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NATIONAL AGENCY FOR FOOD AND DRUG ADMINISTRATION AND CONTROL (NAFDAC) GUIDELINES FOR THE ESTABLISHMENT OF PHARMACEUTICAL PLANTS IN NIGERIA

January 2010

Table of Contents

Part 1 General
Part 2 Organization and Personnel
Part 3 Building and Facilities
Part 4 Water Supply
Part 5 Equipment
Part 6 Material Management
Part 7 Standard Operating Procedure (SOP)
Part 8 Change Control
Part 9 Packaging and Labelling Control
Part 10 Storage and Distribution
Part 11 Quality Control
Part 12 Records and Reports
Part 13 Returned and Recovered Medicinal Products
Part 14 Contract Manufacture
Part 15 Complaints and Recall
Part 16 Self Inspections
Part 17 Penalty
Appendix A Interpretations
Appendix B List of Abbreviations
Appendix C List of References

NATIONAL AGENCY FOR FOOD AND DRUG ADMINISTRATION AND CONTROL ACT 1993 (AS AMENDED)

GUIDELINES FOR THE ESTABLISHMENT OF PHARMACEUTICAL PLANTS IN NIGERIA

1.0 GENERAL PRINCIPLES

1.1 These guidelines are for the general public and in particular industries that want to engage in pharmaceutical manufacturing

1.2 The guidelines also prescribe the minimum good manufacturing practice requirements for the facilities, controls to be used in the manufacture, processing and packing of products for human or animal use, to ensure that such medicinal products meet the requirements for safety, identity, strength, quality and purity characteristics.

1.3 It is necessary to emphasize that no medicinal product should be manufactured, imported, exported, advertised, sold or distributed in Nigeria unless it has been registered in accordance with the provisions of Decree 19 of 1993 (as amended) and the accompanying guidelines.

1.4 The holder of a manufacturing authorisation must manufacture medicinal products so as to ensure that they are fit for their intended use, comply with the NAFDAC requirements of the Marketing Authorisation and do not place patients at risk due to inadequate safety, quality or efficacy. The attainment of this quality objective is the responsibility of senior management and requires the participation and commitment by staff in many different departments and at all levels within the company, by the company’s suppliers and by the distributors. To achieve the quality objective reliably there must be a comprehensively designed and correctly implemented system of Quality Assurance Incorporating Good Manufacturing Practice, and thus Quality Control and Quality Risk Management. It should be fully documented and its effectiveness monitored. All parts of the Quality Assurance systems should be adequately resourced with competent personnel, and suitable and sufficient premises, equipment and facilities. There are additional legal responsibilities for the holder of the manufacturing authorisation and for the authorised person(s).

1.5 Quality Assurance is a wide-ranging concept, which covers all matters, which individually or collectively influence the quality of a product. It is the sum total of the organised arrangements made with the objective of ensuring that medicinal products are of the quality required for their intended use. Quality Assurance therefore incorporates Good Manufacturing Practice plus other factors outside the
scope of this Guide.

1.6 Good Manufacturing Practice is that part of Quality Assurance which ensures that Medicinal products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the marketing authorisation or product specification. Good Manufacturing Practice is concerned with both production and quality control. The basic requirements of GMP are that:

i. all manufacturing processes are clearly defined, systematically reviewed in the light of experience and shown to be capable of consistently manufacturing medicinal products of the required quality and complying with their specifications;
ii. critical steps of manufacturing processes and significant changes to the process are validated;
iii. all necessary facilities for GMP are provided.

2.0 ORGANIZATION AND PERSONNEL

2.1 The manufacturer should have an adequate number of personnel with the necessary qualifications and practical experience. The responsibilities placed on any one individual should not be so extensive as to present any risk to quality. The manufacturer must have an organisation chart. People in responsible positions should have specific duties recorded in written job descriptions and adequate authority to carry out their responsibilities. Their duties may be delegated to designated deputies of a satisfactory qualification level. There should be no gaps or unexplained overlaps in the responsibilities of those personnel concerned with the application of Good Manufacturing Practice.

