2010

Good Manufacturing Practice (2010 revision)

Annex1 to Annex5 Technical Reviewed by ISPE

Michael Lee, Zhao Chunhua

Zhao Yunxia, He Guoling, Ji Yiyun

Initial Translation from NNE Pharmaplan

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 Chinese GMP revised in 2010

1
Annex 1:

Sterile Medicinal Products

Table of Contents
..................................................................................................... 4

Chapter 1 Scope ............................................................................................... 4

..................................................................................................... 4

Chapter 2 Principle............................................................................................ 4
............................................................................... 5

Chapter 3 Cleanliness classification and monitoring ........................................ 5

.................................................................................... 15

Chapter 4 Isolator technology ......................................................................... 15

........................................................................................ 16

Chapter 5 Blow/fill/seal technology ................................................................. 16

................................................................................................... 17

Chapter 6 Personnel ....................................................................................... 17

..........................................................................................……..19

Chapter 7 Premises......................................................................................... 19
................................................................................................... 21

Chapter 8 Equipment ...................................................................................... 21

................................................................................................... 23

Chapter 9 Sanitation........................................................................................ 23

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 ............................................................................................ 24

Chapter 10 Processing.................................................................................... 24
........................................................................................ 29

Chapter 11 Sterilisation ................................................................................... 29

........................................................................................ 31

Chapter 12 Sterilisation method ...................................................................... 31

...................................................................... 37

Chapter 13 Finishing of sterile products.......................................................... 37

........................................................................................ 38

Chapter 14 Quality control .............................................................................. 38

............................................................................................... 39

Chapter 15 Glossary ....................................................................................... 39

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 Chapter 1 Scope

Article 1 The sterile medicinal products, including sterile drug products and

drug substances, refer to the drug product and drug substances which are

subject to sterility test items as required in the statutory drug specifications

Article 2 This annex applies to the whole manufacture process for sterile

drug products, and to the process of sterilisation and sterile production for sterile

drug substances.

Chapter 2 Principle

Article 3 The manufacture of sterile products should meet the requirements of

quality and the intended use. It should minimize risks of microbiological
contamination, and of particulate and pyrogen contamination. The skill, training
and attitudes of the personnel involved are critical factors. The manufacture of

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sterile products must strictly follow the established and validated methods of
preparation and procedure. The sterility or other quality characteristics of
products cannot only rely on any form of terminal process or finished product
test (including sterility test).

Article 4 Sterile medicinal products, according to the manufacturing process, can

be divided into two categories: Termininally sterilised products, where the
products are terminally sterilised; and non-terminally sterilised products, where
the manufacture processes are partially or completely aseptic.

Article 5 The manufacture of sterile products should be carried out in clean areas
entry to which shall be through airlocks for personnel and/or for equipment and
materials. If equipment is used to achieve continuous transfer of materials,
positive pressure air flow shall be used to protect materials and pressure
difference shall be monitored.

Article 6 The various operations of component preparation, product preparation

and filling should be carried out in separate areas within the clean area.

Article 7 Clean areas for the manufacture of sterile products are classified
according to the properties of products, the characteristics of process and
equipment used. Each step of 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.

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 Chapter 3 Cleanliness Classification and Its Monitoring

“ ” “ ”

Article 8 The design of each clean room or suite of clean rooms shall meet the
requirements of corresponding cleanliness classification, of which “in operation”
and “at rest” states shall be defined.

0.36-0.54m/s

B A

C D

/
(3)

0.5 m 5.0 m(2) 0.5 m 5.0 m

(1)
A 3520 20 3520 20
B 3520 29 352000 2900
C 352000 2900 3520000 29000
D 3520000 29000

Article 9 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

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containers that are in direct contact with sterile preparations, making aseptic
connections. Normally such conditions are provided by a uni-directional air flow
work station. uni-directional 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.Uni-directional state must be validated, and data
must be available to prove the validation status.
A 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 operation stages in the
manufacture of sterile products.
The maximum permitted airborne particle concentration for each grade is given
in the following table.
Maximum permitted number of particles per m3 equal to or
greater than the tabulated size
Grade
At rest In operation (3)
0.5 m 5.0 m(2) 0.5 m 5.0 m
(1)
A 3520 20 3520 20
B 3520 29 352000 2900
C 352000 2900 3520000 29000
D 3520000 29000 Not defined Not defined

1 A 1 A

ISO 4.8 5.0 m B

ISO 5

C ISO 7 ISO 8

D ISO 8 ISO14644-1

5.0 m

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 3

“ ”

Note:
(1) To determine the cleanliness level for Grade A zones, a minimum sample
volume of 1m3should be taken per sample location. For Grade A the airborne
particle classification follows ISO 4.8 dictated by the limit for particles 5.0 m.
For Grade B (at rest) the airborne particle classification follows ISO 5, containing
both particle sizes listed in the above table. For Grade C (at rest & in operation)
the airborne particle classification follows ISO 7 and ISO 8 respectively. For
Grade D (at rest) the airborne particle classification follows ISO 8. For measuring
procedure, refer to ISO 14644-1.
(2) 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
particles
5.0 m in remote sampling systems with long lengths of tubing. Isokinetic
sample heads shall be used in uni-directional airflow systems.
(3) “In operation” classification may be demonstrated during normal operations
or simulated operations. Nevertheless worst-case scenario must be required for
media fills during “In operation” classification .

Article 10 The monitoring for aireborne particles of grade A, B, and C zones in

operation should be performed according to procedures as follows,

(1)
The determination of sampling locations should be based on cleanliness level,
results from the qualification of air purification system and the risk assessment.
There must be routine monitoring for in-operation cleanliness.

5.0 m

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(2) 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 should be undertaken during routine equipment set up operations, or
during simulated operations. 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 if alert limits are exceeded. It is
accepted that it may not always be possible to demonstrate low levels of 5.0
m particles at the point of fill when filling is in progress, due to the generation of
particles or droplets from the product itself.

B A B

A
(3) It is recommended that a similar monitoring system be used for Grade B
zones as the one used for Grade A zone. The sampling frequency and the
sample size can be adjusted according to the effectiveness of the segregation
between the adjacent Grade A and B zones.

(4) Where airborne particle monitoring systems are used, the length of tubing
and the radii of any bends in the tubing must be considered in the context of the
effect on test result.

(5) The sample sizes taken for monitoring purposes is not necessary to be the
same as that used for formal qualification of clean rooms and air handling
systems..
A B 5.0 µm

(6) In Grade A and B zones, it should be investigated if a few particle 5.0 m

ocurrs

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 consecutively or on a regular basis.

15 20

“ ”
(7)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

C D

(8)The monitoring of Grade C and D areas in operation (when necessary) 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.

(9) 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.

Article 11 Monitoring in operation should be done on microbe to evaluate its

status. The monitoring methods are settle plates, volumetric air and surface
sampling (e.g. swabs and contact plates),etc. Sampling methods used in
operation should not negatively impact cleanliness level in the zone. Results

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from monitoring should be reviewed as a part of 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.

(1)
Limits for microbiological monitoring of
clean areas during operation:

90mm
3 (2) 55mm 5
cfu/m cfu /4
cfu / cfu /
A 1 1 1 1
B 10 5 5 5
C 100 50 25

settle plates Surface microbiological

air sample
bacteria contact plates Glove print
Grade bacteria
90mm 55mm 5 fingers
cfu/m3
cfu /4hours(2) cfu /plate cfu /glove
A 1 1 1 1
B 10 5 5 5
C 100 50 25
D 200 100 50
D 200 100 50

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 2 4

Notes
(1) These are average values.
(2) Individual settle plates may be exposed for less than 4 hours..At each points,
several settle plates may be used for continuously monitoring and cumulatively
counting.

Article 12 Appropriate alert and action limits should be set for the results of
particulate and microbiological monitoring. Corrective actions shall be defined in
operating procedures in case such limits are exceeded ..

C (1)
A
1.
(2)
2.
C 3.

4.
1.
2.
D
3.

Article 13 The selection of production operations environment for sterile

medicinal products, refer to the examples in the following table.

Classification Examples of operations for terminally sterilised products

Grade A
environment Filling (or sealing)of products, when risk of contamination is
(1)
with aGrade high
C background
1. Filling (or sealing) of products;
Grade C 2. Preparation and filtration of products, when risk of
contamination is high(2);

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 3. Preparation and filling(or sealing) of ophthalmic
preparation, sterile ointment, sterile emulsion or
suspension, etc.
4. Handling of primary packaging materials and tools
after final washing, which are in direct contact with
medicinal products
1. Capping;
2.Material preparation before filling;
3.Preparation and filtration of products(concentration or
Grade D
dilution in a closed system) and ,final washing of primary
packaging material tools a which directly contact with
medicinal products.

Note:
(1) Here the high risk of contamination refers to the situations where the product
promotes microbial growth, and filling operation is slow or the containers - are
wide- necked or must be exposed for more than a few seconds before sealing.
(2) Here the high risk of contamination refers to the situations where the product
promotes microbial growth or must be held for a long period before sterilisation
or is not processed in closed systems.

(1)
1.
(2)

B 2.
A 3.

4.
(1)
1.
B
2
1.
C
2.
D

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 Classificatio Examples of operations for aseptic preparations
n
1. Operation and transfer of those products which are not completely
sealed in process(1), such as filling/sealing, subpackaging,
stoppering capping(2) of products etc.
Grade A 2. Preparation of solutions or products which are not able to go
environment through sterile-filtration before filling;
with a Grade B 3. Assembling of sterilised primary packaging materials and
background apparatus which will directly contact with medicinal products.
Transfer and storage ofthose sterilised and partially sealed
apparatus and materials.Milling, sieving, mixing and subpackaging
of sterile drug substances.
1. Transfer of partially sealed products in fully sealed containers.
2. Transfer and storage of sterized primary packaging materials and
Grade B
apparatus , which will direct contact with medicinal products. in
sealed containers
1. Preparation of solutions or products which could be sterile filtered
Grade C before filling.
2. Filtration of products.
Final washing, assembling or packaging, and sterilisation of primary
Grade D packaging materials and apparatus which will directly contact with
medicinal products.

C D A A

A
Note:
(1) The products before capping are deemed as not completely sealed.
(2)According to the sealing reliability, design of capping equipment, characteristics
of aluminium caps etc, capping operation can be conducted -in Grade A air
supply environment with a Grade C or D background. The Grade A air supply
environment should conform with at least the requirement of Grade A at rest.

