[2.1] PART 2 SECTION 1-5

SECTION 1.

PERSONNEL

SECTION 1. PERSONNEL

• There shall be an adequate number of personnel at all levels having __

knowledge, skills and capabilities relevant to their assigned functions, in good mental and physical health to be able to execute their duties.

1.1

ORGANIZATION, QUALIFICATION AND RESPONSIBILITIES

1.1.1 The organizational structure of the company shall be such that the production and the quality assurance are headed by __, neither of whom shall be responsible to the other. Each shall be given full authority and facilities necessary to execute his/her duties effectively. Neither shall have any interests outside the manufacturer’s organization that prevent or restrict their dedication to the assigned responsibilities or which may be considered to entail a conflict of interest.

different managers

1.1.1 The organizational structure of the company shall be such that the production and the quality assurance are headed by different managers, neither of whom shall be responsible to the other. Each shall be __. Neither shall have any interests outside the manufacturer’s organization that prevent or restrict their dedication to the assigned responsibilities or which may be considered to entail a conflict of interest.

given full authority and facilities necessary to execute his/her duties effectively

1.1.2 The production manager shall be a __. He/she shall be adequately trained and shall posses good practical experience in the field of pharmaceutical manufacture and managerial skill, which enable him/her to perform his/her function effectively. The production manager shall have full authority and responsibility to manage production of drug products.

PRC registered qualified pharmacist or any other related profession (chemist, industrial/mechanical engineer)

1.1.2 The production manager shall be a PRC registered qualified pharmacist or any other related profession (chemist, industrial/mechanical engineer. He/she shall be __, which enable him/her to perform his/her function effectively. The production manager shall have full authority and responsibility to manage production of drug products.

adequately trained and shall posses good practical experience in the field of pharmaceutical manufacture and managerial skill

The production manager shall have full

authority and responsibility to manage production of drug products.

1.1.3 The quality control manager shall be a PRC registered qualified pharmacist or any other related profession. He/she shall __ that will enable him/her to perform his/her function effectively. The quality assurance manager shall have full authority and responsibility in all quality control processes such as establishment, verification and implementation of all quality control procedures. He/she shall have the sole authority to approve starting materials, intermediates, bulk and finished products that meet the specification or to reject those which do not conform to the relevant specification or which are not manufactured in accordance with the approved procedures.

have adequate training and practical experience

The quality assurance manager shall have full authority and responsibility in __.

all quality control processes such as establishment, verification and implementation of all quality control procedures

the quality control manager shall have the sole authority to

Approve starting materials, intermediates, bulk and finished products that meet the specification or to reject those which do not conform to the relevant specification or which are not manufactured in accordance with the approved procedures

1.1.4 The quality assurance manager shall clearly __

define the field of work and the method of delegating responsibilities in his/her absence.

1.1.5 The quality assurance manager shall have personal and professional responsibility for __. The details of this work may be delegated to an appropriately trained and experienced staff who would endorse their work. Finally, the quality assurance manager has to be satisfied directly by the proper operation of quality systems that include appropriate approvals, audits, self-inspections and spot checks that the production and testing have complied with relevant requirements.

ensuring that various checks and tests have been carried out

Finally, the quality assurance manager has to be __

satisfied directly by the proper operation of quality systems that include appropriate approvals, audits, self-inspections and spot checks that the production and testing have complied with relevant requirements.

1.1.6 The production manager and the quality assurance manager are

jointly responsible to establish for the quality, strength, purity and efficacy of the finished products.

1.1.7 To support and assist the key personnel, an adequate number of qualified personnel should be

available in the production and quality assurance. Each personnel shall be adequately trained with their respective assignment

1.1.8 The duties and responsibilities of all employees shall be

clearly defined, well understood and shall be within his/her capacity to perform to ensure quality products.

1.2.1 All employees who are directly and indirectly engaged in the manufacturing activities shall be _

trained in the particular operations that the employees perform in accordance with the principles of Current Good Manufacturing Practice

1.2.2 Training shall be conducted by _. Special attention shall be given to training of personnel working in sterile and clean areas or with highly potent, toxic or sensitizing materials.

qualified individuals

Special attention shall be given to training of personnel working in

sterile and clean areas or with highly potent, toxic or sensitizing materials.