2.2 There should be an adequate organizational structure that clearly defines:
a) Responsibility / duty
b) Authority
c) Interrelationships
d) Qualification of all personnel.

2.3 There should be an adequate number of qualified personnel to perform and supervise the manufacture, processing, and packing of medicinal products.

2.4 Each key personnel engaged in the manufacture, processing and packing of a medicinal product should have the following to perform the assigned functions:
a) Adequate education
b) Experience as appropriate
c) Training

2.5 a) There should be adequate training for employees in the particular operations that they perform and also in current good manufacturing practice as appropriate.
b) Training should be conducted by qualified individuals on a continuing basis.
c) Training in current good manufacturing practice should be in sufficient frequency to assure that employees remain familiar with current good manufacturing practice requirements applicable to them.

2.6 Clean protective apparel, such as head, face, hand, and arm coverings should be worn as necessary to protect medicinal products from contamination.

2.7 Personnel should practice good sanitation and health habits.

2.8 Only employees authorized by supervisory personnel should enter those areas of the buildings and facilities designated as limited-access areas.

2.9 All personnel should have access to medical treatment and checks for communicable diseases and the records should be kept.

2.10 Any person shown at any time to have apparent illness or open lesions that may adversely affect the safety or quality of medicinal products should be excluded from direct contact with components, medicinal product containers, closures, in-process materials and medicinal products until the condition is corrected.

2.11 All personnel should be instructed to report to supervisory personnel any health conditions that may have adverse effect on medicinal products

2.12 Personnel should be instructed to use hand-washing facilities.

2.13 Personnel working in areas where contamination is a hazard, e.g clean areas or areas where highly active, toxic, infectious or sensitizing materials are handled,
should be given specific training.

2.14 The quality control and production units should be distinct organizational units that function and report to management independently of all other functional units.

2.15 Consultants advising on any form of manufacturing process should have sufficient education, training, and experience to advise on the subject for which they are retained.

2.16 Records should be maintained stating the name, address, and qualifications of any consultant and the type of service they provide.

2.17 Eating, drinking, chewing or smoking, or the storage of food, drink, smoking materials or personnel medication in the production and storage areas should be prohibited.

2.18 Any unhygienic practice within the manufacturing areas or in any other area where the product might be adversely affected should be forbidden.

2.19 Direct contact should be avoided between the operator’s hands and the exposed medicinal product or material as well as with any part of the equipment that comes in contact with the medicinal product.

3.0 BUILDINGS AND FACILITIES

3.1 Building(s) used in the manufacture, processing and packing of medicinal product should be:
a) Adequately located
b) Adequately constructed
c) Of suitable size to facilitate cleaning, maintenance, and proper operations as appropriate to the type and stage of manufacture.

3.2 The building should have adequate space for the orderly placement of equipment and materials to prevent mix-ups between different materials or medicinal products and to prevent contamination.

3.3 The building should be designed to maintain orderly flow of personnel, materials, and medicinal products to prevent contamination.

3.4 There should be defined areas of adequate size or other controlled systems to
prevent contamination or mix-ups for the following:

a) Receipt (Receiving Bay), identification, sampling, storage, and quarantine of materials, medicinal product containers, closures, and labels pending the appropriate sampling, testing, or examination by the quality control unit before release for manufacturing or packaging;

b) Holding rejected materials, medicinal product containers, closures, and labels before disposition (example return, reprocessing or destruction);

c) Storage of released materials, medicinal product containers, closures, and labels;

d) Storage of in-process materials;

e) Manufacturing and processing operations;

f) Packaging and labeling operations;

g) Quarantine storage before release or rejection of medicinal products;

h) Storage of medicinal products after release;

i) Control and laboratory operations

j) Aseptic processing, which includes as appropriate:

i. Floors, walls and ceilings of smooth, hard surfaces that can be easily cleaned and disinfected or sterilized routinely

ii. Temperature and humidity controls

iii. An air supply filtered through high-efficiency particulate air filters under positive
pressure, regardless of whether flow is laminar or non-laminar;

iv. A system for monitoring environmental conditions;

v. A system for cleaning and disinfecting the room and equipment to produce aseptic conditions

vi. A system for maintaining any equipment used to control the aseptic conditions.

vii. Operations relating to the manufacture, processing, and packing of penicillins should be performed in facilities separate from those used for other medicinal products for human use.