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 Chapter 4 Isolator technology

D
Article 14 Operations associated with high contamination risk should be
performed inside isoloator. The isolator and the background environment should
be designed so that the required air quality for the respective zones can be
realised. Transfer devices may vary from a single door or double door designs to
fully sealed systems incorporating sterilisation mechanisms.
Special attention should be paid to prevent contamination when transferring of
materials into and out of the isolator.

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.

Article 15 Isolators should be applied for routine operations only after

appropriate validation. Validation should take into account all critical factors of
isolator technology, for examples, the quality of the air inside and outside
(background) the isolator, sanitisation of the isolator, the transfer process and
isolator integrity.

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Article 16 Monitoring should be carried out routinely and should include frequent
leak testing of the isolator and glove/sleeve system.

Chapter 5 Blow/fill/seal technology

A/B C

D
Article 17 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. Under at rest condition,
the suspended particles and microorganism should meet the standards. Under
in operation condition, the microorganism should meet the standards.
Blow/fill/seal equipment used for the production of products which are terminally
sterilised should be installed in at least a grade D environment.

Article 18 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 gowning
operations in the critical zone of the equipment including any aseptic
assembly or set-up? prior to the commencement of filling.

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 Chapter 6 Personnel

Article 19 The total number of personnel shall be rigorously controlled .

Inspections and controls should be conducted outside the clean areas as far as
possible.

Article 20 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.

Article 21 Personnel 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 shall not enter sterile-product areas unless rigorous and
clearly defined cleaning procedures have been followed.

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Article 22 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. Actions to be taken about personnel who
could be introducing undue microbiological hazard should be decided by a
designated competent person.

Article 23 Changing and washing should follow a written procedure designed to

minimize contamination of clean area or carry-through of contaminants to the
clean areas.

Article 24 The garment and its quality should be appropriate for the process and
the grade of the working area. It should be applied in such a way as to protect
the products and personnel from contamination.
The description of gowning 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
face mask should be worn. A jump suit or two-piece trouser suit, gathered at the
wrists and with high neck and appropriate shoes or overshoes should be worn.
They should be virtually free of fibres or particulate matter.

A/B

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 Grade A/B: Headgear should totally enclose hair and, where relevant, beard
and moustache; it should be tucked into the neck of the suit; safety goggles
should be worn; 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 sterilized jump suit should be
used. The suit should shed virtually no fibres or particulate matter and retain
particles shed by the body.

B C

A/B

Article 25 Outdoor clothing should not be brought into changing rooms leading to
grade B and C rooms. Every worker should change clean sterile protective
garments at every time when he enters a grade A/B area; or at least once a shift
while feasibility of the methods should be verified by the results from monitoring.
Gloves should be regularly disinfected during operations. Masks and gloves
should be changed when necessary.

Article 26 Clean area garments should be cleaned and handled in such a

way that it does not introduce additional contaminants which can later
contaminate clean areas. The operations should follow written procedures.
Separate laundry facilities for such clothing’s cleaning and sterilisation are
desirable.

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 Chapter 7 Premises

B
Article 27 The design of the clean premise should avoid the unnecessary access
of supervision or monitoring person . Grade B area should be designed as that
the inside operations could be monitored by supervision or monitoring person
from outside

Article 28 To reduce accumulation of dust and to facilitate cleaning there should

be no uncleanable recesses on shelves, cupboards and equipment in cleaning
area. Doors should be designed to avoid those uncleanable recesses.

A/B

Article 29 Sinks and drains should be prohibited in grade A/B areas used for
aseptic manufacture. In other areas, sinks and drains should have proper design,
layout and maintainance. Cleanable facilities with air break function should be
fitted to prevent backflow. The connection with outside drain system should be
designed to prevent microbial contamination.

Article 30 Changing rooms should be designed as airlocks and used to provide

physical separation of the different stages of changing and so minimize microbial
and particulate contamination of protective clothing. They should be flushed

20
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.

Article 31 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 both doors at a time.

Article 32 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.
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 directly 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 (eg. Install a filter at the
exit) of air leaving a clean area may be necessary for some operations.

Article 33 It should be demonstrated and documented (e.g. the video of smoke

test) that air-flow patterns do not present a contamination risk.

21
Article 34 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.

Article 35 There should be a separate zone and adequate air extraction device
for capping due to the generation of particles from the operation. If there is no
separate zone for capping, it should be demonstrated that the capping operation
will not have negative impact on product quality.

Chapter 8 Equipment

A/B
Article 36 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).

Article 37 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.

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 Article 38: HVAC system for the clean area of sterile medical products

manufacturing should keep running continuously in order to maintain the

corresponding cleanness classification. If the HVAC system is interrupted and

recommenced, testing is necessary to ensure the clean area can meet the

regulated classification requirement.

Article 39 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. The operation can be
restarted when the monitoring result is acceptable.

Article 40 All equipment such as sterilisers, air handling system and process
water systems etc., should be subject to validation and planned maintenance;
their return to use should be approved.

Article 41 Fibre-shedding characteristics of filters should be minimal. Asbestine

filters are prohibited. The filter should not have negative impact on product
quality by reaction with product , release of substances into it or absorption .

Article 42 The process gas (e.g. compressed air, nitrogen, except flammable gas)
should be filtered before entering sterile area. The integrity test of sterilization
filters and vent filters should be performed periodically.

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 Chapter 9 Sanitation

Article 43 Clean areas should be cleaned thoroughly in accordance with an

operation procedure. Where disinfectants are used, more than one type should
be employed. UV should not replace chemical disinfectants. Monitoring should
be undertaken regularly in order to detect the development of resistant strains.

A/B

Article 44 Disinfectants and detergents should be monitored for microbial

contamination; Prepared disinfectants and cleaning agents should be stored in
cleaned containers and should only be stored for defined periods. Disinfectants
and detergents used in Grades A and B areas should be sterile or sterilized prior
to use.

Article 45 Fumigation of clean areas may be useful for reducing microbiological

contamination in inaccessible places. The residue level of the fumigant should
be validated.

Chapter 10 Processing

24
Article 46 Precautions to minimize contamination should be taken during all
processing stages including the stages before sterilisation.

Article 47 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. The process simulation test should imitate as closely as
possible the routine aseptic manufacturing process and include all the critical
subsequent manufacturing steps which may affect the aseptic result. It should
also take into account various
interventions known to occur during normal production as well as worst-case
situations.

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., one batch at least in each time.

25
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:

5000

5000 10000

1. 1

2. 2

10000

1. 1

2. 2

1. When filling fewer than 5000 units, no contaminated units should be

detected.
2. When filling 5,000 to 10,000 units:
One (1) contaminated unit should result in an investigation, including
consideration of a repeat media fill test;
Two (2) contaminated units should result in revalidation, following
investigation.
3. When filling more than 10,000 units:
One (1) contaminated unit should result in an investigation;
Two (2) contaminated units should result in revalidation , following
investigation.
4. All microbial contamination should be investigated.

Article 48 Care should be taken that any validation does not compromise the

processes.

A/B

26
 Article 49 Water used in the purification of sterile APIs, preparation of sterile
medical products, final rinsing of utensils and packing material which directly
contact with products, and preparation of disinfectants and detergents used in
grades A and B areas should meet the specifications of water for injection.

Article 50 Endotoxins for processing water should be monitored regularly.

Records should be maintained of the results of the monitoring and of any
corrective action taken.

Article 51 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 be comfortable because of the nature of the garments worn.

Article 52 Microbiological contamination of starting materials should be minimal.

Specifications should include requirements for microbiological limits, bacterial
endotoxin or pyrogen.

Article 53 Containers and materials with fibre-shedding characteristics should be

minimised in clean areas. They are prohibited to be used in aseptic process.

Article 54 Where appropriate, measures should be taken to minimize the

particulate contamination of the end product.

27
Article 55 Components, containers and equipment should be handled after the
final cleaning process in such a way that they are not recontaminated.

Article 56 The interval between the washing and drying and the sterilisation of
packaging material, 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.

Article 57 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.

Article 58 There should be working limits on contamination immediately before

sterilisation, which are related to the efficiency of the method to be used. Where
appropriate the level of endotoxins or pyrogen should be monitored.

Article 59 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.

28
 Article 60: Unless otherwise specified, the principle for batch classification

of sterile pharmaceutical products:

1. Large/small volume injection: Homogeneous products, which are derived

from the solution that terminally prepared in one tank at once should be

regarded as one batch. One batch of products which is sterilized in different

equipment or in the same equipment but in several loads should be trackable.

2. Powder for injection: Homogeneous products which are produced from

the same batch of sterile APIs within the same continuous production cycle

should be regarded as one batch.

3. Lyophilized powder for injection: Homogeneous products which are

produced by the same Lyophilizer with the same batch of solution within the

same production cycle should be regarded as one batch.

4. Eye Preparation, Sterile Ointment, Emulsion and Suspension:

Homogeneous products, which are terminally prepared in the same tank should

be regarded as one batch.

29
 Chapter 11 Sterilisation

SAL 10-6

F0 8

Article 61 Where possible, heating sterilization is the method of choice for Sterile
products. For terminally sterilized products, the microbial survival probability
(Sterility Assurance Level ,SAL) should be not more than 10-6. For moist heat as
terminal sterilization, the standard sterilization time F0 should be more than 8
minutes. Flow steam treatment should not be considered as terminal
sterilization.
Aseptic process operation or sterile filtration should be considered as
alternatives for thermal instable products.

Article 62 Moist heat, dry heat, radiation, ethylene oxide or filtration could be
applied as sterilization methods. Every sterilization method has its specific
application scope. In any case, the sterilisation process must be in accordance
with the marketing and manufacturing authorisations. All sterilisation processes
should be validated.

Article 63 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

30
measurements and by biological indicators where appropriate.

Article 64 The validity of the sterilisation process should be verified at scheduled

intervals, at leastannually. And whenever significant modifications have been
made to the equipment, revalidation should be performed. Records should be
kept of the results.

Article 65 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.

Article 66 Validated loading patterns should be established for the material

which is sterilised in the chamber of sterilisation equipment.

Article 67 Biological indicators 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.

Article 68 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

31
batch number and an indication of whether or not it has been sterilised.
Indicators such as autoclave tape may be used, where appropriate.

Article 69 Sterilisation records should be available for each sterilisation run.