1.2.3 Training in Current Good Manufacturing Practice shall be on a

continuing basis and with adequate frequency to assure that employees remain familiar with the Current Good Manufacturing Practice requirements relevant to their functions

1.2.4 Training in Current Good Manufacturing Practice shall be in accordance with

written program approved by the production manager and the quality assurance manager.

1.2.5 Records of personnel training in Current Good Manufacturing Practice shall be

maintained and the effectiveness of training programs shall be assessed periodically.

1.2.6 After training, the consequential employees’ performance shall be

appraised to determine their capability to meet the qualification requirement for the jobs.

SECTION 2.

PREMISES

SECTION 2. PREMISES

The premises for manufacturing shall be of __.The individual working areas shall be adequate so that any risk of confusion, cross-contamination and other mistakes that will adversely affect the quality of drugs and devices will be avoided.

suitable size, design, construction and location to facilitate proper operation, cleaning and maintenance.

The individual working areas shall be adequate so that __

any risk of confusion, cross-contamination and other mistakes that will adversely affect the quality of drugs and devices will be avoided.

2.1.1 Premises shall be so located and protected _

against contamination from the environment.

2.1.2 Premises shall be constructed and maintained to_

protect against weather, flood, ground and the access and harboring of vermin, rodents, birds, insects or other animals.

2.1.3 In determining the design and lay-out of premises, consideration should be paid to:

• the compatibility of other manufacturing operations that may be carried out in the same or adjacent premises

• allow the production to take place in areas connected in a logical order according to the sequence of the operations and to the requisite cleanliness levels

• the adequacy of the working space, which shall allow orderly and logical placement of equipment and materials to suit the operation, efficient flow of work, effective communication and supervision to avoid crowding and disorder

• avoid the use of production areas as a general traffic for personnel or materials or for storage other than the materials in process

2.1.3.1 In determining the design and lay-out of premises, consideration should be paid to:

• the compatibility of other manufacturing operations that may be _

carried out in the same or adjacent premises

2.1.3.2 In determining the design and lay-out of premises, consideration should be paid to:

• allow the production to take place in areas __

connected in a logical order according to the sequence of the operations and to the requisite cleanliness levels

2.1.3.3 In determining the design and lay-out of premises, consideration should be paid to:

• the adequacy of the working space, which shall allow

orderly and logical placement of equipment and materials to suit the operation, efficient flow of work, effective communication and supervision to avoid crowding and disorder

2.1.3.4 In determining the design and lay-out of premises, consideration should be paid to:

• avoid the use of production areas as a _

general traffic for personnel or materials or for storage other than the materials in process

2.1.4 The layout of rooms, corridors, and spaces shall provide for __ for operations to be carried out in defined areas and to avoid cross contamination.

logical movements of materials and personnel with minimal (one-way) traffic

2.1.4 The layout of rooms, corridors, and spaces shall provide for logical movements of materials and personnel with minimal (one-way) traffic for operations to be carried out in defined areas and to avoid cross contamination. The design and layout of premises shall fulfill the following requirements:

• the risk of mix-up between different drugs or their components, the possibility of cross-contamination by other drugs or substances and the risk of

• penicillins shall be produced only in separate buildings, with separate air handling facilities dedicated to these products using dedicated equipment, including dedicated packaging lines.

• cephalosporins shall be produced in separate buildings, with separate air handling facilities dedicated to these products using dedicated equipment, including dedicated packaging lines

2.1.4.1 The design and layout of premises shall fulfill the following requirements:

• the risk of mix-up between _

• different drugs or their components, the possibility of cross-contamination by other drugs or substances and the risk of

2.1.4.2 penicillins shall be produced only in separate buildings,

with separate air handling facilities dedicated to these products using dedicated equipment, including dedicated packaging lines.

