and should only be
stored for defined periods unless sterilised. Disinfectants and detergents used in
Grades A and B areas should be sterile prior to use.
63. Fumigation of clean areas may be useful for reducing microbiological
contamination in inaccessible places.
PROCESSING
64. Precautions to minimise contamination should be taken during all processing
stages including the stages before sterilisation.
65. Preparations of microbiological origin should not be made or filled in areas used
for the processing of other medicinal products; however, vaccines of dead

PE 009-15 (Annexes) -11- 1 May 2021
organisms or of bacterial extracts may be filled, after inactivation, in the same
premises as other sterile medicinal products.
66. Validation of aseptic processing should include a process simulation test using a
nutrient medium (media fill).Selection of the nutrient medium should be made
based on dosage form of the product and selectivity, clarity, concentration and
suitability for sterilisation of the nutrient medium.
67. The process simulation test should imitate as closely as possible the routine
aseptic manufacturing process and include all the critical subsequent
manufacturing steps. It should also take into account various interventions known
to occur during normal production as well as worst-case situations.
68. Process simulation tests should be performed as initial validation with three
consecutive satisfactory simulation tests per shift and repeated at defined
intervals and after any significant modification to the HVAC-system, equipment,
process and number of shifts. Normally process simulation tests should be
repeated twice a year per shift and process.
69. The number of containers used for media fills should be sufficient to enable a
valid evaluation. For small batches, the number of containers for media fills
should at least equal the size of the product batch. The target should be zero
growth and the following should apply:
• When filling fewer than 5000 units, no contaminated units should be
detected.
• When filling 5,000 to 10,000 units:
a) One (1) contaminated unit should result in an investigation,
including consideration of a repeat media fill;
b) Two (2) contaminated units are considered cause for
revalidation, following investigation.
• When filling more than 10,000 units:
a) One (1) contaminated unit should result in an investigation;
b) Two (2) contaminated units are considered cause for
revalidation, following investigation1
.
70. For any run size, intermittent incidents of microbial contamination may be
indicative of low-level contamination that should be investigated. Investigation of
gross failures should include the potential impact on the sterility assurance of
batches manufactured since the last successful media fill.
71. Care should be taken that any validation does not compromise the processes.
72. Water sources, water treatment equipment and treated water should be
monitored regularly for chemical and biological contamination and, as
appropriate, for endotoxins. Records should be maintained of the results of the
monitoring and of any action taken.
1 For further details on the validation of aseptic processing, please refer to the PIC/S
Recommendation on the Validation of Aseptic Processing (PI 007).

PE 009-15 (Annexes) -12- 1 May 2021
73. Activities in clean areas and especially when aseptic operations are in progress
should be kept to a minimum and movement of personnel should be controlled
and methodical, to avoid excessive shedding of particles and organisms due to
over-vigorous activity. The ambient temperature and humidity should not be
uncomfortably high because of the nature of the garments worn.
74. Microbiological contamination of starting materials should be minimal.
Specifications should include requirements for microbiological quality when the
need for this has been indicated by monitoring.
75. Containers and materials liable to generate fibres should be minimised in clean
areas.
76. Where appropriate, measures should be taken to minimise the particulate
contamination of the end product.
77. Components, containers and equipment should be handled after the final
cleaning process in such a way that they are not recontaminated.
78. The interval between the washing and drying and the sterilisation of components,
containers and equipment as well as between their sterilisation and use should
be minimised and subject to a time-limit appropriate to the storage conditions.
79. The time between the start of the preparation of a solution and its sterilisation or
filtration through a micro-organism-retaining filter should be minimised. There
should be a set maximum permissible time for each product that takes into
account its composition and the prescribed method of storage.
80. The bioburden should be monitored before sterilisation. There should be working
limits on contamination immediately before sterilisation, which are related to the
efficiency of the method to be used. Bioburden assay should be performed on
each batch for both aseptically filled product and terminally sterilised products.
Where overkill sterilisation parameters are set for terminally sterilised products,
bioburden might be monitored only at suitable scheduled intervals. For
parametric release systems, bioburden assay should be performed on each
batch and considered as an in-process test. Where appropriate the level of
endotoxins should be monitored. All solutions, in particular large volume infusion
fluids, should be passed through a micro-organism-retaining filter, if possible
sited immediately before filling.
81. Components, containers, equipment and any other article required in a clean
area where aseptic work takes place should be sterilised and passed into the
area through double-ended sterilisers sealed into the wall, or by a procedure
which achieves the same objective of not introducing contamination. Non-
combustible gases should be passed through micro-organism retentive filters.
82. The efficacy of any new procedure should be validated, and the validation verified
at scheduled intervals based on performance history or when any significant
change is made in the process or equipment.

PE 009-15 (Annexes) -13- 1 May 2021
STERILISATION
83. All sterilisation processes should be validated. Particular attention should be
given when the adopted sterilisation method is not described in the current edition
of the European (or other relevant) Pharmacopoeia or when it is used for a
product which is not a simple aqueous or oily solution. Where possible, heat
sterilisation is the method of choice. In any case, the sterilisation process must
be in accordance with the marketing and manufacturing authorisations.
84. Before any sterilisation process is adopted its suitability for the product and its
efficacy in achieving the desired sterilising conditions in all parts of each type of
load to be processed should be demonstrated by physical measurements and by
biological indicators where appropriate. The validity of the process should be
verified at scheduled intervals, at least annually, and whenever significant
modifications have been made to the equipment. Records should be kept of the
results.
85. For effective sterilisation the whole of the material must be subjected to the
required treatment and the process should be designed to ensure that this is
achieved.
86. Validated loading patterns should be established for all sterilisation processes.
87. Biological indicators should be considered as an additional method for monitoring
the sterilisation. They should be stored and used according to the manufacturer’s
instructions, and their quality checked by positive controls. If biological indicators
are used, strict precautions should be taken to avoid transferring microbial
contamination from them.
88. There should be a clear means of differentiating products which have not been
sterilised from those which have. Each basket, tray or other carrier of products or
components should be clearly labelled with the material name, its batch number
and an indication of whether or not it has been sterilised. Indicators such as
autoclave tape may be used, where appropriate, to indicate whether or not a
batch (or sub-batch) has passed through a sterilisation process, but they do not
give a reliable indication that the lot is, in fact, sterile.
89. Sterilisation records should be available for each sterilisation run. They should
be approved as part of the batch release procedure.
STERILISATION BY HEAT
90. Each heat sterilisation cycle should be recorded on a time/temperature chart with
a sufficiently large scale or by other appropriate equipment with suitable accuracy
and precision. The position of the temperature probes used for controlling and/or
recording should have been determined during the validation, and where
applicable also checked against a second independent temperature probe
located at the same position.
91. Chemical or biological indicators may also be used, but should not take the place
of physical measurements.