They should be approved as part of the batch release procedure.

Chapter 12 Sterilisation method

Article 70 Sterilisation by heat include moist heat and dry heat, it should

conform to the following requirements:

-
(1) During the validation and production, control instrumentation should normally
be independent of monitoring instrumentation and recording charts. The position
of the temperature probes used for controlling and/or recording should have
been determined during the validation . Each heat sterilisation cycle should be
recorded on a time/temperature chart.

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.

32
(2)Chemical or biological indicators may also be used to monitor aseptic process,
but should not take the place of physical measurements.

(3)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.

(4) 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.

Article 71 Moist heat sterilization should conform to the following requirements:

(1) Sterilization time, temperature and pressure should be used to monitor the
process.
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.

(2) 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

33
be in contact with the sterilizing agent at the required temperature for the
required time.

Article 72 Dry heat sterilization should conform to the following requirements:

(1) 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, which
should be qualified by the integrity test.
(2) Where this process is also intended to remove pyrogens, challenge
tests using endotoxins should be used as part of the validation.
(3) Temperature, time and pressure difference between inside and outside
of the chamber should be recorded during sterilization process.

Article 73 Sterilisation by radiation should conform to the following requirements:

(1) Radiation sterilisation is permissible only when the absence of deleterious

effects on the product has been confirmed experimentally. Radiation sterilisation
should conform to <Chinese Pharmacopeia> and registered authorisation.

(2) Radiation sterilisation process should be validated. The validation protocol

should include the radiation dose, radiation time, packaging material, loading
pattern. Validation procedures should ensure that the effects of variations in
density of the

34
packages are considered.

(3) During the sterilisation procedure the radiation dose should be measured by
using dosimetry indicators.

(4) Biological indicators may be used as an additional control.

(5) Measures should be taken to prevent mix-up between irradiated and

non-irradiated materials. Radiation sensitive colour disks should also be used on
each package to differentiate between packages.

(6) The total radiation dose should be administered within a predetermined time

span.

(7)The radiation sterilisation process should be recorded.

Article 74 Sterilisation with ethylene oxide should conform to the following

requirements:

(1) The Sterilisation with ethylene oxide should conform to <Chinese

Pharmacopeia> and registered authorisation

35
 (2) 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.

(3) 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.

(4) Before exposure to the gas, materials should be brought into equilibrium with
the

humidity and temperature required by the process.

(5) 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.

(6) 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

36
throughout the cycle on a chart. The record(s) should form part of the batch
record.

(7) 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.

Article 75 Filtration of medicinal products which cannot be sterilised in their

final container should conform to the following requirements:

0.22 m

(1)Filtration alone is not considered sufficient when sterilisation in the final

container is
possible. 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 not remove all viruses or
mycoplasmas. Consideration should be given to complementing the filtration
process with some degree of heat treatment.

(2) Due to the potential additional risks of the filtration method as compared with
other
sterilization 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.

37
(3) The integrity of the sterilised filter should be confirmed immediately after use
by an appropriate method such as a bubble point, diffusive flow or pressure hold
test.

(4)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.

(5) The using time of filters with the same specification should be validated.
Normally it should not be used for more than one working day.

Chapter 13 Finishing of sterile products

Article 76 Crimping of the cap should be performed as soon as possible after

stopper insertion. Appropriate measures should be taken to prevent
contamination if the product leaving the clean area/room before capping.

100%

Article 77 The integrity of the sterile medical product containers should be

validated to avoid the product contamination. Containers closed by fusion, e.g.
glass or plastic ampoules should be subject to 100% integrity test. Samples of
other containers should be checked for integrity according to appropriate
procedures.
38
Article 78 Containers sealed under vacuum should be tested for maintenance of
that vacuum after an appropriate, pre-determined period.

Article 79 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, 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.

Chapter 14 Quality control

/
Article 80 Sample plan for sterility testing should based on the result of risk
assessment, Samples should in particular include samples taken from parts of

39
the batch considered to be most at risk of contamination. The sterility testing
samples should at least comply with the followings:
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. or 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.
c. For one batch of product which are sterilised by different equipment or by the
same equipment but in deferent sterilization cycles, samples should be taken
from each equipment/cycle involved.

Chapter 15 Glossary

Article 81 The definitions of the glossary are:

(1)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.

(2)The “in operation” state is the condition where the installation is functioning in
the defined operating mode with the specified number of personnel working.

40
 (3) Laminar flow means the method that the air flows unidirectional with the

stable symmetrical way and enough rate. It can continuously remove the

particles at the critical operation area.

B ISO 5

(4) Isolator is a barrier or system that is equiped with Grade B (ISO 5) or

even higher cleanness air handling units and can isolate completely the internal

environment from external environment (e.g clean room and operators).

The “at-rest” state is the condition where the installation is installed, complete
with production equipment but with no operating personnel present and no
production activities.

(6) Seal means using an appropriate method to keep the containers or

utensils in closed in order to prevent outside microbe entering.

Annex 1 reviewed by Michael Lee, Ji Yiyun, He Guoling

41
 2

Annex 2:

Active Substances Used As Starting Materials

Table of content

.............................................................................................. 43

Chapter 1 Scope ............................................................................................. 43

................................................................................... 43

Chapter 2 Buildings and Facilities................................................................... 43

.............................................................................................. 44

Chapter 3 Equipment ...................................................................................... 44

.............................................................................................. 46

Chapter 4 Materials ......................................................................................... 46

.............................................................................................. 48

Chapter 5 Validation ........................................................................................ 48

.............................................................................................. 52

Chapter 6 Documentation ............................................................................... 52

............................................................................................. 54

Chapter 7 Production Management ................................................................ 54

......................................................... 60

Chapter 8 Rejected Intermediates or APIs...................................................... 60

............................................................................................. 63

Chapter 9 Quality Management ...................................................................... 63

........................................... 64

Chapter 10 Specific Requirement for APIs Manufactured

42
by Fermentation .............................................................................................. 64
................................................................................................. 68

Chapter 11 Glossary........................................................................................ 68

Chapter 1 Scope

Article 1 The annex applies to the manufacture of non-sterile active

substances and the operations of non-sterile process during the sterile
substance production.

Article 2: The point at which production of the active substance begins and its
process should be designated in accordance with the registered and authorised
process.

Chapter 2 Buildings and Facilities

43
 Article 3: The exposed environment where purification, drying, milling, and
packaging of non-sterile active substances are carried out should meet grade D
area described in Annex 1.

Article 4: Where pyrogen or endotoxin specification have been established

for the intermediate or API, , The facilities,should be designed with particular
attention to prevent the microbialogical contamination, e.g. relevant precautions
should be set up according to the intended use of products and process
requirements.

Article 5: Quality control laboratory areas should normally be separated

from production areas. Laboratory areas used for in-process control can be
located in production areas , provided the manufacturing operations do not affect
the accuracy of the laboratory measurements, and the laboratory and its
operations do not adversely affect the production process.

Chapter 3 Equipment

Article 6: Any substances associated with the operation of equipment, such

as lubricants, heating fluids or coolants, should not contact intermediates or APIs
so as to alter their quality beyond the official or other established specifications.
Any deviations from this should be evaluated and handled properly to ensure
that there are no detrimental effects upon the fitness for purpose and quality of
the products.

44
 Article 7: Closed or contained equipment should be used whenever
appropriate. Closed equipment and pipelines can be placed outdoor. Where
open equipment is used, or opened, appropriate precautions should be taken to
avoid the risk of contamination.

Article 8: Where equipment shared with different intermediates or APIs, the

rational should be provided. Appropriate precautions should be taken to prevent
from the risk of cross-contamination.

Article 9: The equipment or component which is difficult to clean should be

used dedicated.

Article 10: Equipment cleaning

1. Where the equipment is assigned to continuous production or campaign

production of successive batches of the same intermediate or API, the
equipment should be cleaned at appropriate intervals to prevent build-up of
contaminants (e.g. degradants or objectionable levels of micro-organisms). The
equipment should be cleaned thoroughly between productions of different
batches to prevent cross-contamination where carry-over with adversely affect
the quality of APIs or intermediates.

2. Non-dedicated equipment (especially the ones for the starting material

purification) should be cleaned between productions of different products to
prevent cross-contamination.

45
 3. Acceptance criteria for residues and the choice of cleaning procedures
and cleaning agents should be defined and justified.

Article 11: Process water used in the final purification steps of non-sterile
APIs should, at a minimum, meet the quality standards of purified water.

Chapter 4 Materials

Article 12: The incoming materials should be labelled correctly. After

sampling (or testing), these material can be mixed with existing stocks (e.g.,
solvents or stocks in silos), then release for production using. Procedures should
be available to prevent discharging wrong incoming materials into the existing
stock.

Article 13: If bulk deliveries are made in non-dedicated tankers,

precautions should be taken to assure no cross-contamination from the tanker.

Article 14: Large storage containers, and their attendant manifolds, filling
and discharge lines should be appropriately labeled.

46
 Article 15: At least one test to verify the identity of each batch of material
should be conducted. A supplier's Certificate of Analysis can be used in place of
performing other tests, provided that the manufacturer has a system in place to
evaluate suppliers.

Article 16: Processing aids, hazardous or highly toxic raw materials, other
special materials, or materials transferred to another production area within the
company’s control do not need to be tested if the manufacturer’s Certificate of
Analysis is obtained, showing that these raw materials conform to established
specifications. Visual examination of containers, labels, and recording of batch
numbers should help in establishing the identity of these materials. The lack of
on-site testing for these materials should be justified and documented.

Article 17 Full analyses should be conducted on at least the first three

batches before reducing in-house testing. However, a dull analysis should be
performed at appropriate intervals and compared to the Certificates of Analysis
from supplier. The reliability and accuracy of the certificates offered by supplier
should be evaluated periodically.

Article 18: Certain materials in suitable containers can be stored outdoors,

provided identifying labels remain legible and containers are appropriately
cleaned before opening and use.

Article 19: Materials should be re-evaluated as appropriate to determine

their suitability for use (e.g., after prolonged storage or exposure to heat or
humidity).

47
 Chapter 5 Validation

Article 20: The critical product quality attributes , critical process

parameters that could affect these attributes, the range for each critical
process parameter expected to be used during routine manufacturing and
process control should be defined before process validation. The reproducibility
of the process operations should be ensured by validation activities.
Critical quality attributes and process parameters should normally be identified
during the development stage or from historical data.