2.1.4.3 cephalosporins _

shall be produced in separate buildings, with separate air handling facilities dedicated to these products using dedicated equipment, including dedicated packaging lines

2.1.4.4 cross contamination of products by live biologicals, or by drug products, such as certain steroids or cytotoxic agents which in trace amounts may produce physiological effects should be prevented by the following methods:

• carrying out production operations in separate buildings or adequately isolating the operations by total enclosure or by making successive batches in the same or in dedicated equipment followed by validated cleaning procedures and where appropriate, fumigation

• controlling airborne contaminants by the use of an appropriate air pressure differential in processing areas and adequate exhaust systems and filters, together with control of recirculated air

• the setting and shielding of production equipment, and wherever possible, the use of equipment solely for one type of drug/product;

• containment of contaminant-transfer by means of airlocks, clothing change and decontamination of containers and other articles prior to their removal from the isolated area

• separate cleaning area for contaminated  clothing

• periodic testing of the environment around the production areas for the presence of the therapeutic substance being processed

• validation of cleaning procedures.

2.1.4.4.1 cross contamination of products by live biologicals, or by drug products, such as certain steroids or cytotoxic agents which in trace amounts may produce physiological effects should be prevented by the following methods:

• carrying out production operations in separate buildings or adequately isolating the operations by

• total enclosure or by making successive batches in the same or in dedicated equipment followed by validated cleaning procedures and where appropriate, fumigation

2.1.4.4.2 cross contamination of products by live biologicals, or by drug products, such as certain steroids or cytotoxic agents which in trace amounts may produce physiological effects should be prevented by the following methods:

• controlling airborne contaminants by

• the use of an appropriate air pressure differential in processing areas and adequate exhaust systems and filters, together with control of recirculated air

2.1.4.4.3 cross contamination of products by live biologicals, or by drug products, such as certain steroids or cytotoxic agents which in trace amounts may produce physiological effects should be prevented by the following methods:

• the setting and shielding of production equipment, and wherever possible,

the use of equipment solely for one type of drug/product

2.1.4.4.4 cross contamination of products by live biologicals, or by drug products, such as certain steroids or cytotoxic agents which in trace amounts may produce physiological effects should be prevented by the following methods:

• containment of contaminant-transfer by means of

• airlocks, clothing change and decontamination of containers and other articles prior to their removal from the isolated area

2.1.4.4.5 cross contamination of products by live biologicals, or by drug products, such as certain steroids or cytotoxic agents which in trace amounts may produce physiological effects should be prevented by the following methods:

• separate cleaning area for

contaminated clothing

2.1.4.4.6 cross contamination of products by live biologicals, or by drug products, such as certain steroids or cytotoxic agents which in trace amounts may produce physiological effects should be prevented by the following methods:

• periodic testing of the __

• environment around the production areas for the presence of the therapeutic substance being processed

2.1.4.4.7 cross contamination of products by live biologicals, or by drug products, such as certain steroids or cytotoxic agents which in trace amounts may produce physiological effects should be prevented by the following methods:

• validation of

cleaning procedures

2.1.5 In all manufacturing rooms (processing and packaging), air supply and air exhaust points shall not be so close or so disposed as to__. The airflow pattern within the facility and each manufacturing area and the throughput rate of air shall be selected to afford adequate protection to the products and personnel.

restrict or negate the supply of clean air to worksites and or movement of product dust or other contaminants away from worksites

2.1.5 In all manufacturing rooms (processing and packaging), air supply and air exhaust points shall not be so close or so disposed as to restrict or negate the supply of clean air to worksites and or movement of product dust or other contaminants away from worksites. The airflow pattern within the facility and each manufacturing area and the throughput rate of air shall be

selected to afford adequate protection to the products and personnel.

2.1.5 A plan of the building(s) showing air handling facilities including _

key air handling equipment and showing air quality standards, flow rates, proportions re-circulated and relative air pressures shall be made available for inspection

2.1.6 Air handling facilities for the production of cytotoxins shall be appropriate. The anteroom should _

operate at a positive pressure relative to the processing area but negative or lower pressure relative to the outside or adjacent room

2.1.7 The processing of materials for drug products shall be separated from the

production of non-drug products.