PE 009-15 (Annexes) -14- 1 May 2021
92. Sufficient time must be allowed for the whole of the load to reach the required
temperature before measurement of the sterilising time-period is commenced.
This time must be determined for each type of load to be processed.
93. After the high temperature phase of a heat sterilisation cycle, precautions should
be taken against contamination of a sterilised load during cooling. Any cooling
fluid or gas in contact with the product should be sterilised unless it can be shown
that any leaking container would not be approved for use.
MOIST HEAT
94. Both temperature and pressure should be used to monitor the process. Control
instrumentation should normally be independent of monitoring instrumentation
and recording charts. Where automated control and monitoring systems are used
for these applications they should be validated to ensure that critical process
requirements are met. System and cycle faults should be registered by the
system and observed by the operator. The reading of the independent
temperature indicator should be routinely checked against the chart recorder
during the sterilisation period. For sterilisers fitted with a drain at the bottom of
the chamber, it may also be necessary to record the temperature at this position,
throughout the sterilisation period. There should be frequent leak tests on the
chamber when a vacuum phase is part of the cycle.
95. The items to be sterilised, other than products in sealed containers, should be
wrapped in a material which allows removal of air and penetration of steam but
which prevents recontamination after sterilisation. All parts of the load should be
in contact with the sterilising agent at the required temperature for the required
time.
96. Care should be taken to ensure that steam used for sterilisation is of suitable
quality and does not contain additives at a level which could cause contamination
of product or equipment.
DRY HEAT
97. The process used should include air circulation within the chamber and the
maintenance of a positive pressure to prevent the entry of non-sterile air. Any air
admitted should be passed through a HEPA filter. Where this process is also
intended to remove pyrogens, challenge tests using endotoxins should be used
as part of the validation.
STERILISATION BY RADIATION
98. Radiation sterilisation is used mainly for the sterilisation of heat sensitive
materials and products. Many medicinal products and some packaging materials
are radiation-sensitive, so this method is permissible only when the absence of
deleterious effects on the product has been confirmed experimentally. Ultraviolet
irradiation is not normally an acceptable method of sterilisation.

PE 009-15 (Annexes) -15- 1 May 2021
99. During the sterilisation procedure the radiation dose should be measured. For
this purpose, dosimetry indicators which are independent of dose rate should be
used, giving a quantitative measurement of the dose received by the product
itself. Dosimeters should be inserted in the load in sufficient number and close
enough together to ensure that there is always a dosimeter in the irradiator.
Where plastic dosimeters are used they should be used within the time-limit of
their calibration. Dosimeter absorbances should be read within a short period
after exposure to radiation.
100. Biological indicators may be used as an additional control
101. Validation procedures should ensure that the effects of variations in density of
the packages are considered.
102. Materials handling procedures should prevent mix-up between irradiated and
nonirradiated materials. Radiation sensitive colour disks should also be used on
each package to differentiate between packages which have been subjected to
irradiation and those which have not.
103. The total radiation dose should be administered within a predetermined time
span.
STERILISATION WITH ETHYLENE OXIDE
104. This method should only be used when no other method is practicable. During
process validation it should be shown that there is no damaging effect on the
product and that the conditions and time allowed for degassing are such as to
reduce any residual gas and reaction products to defined acceptable limits for the
type of product or material.
105. Direct contact between gas and microbial cells is essential; precautions should
be taken to avoid the presence of organisms likely to be enclosed in material
such as crystals or dried protein. The nature and quantity of packaging materials
can significantly affect the process.
106. Before exposure to the gas, materials should be brought into equilibrium with the
humidity and temperature required by the process. The time required for this
should be balanced against the opposing need to minimise the time before
sterilisation.
107. Each sterilisation cycle should be monitored with suitable biological indicators,
using the appropriate number of test pieces distributed throughout the load. The
information so obtained should form part of the batch record.
108. For each sterilisation cycle, records should be made of the time taken to complete
the cycle, of the pressure, temperature and humidity within the chamber during
the process and of the gas concentration and of the total amount of gas used.
The pressure and temperature should be recorded throughout the cycle on a
chart. The record(s) should form part of the batch record.

PE 009-15 (Annexes) -16- 1 May 2021
109. After sterilisation, the load should be stored in a controlled manner under
ventilated conditions to allow residual gas and reaction products to reduce to the
defined level. This process should be validated.
FILTRATION OF MEDICINAL PRODUCTS WHICH CANNOT BE
STERILISED IN THEIR FINAL CONTAINER
110. Filtration alone is not considered sufficient when sterilisation in the final container
is possible. With regard to methods currently available, steam sterilisation is to
be preferred. If the product cannot be sterilised in the final container, solutions or
liquids can be filtered through a sterile filter of nominal pore size of 0.22 micron
(or less), or with at least equivalent micro-organism retaining properties, into a
previously sterilised container. Such filters can remove most bacteria and
moulds, but not all viruses or mycoplasmas. Consideration should be given to
complementing the filtration process with some degree of heat treatment.
111. Due to the potential additional risks of the filtration method as compared with
other sterilisation processes, a second filtration via a further sterilised micro-
organism retaining filter, immediately prior to filling, may be advisable. The final
sterile filtration should be carried out as close as possible to the filling point.
112. Fibre-shedding characteristics of filters should be minimal.
113. The integrity of the sterilised filter should be verified before use and should be
confirmed immediately after use by an appropriate method such as a bubble
point, diffusive flow or pressure hold test. The time taken to filter a known volume
of bulk solution and the pressure difference to be used across the filter should be
determined during validation and any significant differences from this during
routine manufacturing should be noted and investigated. Results of these checks
should be included in the batch record. The integrity of critical gas and air vent
filters should be confirmed after use. The integrity of other filters should be
confirmed at appropriate intervals.
114. The same filter should not be used for more than one working day unless such
use has been validated.
115. The filter should not affect the product by removal of ingredients from it or by
release of substances into it.
FINISHING OF STERILE PRODUCTS
116. Partially stoppered freeze drying vials should be maintained under Grade A
conditions at all times until the stopper is fully inserted.
117. Containers should be closed by appropriately validated methods. Containers
closed by fusion, e.g. glass or plastic ampoules should be subject to 100%
integrity testing. Samples of other containers should be checked for integrity
according to appropriate procedures.