Article 21: Validation should cover those operations determined to be

critical to the quality (especially to the purity and impurity)

Article 22 Approaches to process validation

1. Prospective validation should normally be performed for all API

processes. Concurrent validation can be conducted when API batches are
produced infrequently, only a limited number of API batches have been
produced, or API batches are produced by a modified process, where data
from replicate production runs are unavailable.

48
 2. An exception can be made for retrospective validation for processes that
have been used without significant changes to API quality due to changes in raw
materials, equipment, systems, facilities, or the production process. This
validation approach may be used where:

1.
1) Critical quality attributes and critical process parameters have been
identified;

2.
2) Appropriate in-process acceptance criteria and controls have been
established;

3.
3) There have not been significant process/product failures attributable to
causes other than operator error or equipment failures unrelated to equipment
suitability; and

4.
4) Impurity profiles have been established for the existing API.

3. Batches selected for retrospective validation should be representative of

all batches made during the review period, including any batches that failed to
meet specifications, and should be sufficient in number to demonstrate process
consistency. Where necessary, the testing data of retained samples can be used
as supplements of retrospective validation.

Article 23: Process Validation program

49
 1. The number of process runs for validation should depend on the
complexity of the process or the magnitude of the process change being
considered. For prospective and concurrent validation, three consecutive
successful production batches should be used as a guide, but there may be
situations where additional process runs are warranted to prove consistency of
the process (e.g., complex API processes or API processes with prolonged
completion times).

2. Critical process parameters should be controlled and monitored during

process validation studies. Process parameters unrelated to quality, such as
control variables to minimize energy consumption or equipment use, need not to
be included in the process validation.

3. Process validation should confirm that the impurity profile for each API
is within the limits specified. The impurity profile should be comparable to the
data of the profile determined during process development or of batches used
for pivotal clinical and toxicological studies.

Article 24: Cleaning validation

1. Cleaning procedures should normally be validated. In general, cleaning

validation should be directed to situations or process steps where contamination
or carryover of materials poses the greatest risk to API quality.

50
 2. Validation of cleaning procedures should reflect actual equipment
usage patterns. If various APIs or intermediates are manufactured in the same
equipment and the equipment is cleaned by the same process, a representative
intermediate or API can be selected for cleaning validation. This selection should
be based on the solubility and difficulty of cleaning and the calculation of residue
limits based on activity, toxicity, and stability.

3. The cleaning validation protocol should describe the equipement to be

cleaned, cleaning procedures, cleaning agents, acceptable criteria, parameters
to be monitored and controlled, and analytical methods. The protocol should
also indicate the type of samples (e.g. chemicals or micro organisms), location of
sampling, methods of sampling, label of samples to be obtained. Visual
inspection can be adapted as the testing method to dedicated equipment and
with consistent product quality.

4. Sampling should include swabbing, rinsing, or alternative methods

(e.g., direct extraction), as appropriate, to detect both insoluble and soluble
residues.

5. Validated and high sensitive analytical methods should be used to

detect residues or contaminants. The detection limit for each analytical method
should be sufficiently sensitive to detect the established acceptable level of the

51
residue or contaminant. The method’s attainable recovery level should be
established. Residue limits should be practical based on the most deleterious
residue. Limits can be established based on the minimum known
pharmacological, toxicological, or physiological activity of the API or its most
deleterious component.

6. Equipment cleaning validation protocol should address pyrogen and

endotoxin contamination for those processes where there is a need to control
endotoxins or pyrogens.

7. Cleaning procedures should be monitored by analytical methods

established at appropriate intervals after validation to ensure that these
procedures are effective when used during a routine production.

Chapter 6 Documentation

Article 25: Incoming material quality specification should be established

according to process requirements, the impact on the product quality, material
nature, as well as the suppliers quality assessment .

Article 26: Quality specification should be established for certain materials,

such as process aids, gaskets, and other materials with critical impact on quality
during the production of intermediates or APIs.

Article 27: Master production instructions should include:

52
 1. The name of the intermediate or API being manufactured;

2. A complete list of raw materials and intermediates designated by

names or codes;

3. An accurate statement of the quantity or ratio of each raw material or

intermediate to be used, including the unit of measure. Where the quantity is not
fixed, the calculation for each batch size or rate of production should be included.
Variations to quantities should be included where they are justified;

4. The production location and major production equipment to be used

(model type and materials etc.);

5. Detailed production instructions, including:

1.
1) The sequences to be followed;

2.
2) Ranges of process parameters to be used;

3.
3) Sampling instructions and quality specification of raw materials,
intermediates and APIs;

4.
4) Time limits for completion of individual processing steps and/or the total
process, where appropriate;

5.
5) Expected yield ranges at appropriate phases of processing or according
to time;

6.
6) Where appropriate, special notations and precautions to be followed, or
cross references to these; and

53
 7.

7) The instructions for storage of the intermediate or API to assure its

suitability for use, including the labeling and packaging materials and special
storage conditions with time limits, where appropriate.

Chapter 7 Production Management

Article 28: Production operations

Raw materials should be weighed or measured under appropriate

conditions that do not affect their suitability for use. Weighing and measuring
devices should be of suitable accuracy for the intended use.

If a material is subdivided for later use in production operations, the

receiving container should be suitable and should be so identified with the
following information:

1.

1) Material name and/or item code;

2.

2) Receiving lot number or serial number;

3.

3) Weight or measure of material in the sub-container; and

4.

54
 4) Re-evaluation or retest date if appropriate.

3. Critical weighing, measuring, or subdividing operations should be

reviewed or subjected to an equivalent control. Prior to use, production
personnel should verify that the materials is for intended used t.

4. Actual yields should be compared with expected yields at designated

steps in the production process. Expected yields with appropriate ranges should
be established based on previous laboratory, pilot scale, or manufacturing data.
Deviations in yield associated with critical process steps should be investigated
to determine their impact or potential impact on the resulting quality of affected
batches.

5. If time limits are specified in the master production instruction, these

time limits should be met strictly. Deviations should be documented and
evaluated. Time limits may be inappropriate to a target value, where completion
of reactions or processing steps are determined by in-process sampling and
testing.

6. Intermediates held for further processing should be stored under

appropriate conditions to ensure their suitability for use.

Article 29: In-process controls and sampling

1. The acceptance criteria, type and extent of testing can depend on the
55
nature of the intermediate or API being manufactured, the reaction or process
step being conducted, and the degree to which the process introduces variability
in the product’s quality. Less stringent in-process controls may be appropriate in
early processing steps, whereas tighter controls may be appropriate for later
processing steps (e.g., isolation and purification steps).

2. In-process controls can be performed by qualified personnel in

production department and the process adjusted without prior quality unit if the
adjustments are made within pre-established limits approved by the quality
unit(s). Out-of-specification (OOS) investigations are not normally needed for
in-process tests that are performed during the adjusting process.

3. Written procedures should describe the sampling methods for

in-process materials, intermediates, and APIs.

4. In-process sampling should be conducted according to the written

procedures, and samples should be sealed properly to prevent contamination of
the sampled material and other intermediates or APIs.

Article 30 Viral removal/inactivation steps

1. Viral removal and viral inactivation steps should be performed

according to validated procedure.

2. Appropriate precautions should be taken to prevent potential viral

contamination from pre-viral to post-viral removal/inactivation steps. Open
processing should be performed in areas that are separate from other
processing activities and have separate air handling units.

56
 3. The same equipment is not normally used for different purification
steps, i.e. different products or different phases of the same product. If the same
equipment is to be used, the equipment should be appropriately cleaned and
sanitized before reuse. Appropriate precautions should be taken to prevent
potential virus carry-over (e.g. through equipment or environment) from previous
steps.

Article 31 Blending batches of intermediates or APIs

1. For the purpose of this article, blending is defined as the process of

combining APIs within the same specification to produce a homogeneous API.
In-process mixing of fractions from single batches (e.g., collecting several
centrifuge loads from a single crystallisation batch) or combining fractions from
several batches for further processing is considered to be part of the production
process and is not considered to be blending.

2. Out-Of-Specification batches should not be blended with other

batches.

3. Each batch incorporated into the blend should have been

manufactured using an established process and should have been individually
tested and found to meet appropriate specifications prior to blending.

4. Acceptable Blending operations include but not limited to:

57
 1.

1) Blending of small batches to increase batch size

2.
2) Blending of tailings from batches of the same API to form a single
batch.

5. Blending processes should be adequately controlled and documented

and the blended batch should be tested for conformance to established
specifications where appropriate.

6. The batch record of the blending process should allow traceability

back to the individual batches that make up the blend.

7. Where physical attributes of the API are critical (e.g., APIs intended
for use in solid oral dosage forms or suspensions), validation should include
testing which can show homogeneity of the combined batch, and testing of
critical attributes (e.g., particle size distribution, bulk density, and tap density)
that may be affected by the blending process.

8. If the blending could adversely affect stability, stability testing of the

final blended batches should be performed.

9. The expiry or retest date of the blended batch should be based on the
manufacturing date of the oldest tailings or batch in the blend.

Article 32: Principles for distinguishing batches

58
 In case of continuous production , the homogenous product which is
produced in a fixed time intervalshould be considered as a single batch.

For batch production, a specific quantity of homogenous product which

is blended by a certain number of products should be considered as a single
batch.

Article 33: Contamination control

Adequate controls should be implemented where residual materials are

carried over into successive batches of the same intermediate or API. Such
carryover should not result in the carryover of degradants or microbial
contamination that may adversely alter the established API impurity profile.

Production operations should be conducted in a manner that prevent

contamination of intermediates or APIs from other materials.

Precautions to avoid contamination should be taken when APIs are

handled after purification.

Article 34: Packaging of APIs and intermediates

1. Containers should provide an adequate protection against

deterioration or contamination of the intermediate or API that may occur during
59
transportation and recommended storage. These containers should not be
reactive, additive, or absorptive so as to alter the quality of the intermediate or
API beyond the specified limits.

2. Containers should be clean and, where indicated by the nature of the

intermediate or API, sanitized to ensure that they are suitable for their intended
use.

3. If containers are re-used, they should be cleaned in accordance with

operational procedures and all previous labels should be removed or defaced.

4. Intermediate or API containers that are transported outside of the

manufacturer's control should be properly sealed in a manner such that, the
recipient will be alerted when the seals alter.