2.1.8 separate space for

• cleaning mobile equipment

• storage of cleaning materials

2.1.9 Locker/gowning room shall be directly connected to

but separated from processing areas

2.1.10 Toilets

should not be opened directly to production areas and shall have adequate supply of water and ventilation.

2.1.11 Experimental animals

shall be housed in a separate building. [Refer to Annex on Biological Products for further details on Animal Quarantine and Care]

2.1.12 Defined areas for the following operations are required:

• gowning/change rooms for all personnel

• receiving of starting materials

• incoming goods quarantine

• sampling room for sampling of deliveries of starting materials

• storage for approved materials (chemical and packaging)

• storage of reject materials

• laboratories

• weighing/dispensing of materials

• processing operations

• equipment washing

• storage of cleaned, idle/non-functional equipment

• major repair and maintenance activities

• storage of cleaning tools and supplies

• staging/storage of bulk products

• packaging/ labelling operations

• quarantine storage for finished products

• storage for approved finished products

• distribution center

• cafeteria

• process water treatment

2.1.13 Interior surfaces (walls, floors and ceilings) shall be .

• smooth, free from cracks and open joints,

• shall not retain or shed particulate matter

• shall permit easy cleaning and disinfecting

2.1.13 The floor in processing areas shall be made of

impervious materials, laid to an even surface, shall allow prompt and efficient removal of any spillage.

2.1.13 Walls shall be of

impervious and washable surface.

2.1.13 The coving of junctions between walls, floors and ceilings in critical areas

is necessary.

2.1.14 Drains shall be of adequate size with trapped gullies. Open channels shall be

avoided where possible, but if required, they shall be shallow enough to facilitate cleaning and disinfecting.

2.1.15 Air intakes and exhausts, and associated pipework and ducting shall be installed in a way that

will avoid product contamination

2.1.16 Production areas shall be

effectively lit and ventilated with air control facilities (including temperature, humidity and filtration), appropriate both to the products handled, to the operation undertaken within them and to the external environment. [refer to section 2.1.5, 2.1.6]

2.1.17 Pipework, light fittings, ventilation points and other services in production areas shall be installed in a way that

will have cleanable recesses and preferably located outside the processing areas.

2.1.18 Avoid having exposed

overhead roof joints, pipes and ducts.

2.1.19 Electrical power supply

shall be adequate to ensure the proper functioning of production equipment and laboratory instruments

2.1.20 The condition of buildings shall be

reviewed regularly, and repaired where necessary.

2.1.20 Special care shall be exercised to

ensure that building repair or maintenance operations do not adversely affect products.

2.1.21 Storage areas shall be of

adequate space, provided with suitable lighting, arranged and equipped to allow dry, clean and orderly placement of stored materials and products

2.1.21.2 Storage areas shall be laid-out to permit

effective and orderly segregation of the various categories of materials stored to allow FIFO system

2.1.21.3 Segregated storage shall be provided for

rejected, recalled or returned goods.

2.1.21.4 Storage arrangements shall permit

separation of different labels, as well as other printed materials to avoid mix-up

2.1.21.5 Materials require special storage conditions such as temperature and/or humidity controls. These conditions should be

monitored and records of the monitoring retained.

2.1.22 Doors that lead from production areas directly to the outside, e.g. fire exits, shall be

secured against contamination.

SECTION 3.

EQUIPMENT

SECTION 3. EQUIPMENT

• Equipment used in the manufacturing of drug products shall be of

• appropriate design and construction, adequate size and suitably located in order to assure product quality and process reproducibility and to facilitate its cleaning and maintenance.