PE 009-15 (Annexes) -17- 1 May 2021
118. The container closure system for aseptically filled vials is not fully integral until
the aluminium cap has been crimped into place on the stoppered vial. Crimping
of the cap should therefore be performed as soon as possible after stopper
insertion.
119. As the equipment used to crimp vial caps can generate large quantities of non-
viable particulates, the equipment should be located at a separate station
equipped with adequate air extraction.
120. Vial capping can be undertaken as an aseptic process using sterilised caps or as
a clean process outside the aseptic core. Where this latter approach is adopted,
vials should be protected by Grade A conditions up to the point of leaving the
aseptic processing area, and thereafter stoppered vials should be protected with
a Grade A air supply until the cap has been crimped.
121. Vials with missing or displaced stoppers should be rejected prior to capping.
Where human intervention is required at the capping station, appropriate
technology should be used to prevent direct contact with the vials and to minimise
microbial contamination.
122. Restricted access barriers and isolators may be beneficial in assuring the
required conditions and minimising direct human interventions into the capping
operation.
123. Containers sealed under vacuum should be tested for maintenance of that
vacuum after an appropriate, pre-determined period.
124. Filled containers of parenteral products should be inspected individually for
extraneous contamination or other defects. When inspection is done visually, it
should be done under suitable and controlled conditions of illumination and
background. Operators doing the inspection should pass regular eye-sight
checks, with spectacles if worn, and be allowed frequent breaks from inspection.
Where other methods of inspection are used, the process should be validated
and the performance of the equipment checked at intervals. Results should be
recorded.
QUALITY CONTROL
125. The sterility test applied to the finished product should only be regarded as the
last in a series of control measures by which sterility is assured. The test should
be validated for the product(s) concerned.
126. In those cases where parametric release has been authorised, special attention
should be paid to the validation and the monitoring of the entire manufacturing
process.
127. Samples taken for sterility testing should be representative of the whole of the
batch, but should in particular include samples taken from parts of the batch
considered to be most at risk of contamination, e.g.:

PE 009-15 (Annexes) -18- 1 May 2021
a) for products which have been filled aseptically, samples should
include containers filled at the beginning and end of the batch and
after any significant intervention;
b) for products which have been heat sterilised in their final containers,
consideration should be given to taking samples from the potentially
coolest part of the load.

Annex 2A Manufacture of advanced therapy medicinal products for human use
PE 009-15 (Annexes) -19- 1 May 2021
ANNEX 2A
MANUFACTURE OF ADVANCED THERAPY MEDICINAL
PRODUCTS FOR HUMAN USE
SCOPE
The methods employed in the manufacture of Advanced Therapy Medicinal
Products (ATMPs) are a critical factor in shaping the appropriate regulatory
control. ATMPs can be defined therefore largely by reference to their method of
manufacture. For example, for gene therapy ATMPs, genetic modifications can
be obtained through a variety of methods (e.g. viral & non-viral vectors, mRNA,
ex vivo and in vivo genome-editing tools). The genetically modified cells can be
of human origin (autologous or allogeneic) or of animal origin (xenogeneic cells),
either primary or established cell lines. In a medicinal product, the genetically
modified cells or gene therapy products can be presented alone or combined with
medical devices.
This annex provides additional and specific guidance on the full range of ATMPs
(as defined in the glossary) and the active substances that are used in their
manufacture. This annex applies both to investigational ATMPs and market-
authorised ATMPs. It can also be applied to ATMP manufacturing in hospital
settings and for compassionate use programs, where authorised by national law.
Although one of the objectives of this present annex was to prepare a document
that would stand for several years, the field is quickly changing. It is recognised
that amendments may be necessary to accommodate technological change, to
clarify uncertainty or to specifically recognise important alternatives. Comments
are therefore invited at any stage of the life of this edition.
This annex is divided into two main parts:
1. Part A contains supplementary guidance and alternative provisions on the
manufacture of ATMPs, from control over seed lots and cell banks through
to finishing activities and testing.
2. Part B contains further guidance on selected types of ATMPs and its
substances.
APPLICATION OF THIS ANNEX
This annex, along with several other annexes of the Guide to GMP, provides
guidance, which supplements that in Part I: Basic Requirements for Medicinal
Products and in Part II: Basic Requirements for active pharmaceutical ingredients
of the PIC/S GMP Guide. This annex is not a stand-alone document and should
be applied in conjunction with PIC/S GMP guidelines and annexes. It has

PE 009-15 (Annexes) -20- 1 May 2021
however been written in a manner that it could enable development of a
standalone guide if integrated with PIC/S GMP Part I, Part II, and related
annexes.
Where due to the nature of the product or technical necessities, specific guidance
is provided in this annex, compliance with this annex is expected and takes
precedence over other sections in the PIC/S GMP Guide unless there are good
reasons for not doing so with documented sound scientific rationale applied using
QRM principles.
In certain cases, other national laws may be applicable to the starting materials
for ATMPs. For example:
(a) Tissues and cells used as starting materials of ATMPs may be subject to
other national legislation that cover donation, procurement, testing,
processing, preservation, storage and distribution.
(b) For blood or blood components used as starting materials for ATMPs,
national legislation may provide the technical requirements for the selection
of donors and the collection and testing of blood and blood components.
The manufacturing process for ATMPs is product-specific and different design
approaches are possible. The appropriate application of GMP should be
described, justified in the Clinical Trial Application (CTA) or Marketing
Authorisation (MA), and in accordance with national law. Consideration may be
given to defining which manufacturing process steps are required to manufacture
starting materials, ATMP active substance, or the finished ATMP. In some cases,
the manufacturing process between the ATMP active substance and the final
product can be defined as continuous.
The manufacture and control of genetically modified organisms also needs to
comply with other local, national or regional requirements. Appropriate
containment should be established and maintained in facilities where any
genetically modified organism is handled. Advice should be obtained according
to national law in order to establish and maintain the appropriate Biological Safety
Level. GMP should be adhered alongside these requirements.
Table 1 gives examples of where this annex applies. It should be noted that this
table is illustrative only and is not meant to describe the precise scope. It should
also be understood that adherence to the GMP or GMP principles for the
manufacturing steps indicated in the corresponding table is dependent on
applicable national legislation. The level of GMP requirements increases from
early to later steps in the manufacture of ATMP active substances. The inclusion
of some early steps of manufacture within the scope of this annex does not imply
that those steps will be routinely subject to inspection by the authorities.
According to national legislation more or less stringent approaches on the
application of GMP on those early stages may apply.