3 .5 Production, storage and quality control areas should not be used as a right of way by personnel who do not work in them

3.6 Where starting and primary packaging materials, intermediate or bulk products are exposed to the environment, interior surfaces (walls, floors and ceilings) should be smooth, free from cracks and open joints, and should not shed particulate matter, should permit easy and effective cleaning and if necessary, disinfection.

3.7 Weighing of starting materials should be carried out in a separate weighing room designed for that use.

3.8 In cases where dust is generated (e.g during sampling, weighing, mixing and
processing operations, packing of dry products), specific provisions should be taken to avoid cross-contamination and facilitate cleaning)

3.9 In-process controls can be carried out within the production area provided they do not carry any risk for the production

3.10 Manufacture of sterile products should be carried out in clean areas, entry to which should be through airlocks for personnel and/or for equipment and materials

3.11 Clean areas should be maintained to an appropriate cleanliness standard and supplied with air which has been passed through filters of appropriate efficiency

3.12 The various operations of component preparation, product preparation and filling should be carried out in separate areas within the clean area.

3.13 Clean areas for the manufacture of sterile products should be classified according to the required characteristics of the environment. Each manufacturing operation requires an appropriate environmental cleanliness level in the operational state in order to minimise the risks of particulate or microbial contamination of the medicinal product or materials being handled

3.14 Control laboratories should be designed to suit the operations to be carried out in them. There should be adequate suitable storage space for samples and records.

3.15 Separate rooms may be necessary to protect sensitive instruments from vibration, electrical interference, humidity etc.

3.16 Special requirements as appropriate should be provided in laboratories handling particular substances, such as biological or radioactive samples

3.17 Storage areas should be designed or adapted to ensure good storage conditions.

3.18 Storage areas should be clean and dry and maintained within acceptable temperature limits.

3.19 Where special storage conditions are required (e.g temperature, humidity), these should be provided, checked and monitored.

3.20 Receiving and dispatch bays should protect materials and medicinal products from weather.

3.21 Reception areas should be designed and equipped to allow containers of incoming materials to be cleaned where necessary before storage.

3.22 Where quarantine status is ensured by storage in separate areas, these areas must be clearly marked and their access restricted to authorised personnel.

3.23 Highly active materials or medicinal products should be stored is safe and secure areas.

3.24 Printed packaging materials are considered critical to the conformity of the medicinal product and special attention should be paid to the safe and secure storage of these materials.

3.25 The manufacture of technical poisons such as pesticides and herbicides should not be allowed in premises used for the manufacture of medicinal products

3.26 Building should be designed and equipped so as to afford maximum protection against entry of insects or other animals

3.27 Rest and refreshment areas should be separate from other areas.

3.28 Maintenance workshops should as far as possible be separated from production areas

3.29 Animal houses should be well isolated from other areas, with separate entrance (animal access) and air handling facilities

Lighting
3.30 Adequate lighting should be provided in all areas to facilitate proper operations, cleaning and maintenance.

Heating Ventilation and Air conditioning (HVAC )
3.31 Adequate ventilation, air filtration, air heating, cooling and exhaust systems should be provided to all areas as appropriate.

3.32 The air handling systems should be designed and constructed to minimize risks of contamination and cross contamination.

3.33 Equipment for adequate control over air pressure, micro-organisms, dust, humidity, and temperature should be provided when appropriate for the manufacture, processing and packing of medicinal products.

3.34 Air filtration systems, including pre-filters and particulate matter air filters, should be used when appropriate on air supplies to production areas.

3.35 Where air is re-circulated to production areas, appropriate measures should be to control re-circulation of dust from production.

3.36 In areas where air contamination occurs during production, there should be adequate exhaust systems or other systems adequate to control contaminants.

3.37 Air-handling systems for the manufacture, processing and packing of penicillins should be completely separate from those for other medicinal products for human use. Entry to these areas should be through airlocks for personnel and/or for equipment and materials

Plumbing
3.38 Permanently installed pipe work should be appropriately identified. This can be accomplished by identifying individual lines, documentation, computer control systems or alternative means.