Chapter 8 Rejection

Article 35: Intermediates and APIs failed to meet specifications can be

reprocessed or reworked as described in Articles 36 and 37. The final disposition
of rejected materials should be recorded.

Article 36: Reprocessing

1. Introducing an intermediate or API, including one that does not conform

to standards or specifications, back into the process and reprocessing by
repeating a crystallisation step or other appropriate chemical or physical
60
manipulation steps, e.g., distillation, filtration, chromatography, milling, that are
part of the established manufacturing process is generally considered
acceptable.

2. If such reprocessing is used for a majority of batches, such

reprocessing should be included as part of the standard manufacturing process.

3. Introducing unreacted material back into a process and repeating a

chemical reaction is considered to be reprocessing unless it is part of the
established process. Such reprocessing should be preceded by careful
evaluation to ensure that the quality of the intermediate or API is not adversely
impacted due to the potential formation of by-products and over-reacted
materials.

4. If continuation of a process step after an in-process control test has

shown that the step is incomplete, it still can be processed following the normal
process. This is not considered to be reprocessing.

Article 37: Reworking

1. Batches that have been reworked should be subjected to appropriate

evaluation, testing, stability testing if warranted, and documentation to show that
the reworked product is of equivalent quality to that produced by the original
process. Concurrent validation can be used to define the rework procedure, how
it will be carried out, and the expected results.

61
 2. Reworking should be performed according to approved operational
procedure, comparing the impurity profile of each reworked batch against
batches manufactured by the established process. Where routine analytical
methods are inadequate to characterize the reworked batch, additional methods
should be used.

Article 38: Recovery of materials and solvents

1. Recovery (e.g. from mother liquor or filtrates) of reactants,

intermediates, or the API is considered acceptable, provided that approved
procedures exist for the recovery and the recovered materials meet
specifications suitable for their intended use.

2. Solvents can be recovered and reused in the same process step or in

different process step of the same product, provided that the recovery
procedures are controlled and monitored to ensure that recovered solvents meet
appropriate standards. Provided no adverse impact on product quality , recovery
solvents can be used in different products.

3. Fresh and recovered solvents and reagents can be combined if an

adequate testing has shown their suitability for all manufacturing processes in
which they may be used.

4. The use of recovered solvents, mother liquors, and other recovered

62
materials should be adequately documented with traceability, and the impurity
be tested regularly.

Chapter 9 Quality Management

Article 39: The specifications should include a control of impurities (e.g.

organic impurities, inorganic impurities, and residual solvents). Microbiological or
endotoxin specification should be established where applicable.

Article 40: An impurity profile describing the identified and unidentified

impurities present in a typical batch produced by a specific controlled production
process should normally be established for each API. The impurity profile should
include the identity or some qualitative analytical designation (e.g. retention
time), the range of each impurity observed, and classification of each identified
impurity (e.g. inorganic, organic, solvent). The impurity profile is normally
dependent upon the production process and an origin of the API. Impurity
profiles are normally not necessary for APIs from herbal or animal tissue origin
and manufactured by fermentation process.

63
 Article 41: The impurity profile should be compared at appropriate
intervals against the impurity profile in the register submission or compared
against historical data in order to detect changes to the API resulting from
modifications in raw materials, equipment operating parameters, or the
production process.

Article 42: Stability monitoring of APIs

1) Stability samples should be stored in containers that simulate or are

same with the marketed product container.

2) Normally the first three commercial production batches should be

placed on the stability monitoring program to confirm the expiry date.

3) For APIs with short shelf-lives, testing should be done more frequently
during the stability monitoring.

Chapter 10 Specific Requirement for APIs Manufactured

by Classical Fermentation

(?????)
Article 43: Appropriate control should be used to minimize the risk of

64
microbial contaminations during manufacture of APIs, which are produced by
classical fermentation process

Article 44: Process controls should take into account:

1. Maintenance of the working cell bank;

2. Proper control of inoculation and expansion of the culture;

3. Control of the critical operating parameters during fermentation/cell

culture;

4. Monitoring of the process for cell growth and productivity

5. Harvest and purification procedures while protecting the intermediate or

API from contamination

6. Monitoring of microbial contamination level and, where needed,

endotoxin levels at appropriate stage of production

Article 45: Where appropriate, the removal of media components, host cell
proteins, other process-related and product-related impurities and contaminants
should be demonstrated.

Article 46: Cell bank maintenance and record keeping

1. Access to cell banks should be limited to authorized personnel.

65
 2. Cell banks should be maintained under storage conditions designed to
maintain a required viability level and prevent contamination.

3. Records of the use of the vials from the cell banks and storage
conditions should be maintained.

4. Cell banks should be periodically monitored to determine suitability for

use.

5. When necessary, strain identification should be conducted.

Article 47: Cell culture/fermentation

1. Where aseptic addition of cell substrates, media, buffers, and gases is

needed, closed or contained systems should be used. If the inoculations of the
initial vessel, subsequent transfers or additions (media, buffers) are performed in
open vessels, there should be controls and procedures in place to avoid the risk
of contamination.

2. Where the quality of the API can be affected by microbial

contamination, manipulations using open vessels should be performed in the
proper controlled environment.

3. Personnel should be appropriately gowned and take special

precautions when handling the cultures.

66
 pH

4. Critical operating parameters (for example temperature, pH, agitation

rates, addition of gases and pressure) should be monitored to ensure
consistency with the established process. Cell growth, productivity should also
be monitored where appropriate.

5. As appropriate, fermentation equipment should be cleaned, and

sanitized or sterilised.

6. Culture media should be sterilised before use.

7. There should be appropriate procedures in place to detect microbial

contamination occurred during the process operations and determine the course
of action to be taken, including procedures to determine the impact of microbial
contamination on the product and those to decontaminate the equipment and
return it to normal production condition. When dealing with contaminated
materials, foreign micro organisms observed during fermentation processes
should be identified as appropriate and the effect of their presence on product
quality should be assessed, if necessary.

8. Records of micro contamination events and corresponding handling

should be maintained.

9. Shared (multi-product) equipment should be warranted by conducting

necessary tests after cleaning between product campaigns, as appropriate, to
minimize the risk of cross-contamination.

67
 Article 48: Harvesting, isolation and purification

1. Harvesting steps, either to remove cells or cellular components or to

collect cellular components after disruption, should be performed in equipment
and areas designed to minimize the risk of contamination.

2. Harvest and purification procedures including inactivating cells,

removing cellular debris and media components should be established and
corresponding procedures should be conducted to minimize degradation and
contamination, so as to ensure that the intermediate or API is recovered with
consistent quality.

3. If open systems are used, isolation and purification and should be

performed under environmental conditions appropriate for the preservation of
product quality.

4. Additional controls, such as the use of dedicated chromatography

medium or additional testing, may be appropriate if the equipment is to be used
for harvest, isolation or purification of multiple products.

Chapter 11 Glossary

Article 49: The following glossaries mean:

1. Classical fermentation

68
 “ ”

The term “classical fermentation” refers to processes that use

microorganisms existing in nature and/or modified by conventional methods (e.g.
irradiation or chemical mutagenesis) to produce APIs. APIs produced by
“classical fermentation” are normally low molecular weight products such as
antibiotics, amino acids, vitamins, and carbohydrates.

2. Non-sterile APIs

This refers to APIs of which the sterile inspection items are not listed in
statutory standards.

3. Critical quality attributes

This refers to attributes of physical, chemical, biological or

microorganism, should be of certain limits, scope or distribution, so as to meet
expectant product quality.

4. Process aids

This refers to the materials (e.g. filter aid, activated carbon, etc,
excluding solvents), used as an aid in the production of an intermediate or API
that do not participate in a chemical or biological reaction itself.

5. Mother liquor

The residual liquid remains after the crystallisation or isolation processes.

Annex 2 reviewed by Zhao Chunhua, Zhao Yunxia

69
 3
Annex 3:

BIOLOGICAL MEDICINAL

Table of content

................................................................................................... 71

Chapter 1. Scope ............................................................................................ 71

................................................................................................... 72

Chapter 2 Principle.......................................................................................... 72
.............................................................................................. 73

Chapter 3 Personnel ....................................................................................... 73

................................................................................... 74

Chapter 4 Premises and Equipment ............................................................... 74

......................................................................... 79

Chapter 5 Animal Quarters and Relatives....................................................... 79

....................................................................................... 80

Chapter 6 Production Management ................................................................ 80

....................................................................................... 84

Chapter 7 Quality Management ...................................................................... 84

.............................................................................................. 85

Chapter 8 Glossary ......................................................................................... 85

70
 Chapter 1. Scope

Article 1 The methods employed in the manufacture of biological medicinal

products are a critical factor in shaping the appropriate quality control. Biological
medicinal products prepared by the following methods of manufacture will fall
under the scope of this annex:
DNA

a) Microbial and cell cultures, including those resulting from

recombinant DNA or hybridoma techniques;
b) Extraction from biological tissues
c) Propagation of live agents in embryos or animals

Article 2: Biological medicinal products in this annex include: bacterial vaccines

(including anatoxin), viral vaccines, antitoxins, antiserums, blood products,
cytokines, growth factors, enzymes and in vitro or in vitro diagnostic reagents
and other active biological agents, e.g., toxins, antigens, allergens, monoclonal
antibodies, antigen-antibody complexes, immunoregulators and
microbioecologics, etc.

Article 3: The production and quality control of biological medicinal products

should meet the requirements of the annex and related State regulations.

71
 Chapter 2 Principle

Article 4: The production of biological medicinal products and the test for
intermediates should involve certain specific controls arising from the following
nature of the products and the processes:

1. The production of biological medicinal products involves biological

processes and materials, such as cultivation of cells or extraction of material
from living organisms. These biological processes may display inherent
variability, so that the range and nature of by-products are variable. Moreover,
the materials used in these cultivation processes provide good substrates for
growth of microbial contaminants.

2. Biological analytical techniques involved in the quality control of biological

medicinal products usually have a greater variability than physico-chemical
determinations.

3. Some analytical tests cannot be carried out on the finished product due to
often added adjuvant and protective agents in the finished products to enhance
the potency (immunogenicity) or to maintain biological activity.

72
 Chapter 3 Personnel

Article 5: All personnel involved in manufacture of biological products, quality

assurance, quality control and other related personnel (including those
concerned with cleaning and maintenance) should receive additional technical
and safety protection training specific to the products manufactured and to their
work.