PE 009-15 (Annexes) -21- 1 May 2021
Table 1. Illustrative guide to manufacturing activities within the scope of Annex 2A
Example
Products
Application of this Annex (see note1
)
Gene therapy:
mRNA
Linear DNA
template
preparation
In vitro cell free
transcription
mRNA purification
Formulation,
filling
Gene therapy:
in vivo viral
vectors
Plasmid
manufacturing
Establishment of MCB,
WCB2
Vector manufacturing and
purification
Formulation,
filling
Gene therapy:
in vivo non-
viral vectors
(naked DNA,
lipoplexes,
polyplexes,
etc.)
Plasmid
manufacturing
Establishment of
bacterial bank2 Fermentation and purification
Formulation,
filling
Gene therapy:
ex-vivo
genetically
modified cells
Donation,
procurement and
testing of starting
tissue / cells
Plasmid manufacturing
Ex-vivo genetic modification
of cells
Formulation,
filling
Vector manufacturing3
Somatic cell
therapy
Donation,
procurement and
testing of starting
tissue / cells
Establishment of MCB,
WCB or primary cell lot
or cell pool2
Cell isolation, culture
purification, combination with
non-cellular components
Formulation,
combination,
filling
Tissue
engineered
products
Donation,
procurement and
testing of starting
tissue / cells
Initial processing,
isolation and
purification, establish
MCB, WCB, primary
cell lot or cell pool2
Cell isolation, culture,
purification, combination with
non-cellular components
Formulation,
combination,
filling
1 Application of this annex applies to manufacturing steps illustrated in dark grey. Application of
this annex or principles of this annex apply to steps illustrated in light grey apply depending on
the requirements of national legislation.
2 Refer to points 5.32 for establishment of cell banks and seed lots.
3 In the case of gene therapy ex-vivo genetically modified cells, this guide applies to vector
manufacturing except where otherwise authorised by national law where principles of GMP
should apply.

PE 009-15 (Annexes) -22- 1 May 2021
The following are some non-exhaustive examples in the application of GMP to the
manufacture of ATMP.
Figure 1: Example of gene therapy mRNA
ATMP manufacturing
Figure 2: Example of in vivo viral vector gene
therapy ATMP manufacturing
Linear DNA template
preparation
Plasmid DNA construct
preparation
↓
Transfer of Plasmid
DNA to starter colony
(e.g. E. coli)
↓
Purification,
linearization and
polishing
↓
Storage of linear DNA
template
OR
Plasmid DNA
construct preparation
↓
Polymerase Chain
Reaction (PCR)
↓
Storage of linear DNA
template
ATMP Manufacturing
Transcription
↓
Purification
↓
Harvest
↓
Formulation
↓
Filling
↓
Storage
↓
Distribution for
patient access
Plasmid
Manufacturing
preparation
↓
Transfer of Plasmid
DNA to starter colony
(e.g. E. coli)
↓
Expansion
↓
Dispensing
↓
Storage
ATMP Manufacturing
Establishing MCB or
WCB
↓
Thawing
↓
Transfection
↓
Induction
↓
Harvest
↓
Purification
↓
Formulation
↓
Sterile Filtration
↓
Filling
↓
Storage
↓
Distribution for
patient access
• GMP requirements
can vary from early
steps in making the
plasmid DNA
construct to later
steps but should align
with Annex 2A and
PIC/S GMP Guide
Part II or principles of
these requirements as
applicable under
national legislation.
• Refer to Section 5.23
for additional
information in
determining the
appropriate
application of GMP.
• A Marketing
Authorisation Holder
(MAH) may justify
these steps to be a
continuous process
producing both the
ATMP active
substance and
medicinal product.
• PIC/S GMP Part I and
Part II along with
applicable annexes
apply as appropriate
to the step of
manufacture.
• GMP requirements
can vary from early
steps in making the
plasmid DNA
construct to later
steps but should align
with Annex 2A and
PIC/S GMP Guide
Part II or principles of
applicable under
national legislation.
• Refer to Section 5.23
for additional
information in
determining the
appropriate
application of GMP.
• A MAH may justify
these steps to be a
continuous process
producing both the
ATMP active
substance and
medicinal product.
Part II along with
applicable annexes
apply as appropriate
to the step of
manufacture.

PE 009-15 (Annexes) -23- 1 May 2021
Figure 3: Example of autologous CAR-T therapy ATMP manufacturing
Plasmid Manufacturing
preparation
↓
Transfer of Plasmid DNA to
starter colony
(e.g. E. coli)
↓
Expansion
↓
Dispensing
↓
Storage
Viral Vector Product
Manufacturing
Establishing MCB or WCB
↓
Thawing
↓
Transfection
↓
Induction
↓
Harvest
↓
Purification
↓
Sterile Filtration
↓
Dispensing
↓
Storage
ATMP Manufacturing
Donation or procurement of
patient cells
↓
Transduction
↓
Expansion
↓
Harvest
↓
Formulation
↓
Filling
↓
Storage
↓
Distribution for
patient access
• GMP requirements can
vary from early steps in
making the plasmid DNA
construct to later steps but
should align with principles
of Annex 2A and PIC/S
GMP Guide Part II or
principles of these
requirements as applicable
under national legislation.
• Refer to Section 5.23 for
additional information in
determining the
appropriate application of
GMP.
• GMP requirements applied
to the manufacture of a
viral vector should align
with Annex 2A and PIC/S
GMP Part II or principles of
applicable under national
legislation.
• Refer to Section 5.23 for
additional information in
determining the
appropriate application of
GMP.
• The application of this
guide does not include the
donation or procurement of
patient cells.
• A MAH may justify these
steps to be a continuous
process producing both the
ATMP active substance
and medicinal product.
Part II along with
applicable annexes apply
as appropriate to the step
of manufacture.
PRINCIPLE
The manufacture of ATMPs involves certain specific considerations arising from
the nature of the products and the processes. The ways in which biological
medicinal products are manufactured, controlled and administered make some
particular precautions necessary.
Since materials and processing conditions used in manufacturing processes are
designed to provide conditions for the growth of specific cells and
microorganisms, this provides an opportunity for extraneous microbial
contaminants (e.g. bacteria, fungi) to grow. In addition, some products may be
limited in their ability to withstand a wide range of purification techniques,
particularly those designed to inactivate or remove adventitious viral