3.39 Pipework should be located to avoid risks of contamination.

3.40 Pipe work and other services should be designed and sited to avoid creation of recesses which are difficult to clean. As far as possible, for maintenance purposes, they should be accessible from outside the manufacturing areas.

3.41 Service Pipe work should be cleaned as appropriate

Washing and Toilet facilities
3.42 Adequate, clean washing and toilet facilities should be provided for personnel .

3.43 Washing facilities provided should be equipped with hot and cold water, soap or detergent, air driers or single-service towels, and clean toilet facilities easily accessible to working areas.

3.44 Toilets should not directly communicate with production or storage areas.

Sewage and refuse
3.45 Sewage, refuse, and other wastes in and from the building and immediate premises should be disposed of in a safe and sanitary manner.

3.46 Drains should be of adequate size and, where connected directly to a sewer, should be provided with an air break or other mechanical device to prevent back-siphonage

3.47 Open drains should be avoided. Where unavoidable, should be easily accessible and shallow for easy cleaning and disinfection.

3.48 Containers and/ or pipes for waste materials should be clearly identified.

Sanitation
3.49 Any building used in the manufacture, processing and packing of medicinal product should be maintained in a hygienic condition.

3.51 There should be standard operating procedures assigning responsibility for cleaning.

3.52 The standard operating procedure should describe in sufficient detail the cleaning schedules, methods, equipment and materials to be used in cleaning the buildings and facilities.

3.53 The building should be free of infestation by rodents, birds, insects, and other vermins.

3.54 There should be standard operating procedures for use of suitable rodenticides, insecticides, fungicides, fumigating agents, cleaning and disinfecting agents.

3.55 The standard operating procedures should be designed to protect personnel and prevent the contamination of equipment, components, medicinal product containers, closures, packaging, labeling materials, or medicinal products.

3.56 Rodenticides, insecticides and fungicides should not be used unless registered in accordance with the Food and Drug Act and the Pesticide Registration Regulations of the Agency

Maintenance
3.57 Buildings should be maintained in good state of repair.

3.58 Repair and maintenance operations should not present any hazard to the quality of products.

4.0 WATER SUPPLY

4.1 Water used in the manufacture of medicinal products should be suitable for its intended use.

4.2 Process water should at a minimum meet WHO requirements for drinking (potable) water quality unless otherwise justified. Water not meeting such standards should not be permitted in the potable water system.

4.3 Where water is used for production of medicinal products, stricter measures for purity should be applied to ensure that the water meets quality specifications appropriate for its intended use.

4.4 Where water used in the process is treated by the manufacturer to achieve a defined quality, the treatment process should be validated and monitored with appropriate action limits.

5.0 EQUIPMENT

5.1 Equipment used in the manufacture, processing and packing of medicinal products should be of appropriate design, adequate size, and suitably located to facilitate intended operations, its cleaning, sanitization (where appropriate) and maintenance.

5.2 Equipment should be constructed so that surfaces that come in contact with materials, or medicinal products should not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the medicinal product beyond the official or other established specifications.

5.3 Any substance required for operation of machinery such as lubricants, heating fluids or coolants, should not come into contact with materials, or medicinal products so as to alter the safety, identity, strength, quality, or purity of the medicinal product beyond the official or other established specifications.

5.4 Balances and measuring equipment of an appropriate range and precision should be available for production and control procedures

5.5 Measuring, weighing, recording and control equipment should be calibrated and checked at defined intervals by appropriate methods. Adequate records of such operations should be maintained.

5.6 Automated, mechanical, or electronic equipment or other types of equipment, including computers, or related systems used in manufacturing process should be qualified, routinely calibrated, inspected and checked according to a written program designed to ensure proper performance.

Equipment cleaning and maintenance
5.7 Schedules and procedures (including assignments of responsibilities) should be established for the maintenance of equipment

5.8 Equipment and utensils should be cleaned, maintained, and sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the medicinal product beyond the official or other established specifications.

5.9 Distilled, deionized and where appropriate, other water pipes should be sanitised according to written procedures that detail the action limits for microbiological contamination and measures to be taken.