Article 6: Persons who are responsible for production and quality management
as well as Authorized Person should have an adequate background in relevant
scientific disciplines, such as microbiology, biology, immunology, biochemistry,
biological products, together with sufficient practical experience to enable them
to exercise their functions for the production and quality management
concerned.

Article 7: All personnel engaged in production, maintenance, testing and

animal care (and managers) should be vaccinated with appropriate specific
vaccines and have regular health checks based on the biological safety
evaluation for products.

73
 Article 8: Personnel affected by an infectious disease, dermatosis, or having
open lesions on the exposed surface of the body, and could potentially affect the
quality and safety of the products should be excluded from production areas and
not allowed to engage in the production operations or quality inspections.
Unauthorized person should be excluded from production areas.

Article 9: Production of BCG vaccine and tuberculin products should be

restricted to staff who are carefully monitored by regular checks of
immunological status or chest X-ray.

Article 10: During the manufacturing period, personnel should not pass from
areas where exposure to live organisms or animals to areas where other
products or organisms are handled unless they complied with clearly defined
decontamination measures

Article 11: Production personnel should not engage in animal care.

Chapter 4 Premises and Equipment

Article 12: Air cleanliness classification for production environment of biological

74
medicinal products should be adapted to the requirements of product and
operation. The premises and facilities for production should not result in any
potential contamination risk to starting materials, intermediates and final
products.

Article 13: Facilities such as HVAC should meet specific requirements when
high-risk pathogenic factors involved in the production.

Article 14: Production operations for biological medicinal products should be

carried out in the corresponding classification of clean areas according to the
table as below. Those operations which are not listed out may consult this table
for appropriate classification of clean area:

Classification Examples of operations for biological medicinal

products
Grade A environment All process steps in aseptic preparations as
with grade B required in Annex 1.

75
 background
Products without sterilization and filtration before
filling: their preparation, blending, etc.

Subpackaging of positive serums of

Grade C
immunodiagnostic agents, antigens and antibodies.

Blending of plasma, separation of components, and

pasteurisation before subpackaging.

Closed system environment of fermentation for oral

preparations (sterile operation will be required at
Grade D
where exposed).

Preparation, subpackaging, drying and primary

packaging of in vitro immune reagents, such as
enzyme-linked immunoassay ELISA.

Article 15: During those stages of the manufacturing process in which live
organisms are used, it may require relevant precautions to prevent the risk of
cross-contamination with respect to facilities and equipment, such as the use of
dedicated facilities and equipment, production on a campaign basis and the use
of closed systems.

Article 16: Inactive vaccines (including recombinant vaccine), toxoids, extracts of

bacterial species etc. can share the same filling room, and filling, freeze-drying
facilities on a campaign basis. However, the effective decontamination
procedures, such as cleaning and sterilization when necessary, should be
applied after each filling.

76
Article 17: Premises used for the production of BCG vaccine and tuberculin
products should be strictly separated with others. Dedicated facilities should be
separately used for live organisms.

Article 18: The operation of pathogenic endospore-forming bacteria should be

performed by using dedicated facilities until the inactivation process is
accomplished. The production of bacillus anthracis, clostridium botulinum and
clostridium tetanoides should be carried out by dedicated facilities.

Article 19: For other types of endospore-forming bacteria products, if the

campaign production is adopted for those products, the facilities are dedicated to
each group of products and not more than one product is processed at any time.

DNA
Article 20: Simultaneous production in the same area using closed systems of
biofermenters may be acceptable for products such as monoclonal antibodies
and products prepared by DNA techniques.

Article 21: Positive pressure areas of suitable cleanliness classification should

be used to process sterile products. Operations for pathogenic micro-organisms
should be carried out in specific areas of negative pressure. Where negative
pressure areas or safety cabinets are used for aseptic processing of pathogens,

77
they should be surrounded by a positive pressure sterile zone.

Article 22: HVAC systems should be set up for each of non-sterile (toxic) area
and sterile (non-toxic) area and air from areas of pathogenic organisms should
not be recirculated and used again. Air from areas of pathogenic organisms
where the risk class is grade 2 or above should be filtrated by sterile filtration.
The performance of the sterile filter should be checked regularly.

Article 23: The production areas and equipment used for processing live
organisms should be cleaned up and decontaminated easily, and be validated.

Article 24: Equipment used during handling of live organisms should be able to
maintain cultures uncontaminated by external sources during processing.

Article 25: Pipework systems, valves and vent filters should be properly
designed to facilitate cleaning and sterilization. The use of “clean in place” and
“sterilise in place” systems shall be encouraged. Valves on closed vessels such
as fermentation vessels should be completely steam sterilisable. Air vent filters
should be hydrophobic and validated for their scheduled life span.

Article 26: Isolated and closed systems involved in exposure of toxic species of
bacteria and products should be tested regularly and be demonstrated freedom

78
from leakage risk.

Article 27: Items and equipments contaminated by pathogen during processing

should be separated from unused sterilized items and equipments, and be
marked clearly.

Article 28: A small quantity of reserved items, such as additive and ingredients
(e.g. buffers), which need to be weighed during production process could be
kept in production area.

Article 29: Effective segregation and precautions for cold storage and
thermostatic chamber in clean areas should be taken to prevent production
areas from the contamination.

Chapter 5 Animal Quarters and Relatives

Article 30: Quarters for animals used in production, quarters for animals used in
quality of biological medicinal products and production areas should be
separated from each other. The design, construction and management of animal
quarters should meet relevant regulations of laboratory-used animal
management.

Article 31: For animals used for production and testing, their health state should

79
be monitored and recorded in detail, including at least animal origin, the
breeding and feeding conditions, and the health status.

Article 32: Animals chosen for production and testing use should meet the
requirements of Pharmacopoeia of The People’s Republic of China.

Chapter 6 Production Management

Article 33: Where the necessary tests of raw materials take a long time, it
may be permissible to process materials before the results of the tests are
available. In such cases, release of a finished product is conditional on
satisfactory results of these tests.

Article 34: There should be a perfect system of cell banks (original cell bank,
master cell bank and working cell bank) for cells used in production and testing.
The establishment, maintenance and testing of cell bank systems should be
consistent with the requirements of Pharmacopoeia of The People’s Republic
of China.

Article 35: A perfect system of seed lots for bacterial and viral strains used in
production and testing should be established (original seed lot, master seed lot
and working seed lot). The establishment, maintenance and testing of system for
bacterial/virus strain should be consistent with that defined in Pharmacopoeia of
The People’s Republic of China.

80
Article 36: The suitability of seed lots and cell banks should be demonstrated by
the consistency of the characteristics and quality of the successive batches of
product. Seed lots and cell banks should be established, stored and used in
such a way as to avoid the risks of contamination or alteration.

Article 37: The number of generations (doublings, passages) between the seed
lot or cell bank and the finished product should be consistent with the registered
and approved dossier. Scaling up of the process should not change this
fundamental relationship.

Article 38: Establishment of the seed lot and cell bank should be performed in a
suitably controlled environment to protect the seed lot and the cell bank and, if
applicable, the personnel who handle it. During the establishment of the seed lot
and cell bank, no other living or infectious material (e.g. virus, cell lines or cell
strains) should be handled by operator simultaneously or in the same area.

Article 39: Only under the supervision of delegated person, authorized personnel
shall be allowed to handle the material in the seed lot and cell bank.
Unauthorized person should not access the seed lot and cell bank.

81
 Article 40: Evidence of resources, production, storage, the stability and
recovery of the seeds and banks should be documented. Storage containers
should be kept at an appropriate temperature and clearly labeled. Storage
temperature should be recorded continuously for freezers and properly
monitored for liquid nitrogen. Any deviation from set limits and any corrective
action taken should be recorded. And the inventory record should keep for long
time.

Article 41: Different seed lots or cell banks should be stored in such a way to
avoid errors, confusion or cross-contamination. It is desirable to split the seed
lots and cell banks to store the parts at different locations in prescriptive storage
conditions, so as to avoid loss.

Article 42: During the storage, the storage conditions for master or working seed
lots should be the same, and the storage conditions for master or working banks
should be the same. Once removed from storage, the containers should not be
returned to the stock.

“ ”

Article 43: The batching and batch numbering of biological medicinal products
should be carried out according to “batching procedure for biological medicinal
products” listed in Pharmacopoeia of The People’s Republic of China.

82
Article 44: The suitability of culture media should be tested. Culture media used
in production should not contain any materials which are not approved.

Article 45: While adding materials or taking samples from fermenters or other
vessels, it should be carried out under carefully controlled conditions to ensure
that absence of contamination is maintained, and care should be taken to ensure
that vessels are correctly connected when addition or sampling take place.

Article 46: Containment of centrifugation and blending activities of products

should be implemented to prevent diffuse of live micro-organisms resulting from
suspended particles during the process.

Article 47: “Sterilise in place” used in culture media should be

encouraged .The use of “Sterilise in place” should be encouraged for filters used
for routine addition process of gases, media, acids, alkalis, defoaming agents etc.
to fermenters or reactors.

Article 48: Validated processed should be used for virus removal or

inactivation, and precautions should be implemented during the process to
prevent the recontamination of the treated products.

Article 49: For production by using pathogen materials of grade 2 contamination

83
levels or above, the effective in situ disinfecting facilities should be available for
its releasing contaminants and suspicious contaminants which can not be
removed from working areas until completely inactivation has been
accomplished.

Article 50: Equipment used for chromatography should be dedicated to the

purification of one product and should be sterilised or sanitized between batches.
The use of the same equipment at different stages of processing should be
discouraged. Acceptance criteria, life span and sanitation or sterilisation method
of columns should be defined. Storage and regeneration of chromatography
columns should be validated.

Article 51: Strict cleaning and sterilisation procedures should be established to

prevent from cross-contamination for apparatus and equipments used in
sampling, testing, or routine monitoring. Assessment should be performed for
them based on the risk level of production, when necessary, dedicated
apparatus or equipments should be used exclusively in special area.

Chapter 7 Quality Management

Article 52: Raw materials, original solution, intermediate products and finished
products should be tested strictly in accordance with Pharmacopoeia of The

84
People’s Republic of China or the quality specification approved by SFDA.

Article 53: Testing of intermediate products should be performed at an

appropriate stage of production. When the tests take a long time, it may be
permissible to carry onto next process before the results of the tests are
available. In such cases, release of a finished product is conditional on
satisfactory results of these tests.