PE 009-15 (Annexes) -24- 1 May 2021
contaminants. The design of the processes, equipment, facilities, utilities, the
conditions of preparation and addition of buffers and reagents, sampling and
training of the operators are key considerations to minimise such contamination
events (i.e. engineering and technical controls). In addition, manufacturing
processes need to be well designed and controlled so as not to add further
variability to the product.
Product specifications such as those in pharmacopoeial monographs, CTA, and
MA will dictate whether and to what manufacturing stage substances and
materials can have a defined level of bioburden or need to be sterile. Similarly,
manufacturing must be consistent with other specifications set out in the CTA or
MA (e.g. number of generations (doublings, passages) between the seed lot or
cell bank).
For biological materials that cannot be sterilized (e.g. by filtration), processing
must be conducted aseptically to minimise the introduction of contaminants.
Where they exist, other guidance documents should be consulted on the
validation of specific manufacturing methods (e.g. virus removal or inactivation).
The application of appropriate environmental controls and monitoring and,
wherever feasible, in-situ cleaning and sterilisation systems together with the use
of closed systems and sterile disposable product-contact equipment can
significantly reduce the risk of accidental contamination and cross-contamination.
ATMPs require a combination of unique biological methods and standard
physico-chemical assays for their Quality Control (QC). For many cell-based
products, there is variability introduced through the starting materials that cannot
be overcome by the manufacturing process or In-Process Controls (IPCs).
Adequate control of the starting and raw materials, well defined characterisation
of the ATMP active substance and ATMP drug product release testing form the
crucial part of the QC. Controls should take into consideration the intrinsic
variability of the biological material needed for ATMP manufacturing. A robust
manufacturing process is therefore crucial and in-process controls take on a
particular importance in the manufacture of biological active substances and
medicinal products.
PART A: GENERAL GUIDANCE
Part A provides alternative or supplementary provisions to respective sections in
Part I, II and annexes of the PIC/S GMP Guide, where necessary. Where this
annex provides specific guidance for the manufacture of ATMPs (including
modification, replacement or redundancy of other sections), this will be clearly
indicated. In the absence of specific guidance for ATMPs, compliance with other
sections in the PIC/S GMP Guide is expected.
Note: Where the term Marketing Authorisation Holder (MAH) is used, unless
otherwise specified, it should be intended to signify the “Sponsor” for
investigational ATMP that is used according to a CTA or equivalent.

PE 009-15 (Annexes) -25- 1 May 2021
SUPPLIMENTARY PROVISIONS TO PIC/S GMP GUIDE PART I
CHAPTER 1 PHARMACEUTICAL QUALITY SYSTEM
Pharmaceutical Quality System
1.1 ATMPs are not sold or supplied before an Authorised Person has certified that
each production batch has been produced and controlled in accordance with the
requirements of the CTA, MA and any other regulations relevant to the
production, control and release of medicinal products as applicable. Special
provisions apply for the supply of products that have a two-step release process
(described in Section 6.14) or such that do not meet release specifications where
there is no alternative treatment available (described in Sections 6.11 to 6.13).
(Replaces PIC/S GMP Guide Part I Section 1.4, xv)
Quality Risk Management
1.2 GMP applies to the lifecycle stages from the manufacture of investigational
ATMP, technology transfer, and commercial manufacturing through to product
discontinuation. The biological processes may display inherent variability, so that
the range and nature of by-products may be variable. As a result, Quality Risk
Management (QRM) principles as detailed in Annex 20 are particularly important
for this class of medicinal products and should be used to develop their control
strategy across all stages of development and manufacturing steps to minimise
variability and to reduce the opportunity for contamination and
cross-contamination. (Replaces PIC/S GMP Guide Part I Section 1.2)
CHAPTER 2 PERSONNEL
2.1 The health status of personnel should be taken into consideration for product
safety. Personnel (including those concerned with cleaning, maintenance or
quality control) employed in areas where ATMP active substances and products
are manufactured and tested should receive training, and periodic retraining,
specific to the products manufactured and to the duties assigned to them,
including any specific safety measures to protect product, personnel and the
environment.
2.2 Any changes in the health status of personnel, which could adversely affect the
quality of the product, should prevent work in the production area. Health
monitoring of staff should be commensurate with the risk; medical advice should
be sought for personnel involved with hazardous organisms. General
consideration should be given to Occupational Health & Safety (OH&S) for
personnel involved with hazardous substances as required by national law.
2.3 Every person entering the manufacturing areas should wear clean protective
garments appropriate to the operations to be carried out.
Where required to minimise the opportunity for cross-contamination, restrictions
on the movement of all personnel (including QC, maintenance and cleaning
personnel) should be controlled based on QRM principles.

PE 009-15 (Annexes) -26- 1 May 2021
In general, personnel should not pass from areas of exposure to live
micro-organisms, genetically modified organisms, toxins or animals to areas
where other products, inactivated products or different organisms are handled. If
such route is unavoidable, a Contamination Control Strategy (CCS) based on
QRM principles should be applied (refer to Section 3.4 CCS). (Replaces PIC/S
GMP Guide Part I Section 2.18)
CHAPTER 3 PREMISES AND EQUIPMENT
PREMISES
Production Areas
3.1 Cross-contamination should be prevented for all products by appropriate design
and operation of manufacturing facilities. The measures to prevent cross-
contamination should be commensurate with the risks to product quality. QRM
principles should be used to assess and control the risks.
Depending on the level of risk presented by some ATMPs and the materials
involved in their production (for example, viruses), it may be necessary to
dedicate premises and equipment for manufacturing and/or packaging operations
to control the risk. Segregated production areas should be used for the
manufacture of ATMPs presenting a risk that cannot be adequately controlled by
operational and/or technical measures. (Replaces PIC/S GMP Guide Part I
Section 3.6)
3.2 Concurrent production of two or more different ATMPs/batches in the same area
might be permitted due to adequate operational and/or technical control where
justified under QRM principles applied across the entire sequence of
manufacturing steps. For example:
(a) The use of more than one closed isolator (or other closed systems) in the
same room at the same time is acceptable, provided that appropriate
mitigation measures are taken to avoid cross-contamination or mix-ups of
materials.
(b) When more than one isolator is used to process different viral vectors within
the same room there should be 100% air exhaustion from the room and the
facility (i.e. no recirculation). In addition, in case of concurrent production of
viral vectors, it is necessary to provide for closed, separate and unidirectional
waste handling.
(c) The possibility of using more than one biosafety cabinet (BSC) in the same
room is only acceptable if effective technical and organisational measures
are implemented to separate the activities. The simultaneous use of more
than one BSC entails additional risks and, therefore, it should be
demonstrated that the measures implemented are effective to avoid risks to
the quality of the product and any mix-ups. The rationale should be justified
based on QRM principles.
(d) The use of multiple closed systems in the same area is permitted, in the case
that their close state can be demonstrated. (refer to point 3.13.)