3.1 DESIGN AND CONSTRUCTION

The design and construction of equipment shall fulfill the following requirements:

• the equipment surfaces coming in contact with any raw material, intermediate, bulk or finished product shall not be reactive, additive or  absorptive so as to alter safety, strength, identity, quality or purity of the drug beyond the established limits

• equipment shall not adversely affect the product through leaking valves, lubricant drips, inappropriate repairs, maintenance, modifications or adaptations

• materials required for specific operations, such as lubricants or coolants shall not come into contact with any in-process materials as to alter the strength, safety, identity, quality, or purity of raw material, intermediate, bulk or the finished product beyond the established limits

• equipment shall be easily and conveniently cleanable

• all equipment designated for use with flammable substances or chemicals shall be explosion proof

• equipment employed for weighing, measuring, testing and recording shall be regularly checked for accuracy and calibrated according to an appropriate program and procedure; and records shall be maintained. Calibration conducted shall be traceable to a primary standard of calibration of an appropriate national government agency and other reliable agency. Records of calibration shall be provided and maintained

• filters for liquid filtration used in the processing of products shall not release fibers or substances into such products.

The design and construction of equipment shall fulfill the following requirements:

the equipment surfaces coming in contact with any raw material, intermediate, bulk or finished product

shall not be reactive, additive or  absorptive so as to alter safety, strength, identity, quality or purity of the drug beyond the established limits

The design and construction of equipment shall fulfill the following requirements:

equipment shall not adversely affect the product through

leaking valves, lubricant drips, inappropriate repairs, maintenance, modifications or adaptations

The design and construction of equipment shall fulfill the following requirements:

materials required for specific operations, such as lubricants or coolants

shall not come into contact with any in-process materials as to alter the strength, safety, identity, quality, or purity of raw material, intermediate, bulk or the finished product beyond the established limits

The design and construction of equipment shall fulfill the following requirements:

equipment shall be easily and

conveniently cleanable

The design and construction of equipment shall fulfill the following requirements:

all equipment designated for use with flammable substances or chemicals

shall be explosion proof

The design and construction of equipment shall fulfill the following requirements:

equipment employed for weighing, measuring, testing and recording.

shall be regularly checked for accuracy and calibrated according to an appropriate program and procedure; and records shall be maintained

Calibration conducted shall be traceable to a

primary standard of calibration of an appropriate national government agency and other reliable agency. Records of calibration shall be provided and maintained

The design and construction of equipment shall fulfill the following requirements:

filters for liquid filtration used in the processing of products

shall not release fibers or substances into such products.

3.2.1 Equipment shall be suitably installed and located to

eliminate cross- contamination

3.2.2 Equipment shall be located at a

sufficient distance from other equipment to avoid congestion and to ensure that products do not become admixed or confused with one another.

3.2.3 All open mechanical belts and pulleys shall be .

equipped with safety guards

3.2.3 Water, steam and pressure or vacuum lines shall be installed so as to be

easily accessible during all phases of operation. These shall be adequately labeled and marked to be easily recognized.

3.2.4 Each piece of equipment shall be clearly marked with an identifying number.

This number will be used on all batch directions to designate the particular unit or apparatus used in that specific batch.

3.2.5 All pipes, tanks, jackets for steam or coolant

shall be properly insulated to prevent possible injury and to minimize energy loss

3.2.6 Piping to equipment designated for use with the pressurized steam

shall be properly trapped and drained.

3.2.7 Heating, ventilation, air conditioning, potable water, purified water, distilled water, clean steam, compressed air, gases and other support systems

must undergo validation.

3.3.1 Equipment shall be subjected to regular maintenance checks at appropriate intervals to

prevent malfunctions or contamination that can alter the strength, safety, identity, quality, or purity of the product beyond established limits.

3.3.2 Written procedures shall be established and followed for maintenance of equipment. The preventive maintenance program shall be structured to assure:

• all equipment requiring preventive maintenance is  identified

• the preventive maintenance schedule allocates priorities for maintenance

• the frequency for preventive maintenance for each equipment is identified

• the maintenance records are kept

• that a preventive maintenance activity for critical pieces of equipment exceeds the scheduled time interval for that activity, quality assurance is advised of the deviation in the maintenance schedule.

3.3.3 A written record of major equipment maintenance and use shall be included in

individual equipment logs which also identifies the date, time, product, strength and batch or lot number of each batch processed.

For equipment used solely for one product the record can be included in the .

production batch records

3.3.4 A comprehensive program shall cover equipment calibration.

Records shall be maintained and to highlight trends and/or exceptional reports