Article 54: It may be necessary to retain samples of intermediate products in

sufficient quantities and under appropriate storage conditions to allow the
repetition or confirmation of a batch control.

Article 55: Continuous monitoring of certain production processes is

necessary, for example fermentation. Such data should form part of the batch
record.

Article 56: Where a continuous culture (e.g. microcarrier culture) is used, special
consideration should be given to the quality control requirements according to
the nature of the process method.

Chapter 8 Glossary

85
 Article 56: The following glossary meaning:
( )

1. Starting Material
All biological and chemical materials used in the manufacture of biological
products, excluding excipient.

( )

2. Excipient
Auxiliary materials used in the preparation of biological medicinal products,
e.g., adjuvants, stabilisers, excipients.

Annex 3 reviewed by Michael Lee, Zhao Chunhua

86
 4

Annex 4:

Blood Products

Chapter 1 Scope

Article 1: Blood products in this annex refer specifically to human plasma

protein products. The provisions of this annex apply to the production, quality

control, storage and transportation of blood products.

Article 2: The production processes of blood products mentioned in this

annex include receiving, storage, re-checking, and fractionation of plasma, the

preparation and testing of blood products, and storage of finished products.

“ ”

Article 3: The collection, testing, storage and transportation of plasma used

as source material of blood production should comply with “Procedure for

87
Plasma in Blood Products” listed in “Pharmacopoeia of the People’s Republic of

China” and the “Control Regulations for Plasmapheresis Centres” enacted by

Ministry of Health.

Article 4: The management of blood products should also consist with any

relevant regulations enacted by the State Council.

Chapter 2 Principle

HIV HBV HCV

Article 5: Plasma used as raw material may have certain blood borne

pathogens (e.g. HIV, HBV and HCV). The safety of these products therefore

relies on the strictly control of plasma used as material and its origin as well as

on the subsequent manufacturing procedures, including virus removal and

inactivation processes during which strict quality control on starting materials

and products should be implemented.

Chapter 3 Personnel

88
 Article 6: Legal representative and responsible person of manufacturers

should have professional knowledge of blood products, and have been well

trained with knowledge of relevant regulations.

Article 7: Persons who are responsible for production management should

have relevant professional knowledge such as microbiology, biology,

immunology and biochemistry etc; and have at least 3 years practical

experience in the production or quality management of blood product production.

Article 8: Persons who are responsible for quality management should have

relevant professional knowledge such as microbiology, biology, immunology and

biochemistry etc; and have at least 5 years practical experience in the

production or quality management of blood product production; and have been

engaged in activities relating quality assurance and quality control of blood

products.

89
 Article 9: Persons who are involved in the production, quality assurance and

quality control of blood products and all related personnel including those

concerned with cleaning or maintenance, should be given relevant information

and training in bio-safety containment, especially in knowledge of the prevention

of blood borne diseases.

Article 10: Vaccines which can prevent from blood borne diseases should be

inoculated for relevant persons who engage in the production, quality assurance

and quality control of blood products.

Chapter 4 Premises and Equipment

Article 11: The premises used for the production of blood products should be

an independent building that can not be shared with other products, and should

be equipped with dedicated facilities and equipments.

Article 12: The testing laboratory for plasma used as source materials and

90
blood products should comply with the “Regulations of Administration of

Pathogenic Microorganism Laboratories” enacted by State Council and National

Standards of the “General Requirements of Biosafety in Laboratory”

Article 13: The testing laboratory for source plasma should be set up

independently, equipped with dedicated testing equipments, in place inactivation

and disinfection equipments. The HVAC system should also be independent if

available.

Article 14: The bag opening, combination, separation, extraction and

pasteurization before sub-packing of material plasma should be performed in a

grade D clean area as a minimum.

Article 15: The areas for melting of plasma, separation of components and

production after inactivation of virus should be independent from each other,

equipped with dedicated equipments and separate HVAC system.

Article 16: In the production process of blood products, protective measures

91
should be taken against cross-contamination to products before and after their

inactivation. Dedicated and isolated premises and equipments as well as HAVC

system should be used for products which have been followed with viral

inactivation and/or removal procedures.

Chapter 5 Plasma Used As Source Materials

Article 17: The following items should be checked for each received batch of

plasma used as source materials:

1) The collection units of raw material plasma should be confirmed with the

legal plasma collecting stations approved by legal authorities.

2) Complete monitoring records of temperature during transportation, the

temperature should meet the relevant requirements.

3) Packaging of plasma bag should be in its integrity and with no damage.

4) Label information on plasma packaging should be completed , and at least

92
 including name of donor, donation code, blood type, reference number of

plasma, date of collection, weight of plasma and collection stations.

5) Testing of plasma should meet the relevant requirements and with test

reports.

Article 18: Each plasma should be retested and recorded after receiving by

the manufacture. The quality of plasma should be consistent with the relevant

requirements listed in Pharmacopoeia of the People’s Republic of China.

Unqualified plasma can not be used in production and should be destroyed

according to relevant regulations.

Article 19: Quarantine time of plasma used as source material should

comply with relevant regulations.

Article 20: Before put into production, the quality assessment should be

performed on each batch of incoming plasma used as source materials in order,

including :

1) The collection units of raw material plasma should be confirmed with the legal

plasma collecting stations approved by regulatory agencies.

93
2) The monitoring records temperature during transportation and storage are

complete, and the temperature condition meets the requirements. Deviations

of temperature during transportation and storage should be handled

according to the procedures and the relevant records for this should be

available.

3) Retesting should be conducted on each bag of the plasma by using qualified

invitro diagnostic reagents according to approved procedures and make sure

it comply with the requirements.

4) Storage time limit has been reached according to the requirement of

quarantine.

5) Package-broken plasma of off-retest plasma have been removed and

disposed in accordance with the relevant provisions.

Article 21: There must be a system in place which enables the path taken by

each donation to be tracked forward from donor of each donation of plasma, and

also track the plasma of each donor al least 3 months prior to the last donation of

94
plasma.

Article 22: A mutual information system between the plasma collecting

station and the manufactures should be set up so that they can inform each

other if the following events occur:

1) It is found that the plasma donor does not meet the relevant donor health

criteria;

2) A subsequent donation from a donor, who is previously found negative for

pathogeny, is found positive for any of the pathogeny.

3) Retesting of plasma used as source material does not meet the requirements.

4) It is found that testing for pathogens has not been carried out according to

procedures.

HAV HBV HCV

HIV -

- CJD vCJD

5) The plasma donor has developed an infectious disease caused by an agent

potentially transmissible by plasma-derived products (HAV/HBA/HCV and other

95
hepatitis viruses, HIV and other agents in the light of current knowledge) and

Creutzfeldt-Jakob disease (CJD or vCJD).

Article 23: Relevant procedures should be established and specify the

responding activities when any event stated in Article 22 occurs. Re-assessment

of quality risks for the blood products manufactured using relevant source

plasma and re-assessment of the batch record in production should be carried

out according to athogeny, inventory rating, quarantine, the nature of the

products and its production process. Recall the released finished products when

necessary.

HIV HBV HCV

Article 24: Where there are indications that a donation contributing to a

plasma pool was infected with HIV, HBV or HCV, the manufacture should be

stopped immediately, and the relevant components, intermediates, bulk products

and finished products using the same batch of plasma as source materials

should be disposed as well. It should recall all the released products if any and

report to the relevant pharmaceutical competent authorities.

96
 Article 25: Quality audit for the plasma collection station should be regularly

performed by Quality Management Department as least once every 6 months,

and relevant reports should be made.

Chapter 6 Production and Quality Control

Article 26: Validation and monitoring of the storage, temperature and

conditions during transportation of plasma used as source materials, protein of

plasma, intermediates and finished products should be carried out, and there

should be relevant records.

HIV HBV HCV

Article 27: In vitro diagnostic reagents used for marking specific pathogen

(e.g., HIV, HBV, HCV and Treponema pallidum) should be approved by SFDA

and qualified by National Institute for the control of Pharmaceutical and

Biological products. Their testing, stocking, storing, releasing and using should

be regarded and managed the same as starting materials.

97
 Article 28: After mixing, the plasma should be sampled and tested according

to Chinese Pharmacopoeia and comply with the relevant requirements. If the

test results does not meet the requirements, the mixed plasma should be

disposed and should not be use in the manufacturing process.

Article 29: Personnel engaged in the thawing, opening bags and pooling of

plasma should wear appropriate protective clothing, masks and gloves.

Article 30: Environment monitoring of opening bags and pooling of plasma

process should be carried out periodically. Microorganism Limit Test should be

used for mixed plasma in order to minimize the organism contamination during

the operation process.

Article 31: Methods for clearly distinguishing and marking between products

or intermediates undergone a process of virus removal or inactivation and those

without any treatments should be in place. Appropriate precautions should be

taken to prevent from mixing up.

Article 32: The manufacturing facilities and equipments should not be used

98
in the validation of virus removal and inactivation methods.

Article 33: The release of blood products should comply with the

requirements of “Regulations on Batch Release of Biological Products”.

Chapter 8 Handling of Rejected Plasma, Intermediates or Finished

Products

Article 34: SOPs for safely and effectively handling rejected plasma,

intermediates and finished products should be established, and the records

should be available.

Annex 4 reviewed by Michael Lee, Zhao Chunhua

99
 5

Annex 5 Chinese Medicine Preparations

Chapter 1 Scope

Article 1: This annex applies to the pretreatment of Traditional Chinese

Medicinal Materials (TCMMs), extraction of Traditional Chinese Medicines
(TCMs), and the production, quality control, storage and transportation of
Chinese Medicine Preparations (CMPs).

Refer to this annex for folk medicine, such as Tibetan, Miao Medicine, Mongolian,
etc.

Chapter 2 Principle

100
Article 2: The quality is closely related to quality and pretreatment of TCMMs
and the extraction process of TCMs. Therefore, the process should be strictly
controlled to prevent from the microorganism contamination and degeneration in
the process of pretreatment for TCMMs, and extraction and storage of TCMs.

GAP

Article 3: The source of TCMMs should be relatively stable. The purchasing

activities could be monitored when necessary. The origin of the TCMs used for
the parenteral production should be consistent with the declared origin in the
registration, and production should follow good manufacturing practices. (for
example, TCMs GAP, Good Agriculture Practice)

Article 4: New testing items for quality standards of CMPs can be added
appropriately based on the mandatory specifications to ensure the quality of the
products is in control.