PE 009-15 (Annexes) -27- 1 May 2021
3.3 The measures and procedures necessary for containment (i.e. for environment
and operator safety) should not conflict with those for product quality.
3.4 Special precautions should be taken in the case of manufacturing activities
involving infectious viral vectors (e.g. oncolytic viruses, replication competent
vectors) that should be segregated based on a documented CCS and QRM
principles. The manufacturer should justify the level of segregation required
based on the CCS and through QRM principles. The outcome of the QRM
process should determine the necessity for and extent to which the premises and
equipment should be dedicated to a particular product. In some cases, dedicated
facilities, dedicated areas or dedicated equipment may be required in accordance
with the national law. Simultaneous incubation and/or storage of replication
competent vectors/products, or infected materials/products, with other
materials/products is not acceptable.
3.5 Air handling units should be designed, constructed and maintained to minimise
the risk of cross-contamination between different manufacturing areas and may
need to be specific for an area. Consideration, based on QRM principles, should
be given to the use of single pass air systems.
3.6 If materials (such as culture media and buffers) have to be measured or weighed
during the production process, small stocks may be kept in the production area
for a specified duration based on defined criteria (e.g. duration of manufacture of
the batch or of the campaign). (Replaces PIC/S GMP Guide Part I Section 3.13)
3.7 Positive pressure areas should be used to process sterile products, but negative
pressure in specific areas at the point of exposure of pathogens is acceptable for
containment reasons. Where negative pressure areas or BSCs are used for
aseptic processing of materials with particular risks (e.g. pathogens), they should
be surrounded by a positive pressure clean zone of appropriate Grade. These
pressure cascades should be clearly defined and continuously monitored with
appropriate alarm settings as defined by Annex 1. The design of such areas
should be such that measures put in place to prevent release of material into the
surrounding environment should not compromise sterility assurance level (SAL)
of the product and vice versa.
3.8 Air vent filters that are directly linked to the sterility of the product (e.g. to maintain
the integrity of a closed system) should be hydrophobic, monitored during use
(e.g. pressure differential monitoring if appropriate) and validated for their
scheduled life span with integrity testing at appropriate intervals based on
appropriate QRM principles. If pressure monitoring or integrity testing is
technically not feasible for the filter system, vendor supplied information may be
considered for approval. However, this has to be taken into account in the CCS
as an additional risk factor especially for short shelf life ATMPs, where
microbiological quality tests are not available at the time of batch release prior to
medical product administration.
3.9 Drainage systems must be designed so that effluents can be effectively
neutralised or decontaminated to minimise the risk of cross-contamination. They
must comply with national law to minimize the risk of contamination of the external
environment according to the risk associated with the biohazardous nature of
waste materials. (Replaces PIC/S GMP Guide Part I Section 3.11)

PE 009-15 (Annexes) -28- 1 May 2021
3.10 The degree of environmental control of particulate and microbial contamination
of the production premises should be adapted to the product and the production
step, bearing in mind the potential level of contamination of the starting materials
and the risks to the product. The microbiological environmental monitoring
programme should be supplemented by the inclusion of methods to detect the
presence of specific microorganisms (e.g. host organism, yeasts, moulds,
anaerobes, etc.) where indicated by the QRM principles.
3.11 Where processes are not closed and there is exposure of the product to the
immediate room environment without a subsequent microbial inactivation
process, (e.g. during additions of supplements, media, buffers, gasses,
manipulations) appropriate environmental conditions should be applied. For
aseptic manipulations parameters in line with Annex 1 (i.e. Grade A with Grade
B background) should be applied. The environmental monitoring program should
include testing and monitoring of non-viable contamination, viable contamination
and air pressure differentials. The monitoring locations should be determined
having regards to the QRM principles. The number of samples, volume, and
frequency of monitoring, alert and action limits should be appropriate taking into
account the QRM principles. Sampling methods should not pose a risk of
contamination to the manufacturing operations. Where appropriate control is
required in the process, temperature and relative humidity should be monitored.
All environmental monitoring results should be trended.
3.12 Only in exceptional circumstances when an appropriate manufacturing
environment is not available, a less stringent environment than that specified in
Section 3.11 above may be acceptable for processes that are not closed where
approved by the Competent Authority and in accordance with CTA or MA or other
national requirements. However, this option should be considered exceptional
and applicable only if the product is intended to treat a life-threatening condition
where no alternative therapeutic options exist. The environment must be
specified and justified to provide patient benefit that outweighs the significant risk
created by manufacturing under less stringent environments. If the Competent
Authority grants an approval, the manufacturer must pursue establishing the
appropriate environment as improvements in the technology occur.
3.13 For closed systems, a lower classified area than Grade A in background Grade B
might be acceptable based on the outcome of a QRM assessment. The
appropriate level of air classification and monitoring should be determined having
regard to the specific risks, considering the nature of the product, the
manufacturing process and the equipment used. QRM should be used to
determine whether the technology used supports reduced monitoring, in
particular where monitoring can be a source of contamination. This is in addition
to:
(a) The use of technologies as e.g. processing inside single use sterile
disposable kits, or processing using closed, automated manufacturing
platform or incubation in closed flasks, bags or fermenters in Grade C
may be acceptable if adequate control measures are implemented to
avoid the risk of microbial contamination and cross-contamination (e.g.
appropriate control of materials, personnel flows and cleanliness).
Particular attention should be paid if the materials are subsequently
moved to a clean area of higher Grade.