5.10 Standard operating procedures should be established and followed for cleaning and maintenance of equipment including utensils. These procedures should include the following:

a. Assignment of responsibility for cleaning and maintaining equipment;

b. Maintenance and cleaning schedules, including, where appropriate, sanitizing schedules;

c. A description in sufficient detail of the methods, equipment, and materials used (including dilution of cleaning agents used to clean equipment) in cleaning and maintenance operations,

d. Instructions for disassembling and reassembling equipment to ensure proper cleaning and maintenance where appropriate

e. Instructions for the removal or obliteration of previous batch identification;

f. Instructions for the protection of clean equipment from contamination prior to use;

g. Inspection of equipment for cleanliness immediately before use.

5.11 Proper records should be kept of maintenance, cleaning, sanitizing, and inspection.

5.12 Written records of qualification, calibration, checks and inspections should be maintained.

5.13 Appropriate controls should be exercised over computer or related systems to ensure those changes in master production and control records or other records are instituted only by authorized personnel.

5.14 Input to and output from the computer or related system of formulas or other records or data should be checked for accuracy. The degree and frequency of input/output verification should be based on the complexity and reliability of the computer or related system.

5.15 A backup file of data entered into the computer or related system should be maintained in both soft and hard copies.

Filters
5.16 Filters for liquid filtration used in the manufacture, processing, or packing of injectable medicinal products intended for human or animal use should not release fibers into such products.

5.17 Fiber-releasing filters may not be used in the manufacture, processing, or packing of these injectable medicinal products unless it is not possible to manufacture such medicinal products without the use of such filters. Where use of a fiber-releasing filter is necessary, an additional non-fiber-releasing filter of 0.22 micron maximum mean porosity (0.45 micron where the manufacturing conditions so dictate) should subsequently be used to reduce the content of particles in the injectable medicinal product.

5.18 Use of an asbestos-containing filter, with or without subsequent use of a specific nonfiber-releasing filter, is permissible only upon submission of proof to the Agency that use of a non-fiber-releasing filter will, or is likely to, compromise the safety or effectiveness of the injectable medicinal product.

5.19 Filters should be cleaned, checked for damage, sterilized, tested for efficiency, changed at specified intervals according to written program and appropriately documented.

6.0 MATERIALS MANAGEMENT

General requirements
6.1 Standards or specifications should be written and followed for all materials

6.2 Standard operating procedures on the receipt, identification, storage, handling, sampling, testing, and approval or rejection of materials should be established and followed

6.3 Materials should at all times be handled and stored in a manner to prevent degradation and contamination.

6.4 Bagged or boxed components of materials should not be stored on the floor and should be suitably spaced to permit cleaning and inspection.

6.5 Each material should be assigned and identified with a distinctive code, batch or receipt number.

6.6 A system should be in place to identify the status of each batch (quarantine, approved or rejected).

6.7 Manufacturers of intermediates and/or APIs should have a system for evaluating suppliers of critical materials.

6.8 Where the supplier of a critical material is not the manufacturer of that material, the name and address of that manufacturer should be known by the intermediate and/or API manufacturer.

6.9 Materials should be purchased according to specification, from a supplier or suppliers approved by the quality control unit (s).

6.10 Changing the source of supply of raw materials should be through a documented formal change control system which should be established to evaluate changes that may affect quality of medicinal products

6.11 Written procedures should provide for the identification, documentation, appropriate review, and approval of changes in raw materials specifications.

6.12 Records of material receipt should indicate the source, dates of receipt, sampling, analysis and quality control release

Receipt and storage of untested materials
6.10 Each material should be examined visually when received for appropriate labeling as to contents, container damage or broken seals and contamination.
6.11 Materials should be held under quarantine until they have been sampled, examined or tested as appropriate.

Testing and approval or rejection of materials
6.12 Each batch of materials should be withheld from use until the batch has been sampled, examined or tested as appropriate and released for use by the quality control unit.

6.13 Representative samples of each shipment of each batch should be collected for testing or examination.

6.14 Sampling methods should specify the number of containers to be sampled, which part of the container to sample and the amount of material to be taken from each container.

