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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

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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.

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A

0.36-0.54m/s

B A

C D

/

(3)

0.5 m 5.0 m(2) 0.5 m 5.0 m

A (1) 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

At rest In operation (3) Grade

0.5 m 5.0 m(2) 0.5 m 5.0 m

A (1) 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

2

5.0 m

8

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.

A

A

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 m

(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.

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(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:

cfu/m3 90mm

cfu /4 (2) 55mm cfu /

5 cfu /

A 1 1 1 1

B 10 5 5 5

C 100 50 25

D 200 100 50

1

Surface microbiological

Grade air sample bacteria

cfu/m3

settle plates bacteria

90mm cfu /4hours(2)

contact plates55mm cfu /plate

Glove print 5 fingers cfu /glove

A 1 1 1 1

B 10 5 5 5

C 100 50 25 D 200 100 50

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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

A (1)

C

1. 2. (2) 3.

4.

D

1. 2. 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 with aGrade C background

Filling (or sealing)of products, when risk of contamination is high(1)

Grade C 1. Filling (or sealing) of products; 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

Grade D

1. Capping; 2.Material preparation before filling; 3.Preparation and filtration of products(concentration or dilution in a closed system) and ,final washing of primary packaging material tools a which directly contact with medicinal products.

1

2

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.

BA

1. (1)(2)

2. 3.

4.

B 1.(1)

2

C 1. 2. D

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1

2

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.

Classification

Examples of operations for aseptic preparations

Grade A environment

with a Grade B background

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.

2. Preparation of solutions or products which are not able to go through sterile-filtration before filling;

3. Assembling of sterilised primary packaging materials and 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.

Grade B

1. Transfer of partially sealed products in fully sealed containers. 2. Transfer and storage of sterized primary packaging materials and

apparatus , which will direct contact with medicinal products. in sealed containers

Grade C 1. Preparation of solutions or products which could be sterile filtered

before filling. 2. Filtration of products.

Grade D Final washing, assembling or packaging, and sterilisation of primary packaging materials and apparatus which will directly contact with medicinal products.

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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

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:

D

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.

C

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 clothings cleaning and sterilisation are desirable.

Scott Wheelwright

Scott Wheelwright

Scott Wheelwright

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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

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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.

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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

scottw

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

3

1

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.

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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

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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.

scottw

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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.

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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.

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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

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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 manufacturers 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

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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.

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(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

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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 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

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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 and registered authorisation

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(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

37

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.

38

(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.

39

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

40

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.

41

(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

42

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

43

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

D

44

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.

45

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.

46

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.

47

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 companys control do not need to be tested if the manufacturers 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).

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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.

49

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

50

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.

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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

52

residue or contaminant. The methods 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:

53

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

54

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.

55

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

56

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 products 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.

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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:

58

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

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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

60

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

61

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.

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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

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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.

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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

65

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.

66

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.

67

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.

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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

69

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

70

3

Annex 3:

BIOLOGICAL MEDICINAL

Table of content

3

................................................................................................... 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

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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.

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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.

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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.