PE 009-15 (Annexes) -29- 1 May 2021
(b) If the closed system can be shown to remain integral throughout the
entire usage, a background of Grade D might be acceptable.
Requirements of Annex 1 regarding the provision of closed system should be
considered.
3.14 In exceptional circumstances, it is permissible to perform a manufacturing step in
premises that are not under direct control of the ATMP manufacturer or MAH
(including for example placing equipment used to perform manufacturing steps in
hospital wards or theatre) where approved by the Competent Authority and in
accordance with CTA or MA or other national requirements. In such cases, it
should be demonstrated that the process maintains its validated status in
accordance to principles and guidelines in Annex 15, Annex 20 and in this annex.
These arrangements should be subject to approval by the Competent Authority.
The responsibilities of each parties should be defined in written technical
agreements.
EQUIPMENT
3.15 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 it will affect the quality of
the product and thus present any hazard.
In addition, if single use systems (i.e. disposable systems) are used, the
manufacturer should take into account and verify the impact on the product from
extractable, leachable, insoluble particulate and insoluble matter derived from
such systems. Annex 1 regarding provisions for single use systems should be
considered. (Replaces PIC/S GMP Guide Part I Section 3.39)
3.16 Where required to minimise the risk of cross-contamination, restrictions on the
movement of equipment should be applied. In general, equipment should not be
moved from high-risk areas to other areas, or between high-risk areas (e.g.
equipment used for the handling of cells from infected donors or the handling of
oncolytic viruses). Where the relocation of equipment is unavoidable, after
reviewing engineering and/ or technical modifications, the risk should be
assessed in line with QRM principles, mitigated and monitored to ensure an
effective cross-contamination control strategy (refer to Section 3.4 CCS). The
qualification status of the equipment moved should also be considered.
3.17 The design of equipment used during handling of live organisms and cells,
including those for sampling, should be considered to prevent any contamination
during processing.
3.18 Primary containment4
should be designed and periodically tested to ensure the
prevention of escape of biological agents into the immediate working
environment.
4 See Main GMP Glossary on ‘Containment’.

PE 009-15 (Annexes) -30- 1 May 2021
3.19 Electronic systems used to support manufacturing must be qualified in
accordance with Annex 11 and 15. Any analytical testing performed on materials
not used in manufacturing but that support bioinformatics informing the
manufacturing process (e.g. patient gene sequencing) should be validated. Such
analytical equipment is expected to be qualified prior to use.
CHAPTER 4 DOCUMENTATION
Specifications
4.1 Specifications for ATMP starting and raw materials may need additional
documentation on the source, origin, distribution chain, method of manufacture,
and controls applied, to assure an appropriate level of control and oversight
including their microbiological quality.
4.2 Some products may require specific definition of what materials constitute a
batch. For autologous and donor-matched situations, the manufactured product
should be viewed as a batch.
Traceability
4.3 Where human cells or tissues are used, full traceability is required from starting
and raw materials, including all substances coming into contact with the cells or
tissues through to confirmation of the receipt of the products at the point of use
whilst maintaining the privacy of individuals and confidentiality of health-related
information, according to national legislation.
4.4 For starting materials of human origin, the identification of the supplier and the
anatomical environment from which the cells/tissues/virus originates (or, as
appropriate, the identification of the cell-line, master cell bank, seed lot) should
also be described.
4.5 A system that enables the bidirectional tracking of cells/tissues contained in
ATMPs from the point of donation, through manufacturing, to the delivery of the
finished product to the recipient should be created. This system can be manual
or automated. It should be used throughout the manufacturing lifecycle to include
clinical trial and commercial batches.
4.6 Traceability records should be kept as an auditable document and unequivocally
linked to the relevant batch record. The storage system should ensure that
traceability data allow for easy access, in case of an adverse reaction from the
patient.
4.7 Traceability records for cellular and tissue-based products and for any
personalized ATMP must be retained 30 years after the expiry date of the product
unless otherwise specified in the MA/CTA or national law. Particular care should
be taken to maintain the traceability of products for special use cases, such as
donor-matched cells. National requirements applied to blood components in
regard to traceability requirements and notification of serious adverse reactions
and events apply to blood components when they are used as starting or raw
materials in the manufacturing process of medicinal products. Human cells

PE 009-15 (Annexes) -31- 1 May 2021
including haematopoietic cells must comply with the principles laid down in
national law concerning traceability.
4.8 When xenogeneic cells are used as starting materials for ATMPs, information
permitting the identification of the donor animal should be kept for 30 years unless
otherwise specified in the MA/CTA or national legislation.
CHAPTER 5 PRODUCTION
General
5.1 ATMPs must comply with the applicable national requirements on minimising the
risk of transmitting animal spongiform encephalopathy agents via human and
veterinary medicinal products.
Viral safety for gene therapy ATMPs should be ensured by having systems in
place that ensure the quality of starting (including cell banks and viral seed
stocks) and raw materials through the production process.
5.2 The conditions for sample collection, additions and transfers involving replication
competent vectors or materials from infected donors should prevent the release
of viral/infected material.
5.3 At every stage of processing, materials and products should be protected from
microbial and any other contamination. Appropriate contamination control and
monitoring strategies should be implemented (refer to Section 3.4 CCS).
Particular consideration should be given to the risk of cross-contamination
between cell preparations from different donors and, where applicable, from
donors having different positive serological markers. (Replaces PIC/S GMP
Guide Part I Section 5.10)
5.4 The use of antimicrobials may be necessary to reduce bioburden associated with
the procurement of living tissues and cells. However, the use of antimicrobials
does not replace the requirement for aseptic manufacturing. When antimicrobials
are used, their use should be recorded; they should be removed as soon as
possible, unless the presence thereof in the finished product is specifically
foreseen in the CTA or MA (e.g. antibiotics that are part of the matrix of the
finished product). Additionally, it is important to ensure that antimicrobials do not
interfere with any product microbial contamination testing or sterility testing, and
that they are not present in the finished product (unless specifically justified in the
CTA or MA).
5.5 Labels applied to containers, equipment or premises should be clear, well defined
and in the manufacturer’s agreed format.
Care should be taken in the preparation, printing, storage and application of
labels, including any specific text for patient-specific or autologous product. For
products containing cells derived from human cells or tissue, donor’s labels
should contain all relevant information that is needed to provide full traceability.
In the case of autologous products, the unique patient identifier and the statement
“for autologous use only” should be indicated on the outer packaging or, where