Article 5: Measures for premises should be taken in accordance with

requirements of production process including sealing, ventilation, air exhaustion,
dust removal, dehumidification, air purification, etc.

Chapter3 Organization and Personnel

101
Article 6: There should be designated persons in Quality Management
Department to be responsible for the quality management of TCMMs.

Article 7: The persons who are responsible for the quality management of
TCMMs should at least have the following qualifications:

1.

1. They should have college degrees of TCM, pharmacognosy or related majors,

and at least have three years practical experience in TCM production and quality
management, or have practical experience in the identification of TCMMs for
more than eight years.

2.
2. The capability to identify real or fake and the quality of TCMMs.

3.

3. The practical capability to control the quality of TCMMs.

4.

4. Familiar with the requirements of management and handling of the toxic

TCMMs according to the production needs.

The person who are responsible for the quality management of TCMMs should
engage in the following working areas:

1.
1. To sample TCMMs;

2.

102
2. To identify and evaluate the quality of TCMMs, and propose whether the
TCMMs should be released.
3.

3. To train the operators how to handle TCMMs, including toxic TCMMs.

4.

4. To collect, prepare and manage the specimens of TCMMs.

Chapter 4 Premises and Facilities

Article 9: Effective measures should be taken for production steps of TCMMs

which are easy to generate dust, such as sampling, screening, weighing, milling,
and mixing, etc. to contain dust, and avoid contamination and
cross-contamination, including installation of dust-traps, ventilation facilities or
set up dedicated premises (operation room), etc.

Article 10: Picking benches should be set up in the pretreatment premises of

TCMMs, and their surface should be smooth, easy to clean and non-flakes off.

Article 11: Premises for extraction and concentration of TCMMs should be

consistent with process requirements, and be equipped with good ventilation
systems, and steam control, anti-contamination and anti cross-contamination

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measures, etc.

Article 12: The extraction, concentration and collecting cream process of

TCMMs should use closed system to prevent contamination. The production
environment could be in non clean area for closed system; and the
environmental control level at the open point should be consistent with the
cleanliness class of the compounding step in formulation.

Article 13: There should be dedicated facilities for temporary storing and
handling of residues from extraction step.

Article 14: The cleanliness class of operations such as preparation, comminution,

mixing, and sifting of exudates should be consistent with the cleanliness class of
the compounding step of formulation process. The premises for crushing, mixing
and screening of the directly used TCMMs should be a closed system. There
should have good ventilation, dust collection facilities and the person and
material flow, production operation should refer to the management of the
cleanrooms.

D
Article 15: For injection CMPs, the final purification process should be performed
at least in Grade D area.

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Article 16:CMPs for external use of non-traumatic surface and other particular
CMPs can be produced in non-clean premises, but must be controlled and
managed effectively.

Article 17: Specimens room of TCMs should be separated from the production
area.

Chapter 5 Material

Article 18: Each received TCMMs should be classified by their origin, harvest
time, part of collection, grade and shape (e.g. whole plants or cut-off plants),
packaging format, etc. and identified and managed by lot numbers.

Article 19: The packaging of the purchased TCMMs should be labeled with the
name, origin, time of harvesting (processing), specifications. The packaging of
the TCMMs and the extraction of TCMs should be labeled with name, batch
number, specification, produ tion time, manufacturer, etc. and the certificate
should be provided.

Article 20: The raw medicinal material storage and the clean material storage for
TCMMs should be separated; The storage condition should be in accordance
with the regulated quality standard. The fresh TCMMs should be stored in proper
storages (for example, the cold storage facilities)

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Article 21: Toxic and smelly TCMMs should be stored in dedicated
storages(cupboards).

Article 22: The storage area should have appropriate facilities and effective
measures to ensure that TCMMs, extracts of TCMs, and CMPs are stored with
required humidity, temperature or light protection; these conditions should be
provided and monitored.

Article 23: The stored TCMMs and prepared slices should be maintained
regularly. The storage area should be well aerated, and be equipped with
appropriate facilities or safe and effective measures to give protection against
the entry of insects, birds or rodents etc, and prevent the spread of any such
animals brought in with the TCMMs to prevent cross-contamination.

Article 24: The effective and reliable measures should be taken to prevent
against any quality changes of TCMMs, extracts of TCMs, and CMPs during
transportation.

Chapter 6 Document Management

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Article 25: The manufacturing procedures and other standard documents should
be established to effectively control the quality of products:
1.

1. Maintenance system for TCMMs should be established, and the operation

procedures should be established and classified.

2.

2. Production process and operating procedures for pretreatment of TCMMs,

extraction of TCMs, and CMPs should be established; and the parameters for
each critical production step must be clear, e.g. the standard feed amount, and
the requirements of extraction, concentration, refinement, drying, screening,
mixing and storage etc. The storage conditions and time limits should also be
clear and definite.
3.

3. The yield range of each extract of TCMMs should be established and

implemented according to factors such as the quality of TCMMs and charging
rate;

4.

4. The quality standards and testing methods for each pretreated TCMMs,
extracts of TCMs, and CMPs should be established. Where necessary, the
quality standards and testing methods for intermediate products of CMPs should
also be established.

Article 26: The situation of production management, production hygiene

management and quality management of the process from pretreatment to

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extraction should be recorded.

1.

1. The batch numbers and the quantity for each batch of TCMMs used in mix
charging should be recorded.

2.
2. The operation records for production of extracts of TCMs should include the
extraction, concentration, collection of exudates, purification, etc;

(1)
(1) Records for material name, batch number, quantity of charging and charging
monitoring.

(2)

(2) Records for equipment numbering, related solvents, time of dipping, time of
heating-up, time of extraction and recycling of solvent.

(3)
(3) Records for concentration and drying process, including concentration
equipment number, concentration temperature, drying time and the extraction
quantity of drying exudates;

(4)
(4) Records of refine process, including equipment number, solution usage,
refine conditions, recovery rate, etc.

(5)
(5) Operation records for other production process.

(6)
(6) Records of TCMMs residue treatment.

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 Chapter 7 Production Management

Article 27: TCMMs should be selected, sorted, sheared, washed, dipped or

carried out by required process before use; the unprocessed materials should
not be directly used for the extraction.

The TCMMs used for TCMs injection should be the raw TCMMs, and being
processed by the manufacturer.

Article 29: The TCMMs used fresh should be charged within a defined period.
Appropriate measures should be taken to store the fresh used TCMMs. The
storage condition and time limit should be regulated and validated to ensure
there is no adverse affect on the product quality and the intended use.

The following measures should be taken during the production process to

prevent from the microorganism contamination:
1.

1. The treated TCMMs should not directly contact with the floor and should not
be dried in the open air.

2.

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2. The selected TCMMs should be washed by flowing water. The used water
should not be used for washing other TCMMs. Different TCMMs should not be
washed in the same container simultaneously;

Article 31: Provisions for the operation of toxic TCMMs should be made to avoid
contamination and cross-contamination.
.

Article 32 The quality of process water used for washing, dipping and extracting
of TCMMs should not less than the portable water standard. The water used for
extraction of sterile Chinese Medicine preparations should be the purified water.

Article 33: There should be an approved method for solvent recovery. The reuse
of recycled solvent should not cause any cross-contamination to products, and
should not affect on the quality and safety of products.

Chapter 8 Quality Management

Article 34: The quality of TCMMs should meet the national standards of
pharmaceutical products and the provincial (autonomous regions’ and

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municipalities’) processing specifications. Under the existing technical
conditions the necessary quality control items should be added to related
standards according to their impact on TCMMs.

Article 35: When using organic solvents during TCMMs extraction, refining
process and the solvent could have adverse affect on product quality and safety,
the limits of residual solvents should be added in quality standard of TCMMs
extracts and CMPs.

Article 36 The items of quality control for TCMMs should at least include:

1.
1. Identification;

2.
2. The qualitative and quantitative indicators of related ingredients in TCMMs;

3.

3. The granularity measurement of crushed pharmacognostic products;

4.

4. The test of microbial limits for the powder of TCMMs used directly for mixing
should be done before the process starting;
5.

5. The raw medicinal material testing should be added to the outsourced

Traditional Chinese Herbal Pieces;
6.

6. Other necessary testing items.

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Article 37: The quality standards for recycled solvent should be established
and be appropriate with their intended purpose.

Article 38: The specimens of TCMMs used for production should be established
by manufacturers, e.g. the original plants (animals, minerals), used parts, treated
materials, approved substitutes and counterfeits, etc.

Article 39: The time-limit on the storage of each adopted TCMMs should be set
down according to their characteristics and the storage conditions. They should
be reviewed regularly.

Article 40: Stability research for TCMMs and intermediate products should be
carried out according to their characteristics and packaging containers in order
to determine the storage conditions and time limit.

Article 41: Samples for each batch of TCMMs should be retained. The amount of
the reserved samples should at least satisfy the needs of identification.
Reserved samples should be kept for one year after the expiration date of
corresponding preparations.

Article 42 The maintenance and operation records of the TCMMs should be kept
during its storage period.

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 Chapter 9 Contract Manufacturing

Article 43: The following requirements about contract manufacturing for the
pretreatment of
TCMMs:

1.

1. The source and quality of TCMMs should be validated by contract giver

before commission.

2.

2. The quality testing standards for the handover of contract manufacturing

products should be established, and tested by the contract consignor;

3.

3. Before product release, the testing reports of TCMMs should be consulted in

order to validate the quality.

Article 44: Attention should be paid on the following aspects for contract
extraction of TCMs, and should be confirmed in the contract manufacturing
agreement:

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 1.

1. The quality standards of TCMMs;

2.

2. The quality standards for the extract of TCMs;

3.

3. The yield range of extracts;

4.

4. The packaging containers, storage conditions and storage time limit of

extracts;

5.

5. The transportation of extracts:

(1)

(1) The material and specification of packaging containers used for

transportation of extracts;

(2)

(2) Measures for preventing quality change during transportation;

6.

6. Handover of the extracts:

(1)

(1) The handover records for each batch of extracts;

(2)

(2) The contract manufacturer should provide the production records for each
batch of extracts to the contract consignor.

Chapter 10 Glossary

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 1.

1. Raw Medicinal Material

Traditional Chinese Medicinal Materials which have not been pretreated and
processed.

Annex 5 reviewed by Zhao Chunhua

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