PE 009-15 (Annexes) -32- 1 May 2021
there is no outer packaging, on the immediate packaging or as otherwise
specified in national law.
Alternative approaches/measures are permitted as long as the risk of erroneous
administration of the product is adequately mitigated. For investigational ATMPs
that are blinded, the requirement to state “autologous use” can be substituted by
a barcode or an alternative equivalent mechanism that ensures blinding while
maintaining patient safety. (Replaces PIC/S GMP Guide Part I Section 5.13)
5.6 When setting up a programme for primary and secondary packaging operations,
particular attention should be given to minimising the risk of cross-contamination,
mix-ups or substitutions. Sterility and/or low bioburden requirements should be
adhered to and segregation strategies should be applied. (Replaces PIC/S GMP
Guide Part I Section 5.49)
5.7 If closed systems are used for the production of ATMPs, checks should be carried
out to ensure that all pieces of the equipment are connected in a correct manner
to assure the closed state. Special attention should be given to apply these tests
to automated systems. If feasible and based on QRM principles, for example
considering testing carried out by vendors, the integrity of single use systems
should be verified at adequate frequency prior to use and potentially post use,
possibly automatically. The integrity of reused equipment should be verified
before use after cleaning and sterilisation.
5.8 A system is no longer considered closed when materials are added or withdrawn
without aseptic techniques (e.g. without use of sterile connectors or filters
aseptically connected).
5.9 Where chromatography equipment is used, a suitable control strategy for
matrices, the housings and associated equipment (adapted to the risks) should
be implemented when used in campaign manufacture and in multi-product
environments. The re-use of the same matrix at different stages of processing is
discouraged due to risk of carryover contamination. Any such re-usage should be
supported by appropriate validation data. Acceptance criteria, operating
conditions, regeneration methods, life span, and sanitization or sterilisation
methods of chromatography columns should be defined.
5.10 Careful attention should be paid to specific requirements at any cryopreservation
stages, e.g. the rate of temperature change during freezing or thawing. The type
of storage chamber, placement and retrieval process should minimise the risk of
cross-contamination, maintain the quality of the products and facilitate their
accurate retrieval. Documented procedures should be in place for the secure
handling and storage of products with positive serological markers.
5.11 The suitability of selected packaging material should be considered. The
adhesiveness, durability and legibility of printed text of labels used for containers
that are stored at ultra-low temperatures (- 60 °C or lower) should be verified.
Additionally, apply a holistic approach to minimize the risk to container closure
integrity (CCI) that can occur during storage at ultra-low temperatures. Evidence‐
based data should be generated to support the selection of the appropriate
primary packaging components and qualification of the container/closure sealing
process.

PE 009-15 (Annexes) -33- 1 May 2021
Prevention of Cross-contamination in Production
5.12 An evidence-based QRM process should be used to assess and control the
cross-contamination risks presented by the products manufactured. Factors to
take into account include:
(a) vectors used and the risk of occurrence of replication competent virus
(including different level of risk derived from the use of replication limited,
replication defective, conditional replication and replication incompetent
vectors),
(b) facility/equipment design and use,
(c) personnel and material flow,
(d) microbiological and other adventitious agent controls,
(e) characteristics of the starting materials/active substance and raw materials,
(f) process characteristics,
(g) clean room conditions,
(h) cleaning processes, and
(i) analytical capabilities relative to the relevant limits established from the
evaluation of the products.
The outcome of the QRM process should be the basis for determining the process
workflow and necessity for and extent to which premises and equipment should
be dedicated or single use systems should be used for a particular product. This
may include dedicating specific product contact parts or dedication of the entire
manufacturing facility. It may be acceptable to confine manufacturing activities to
a segregated, self-contained production area within a multiproduct facility, where
justified. Results should be reviewed jointly with the CCS.
(Replaces PIC/S GMP Guide Part I Section 5.20)
5.13 The methods used for sterilisation, disinfection, virus removal or inactivation
should be validated. In cases where a virus inactivation or removal process is
performed during manufacture, measures to avoid the risk of recontamination
should be taken. (refer to Section 5.19(a))
5.14 An emergency plan for dealing with accidental release of viable organisms should
be in place. This should address methods and procedures for containment,
protection of operators, cleaning, decontamination and safe return to use.
Accidental spillages, especially of live organisms, must be dealt with quickly and
safely. Decontamination measures should be available for each organism or
groups of related organisms in line with the QRM process. Decontamination
measures should be validated for effectiveness.
5.15 If obviously contaminated, such as by spills or aerosols, or if a potential
hazardous organism is involved, production and control materials, including

PE 009-15 (Annexes) -34- 1 May 2021
paperwork, must be adequately disinfected, or the information transferred out by
other means. An assessment of the impact on the immediate products and any
others in the affected area should also be made.
5.16 The risks of cross-contamination should be assessed having regard to the
characteristics of the product (e.g. biological characteristics of the starting
materials, possibility to withstand purification techniques) and manufacturing
process (e.g. the use of processes that provide extraneous microbial
contaminants the opportunity to grow). For ATMPs that cannot be sterilised, any
open processing (e.g. filling) must be conducted aseptically to minimise the
introduction of contaminants.
5.17 In all manufacturing steps that may lead to unwanted formation of aerosols (e.g.
centrifugation, working under vacuum, homogenisation, and sonication)
appropriate mitigation measures should be implemented to avoid cross-
contamination. Special precautions should be taken when working with infectious
materials.
5.18 Measures to prevent cross-contamination appropriate to the risks identified
should be put in place. Measures that can be considered to prevent cross-
contamination include, among others:
(a) segregated premises,
(b) dedicating the entire manufacturing facility or a self-contained production
area on a campaign basis (separation in time) followed by a cleaning process
of validated effectiveness,
(c) adequate cleaning procedures:
i. the cleaning procedure (technique, number of sanitation steps, etc.)
should be adapted to the specific characteristics of the product and
of the manufacturing process;
ii. a risk-assessment should be used to determine the cleaning and
decontamination procedures that are necessary, including the
frequency thereof;
iii. as a minimum, there should be appropriate cleaning and
decontamination between each batch; and
iv. all cleaning and decontamination procedures should be validated.
(d) use of “closed systems” for processing and for material or product transfer
between individual processing equipment,
(e) use of air locks and pressure cascade to confine potential airborne
contaminant within a specified area,
(f) utilisation of single use systems,
(g) other suitable organisational measures, such as the:

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