6.15 The sampling method should be based on appropriate criteria such as:
a) Statistical criteria (variability, confidence levels, degree of precision desired)
b) Criticality of the material,
c) Past quality history of the supplier
d) Quantity needed for analysis and retention

6.16 Samples should be collected in accordance with the following procedures:
a. The containers of components selected should be cleaned where necessary, by appropriate means.

b. The containers should be opened, sampled, and resealed in a manner designed to prevent contamination of their contents and contamination of other materials.

c. Sterile equipment and aseptic sampling techniques should be used when necessary.

d. Where it is necessary to sample a component from the top, middle, and bottom of its container, such sample subdivisions should not be combined for testing.

6.17 Sample containers should be identified so that the following information can be determined:
a) Name of the material sampled.
b) The batch or lot number
c) The number of the sample
d) The container from which the sample was taken
e) The date on which the sample was taken
f) The name and signature of the person who collected the sample.

6.18 Sampling should be conducted at defined locations and by procedures designed to prevent contamination of the material sampled and contamination of other materials.

6.19 Containers from which samples are withdrawn should be opened carefully and subsequently re-closed. They should be marked to indicate that a sample has been taken from them.

6.20 Samples should be examined and tested as follows:
a) At least one test should be conducted to verify the identity of each material. Specific identity tests, where they exist, should be used.

b) Each component should be tested for conformity with all appropriate written specifications for purity, strength, and quality.

c) A report of analysis may be accepted from the supplier of a component, provided that at least one specific identity test is conducted on such component by the manufacturer

d) Containers and closures should be tested for conformance with specifications.

e) A certificate of testing may be accepted from the supplier, provided that at least a visual identification is conducted on such containers/closures by the manufacturer

f) The manufacturer should establish the reliability of a supplier’s analyses through appropriate validation of the supplier’s test results at appropriate intervals.

g) Components should be microscopically examined as appropriate.

h) Each batch of material that is liable to contamination with filth, insect infestation, or other extraneous adulterant should be examined against established specifications for such contamination

i) Each batch of material that is liable to microbiological contamination that is objectionable in view of its intended use should be subjected to microbiological tests before use.

6.21 Any batch of material that meets the appropriate written specifications of identity, strength, quality, purity and related tests may be approved and released for use.

6.22 Any batch of material that does not meet specifications should be rejected.

6.23 Materials in different stages of testing should be identified with the appropriate label colour code

Use of approved materials
6.23 Materials approved for use should be rotated so that the first-to-expire approved stock is used first.

6.24 Deviation from this requirement is permitted where such deviation is temporary and appropriate.

Retesting of approved materials
6.25 Materials should be retested or re-examined as appropriate for identity, strength, quality, purity and approved or rejected by the quality control unit as necessary.

Rejected Materials
6.26 Rejected materials should be identified and quarantined in restricted areas to prevent their use in manufacturing or processing operations.

6.27 Disposal of rejected materials should be conducted in accordance with standard operating procedures and environmental regulations.

6.28 Disposal of rejected material should be approved and documented by authorized personnel

Containers and closures
6.29 Containers and closures should not be reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the medicinal product beyond the official or established requirements.

6.30 Container closure systems should provide adequate protection against external factors that can cause deterioration or contamination of the medicinal product.

6.31 Product containers and closures should be clean and, where indicated by the nature of the medicinal product, sterilized and processed to remove pyrogenic properties to ensure that they are suitable for their intended use.

6.32 Standards or specifications, methods of testing, and, where indicated, methods of cleaning, sterilizing, and processing to remove pyrogenic properties should be written and followed for medicinal product containers and closures.

7.0 STANDARD OPERATING PROCEDURES

General requirements
7.1. Standard Operating Procedures should be written for all operations.

7.2 Standard operating procedures, including any changes, should be drafted, reviewed and approved by the appropriate organizational units and reviewed and approved by the quality control unit

7.3 Standard operating procedures for all operations should be followed in the execution of the various operations to which they relate and should be documented at the time of performance.

Production and Process controls
7.4 There should be standard operating procedures for production and process controls to ensure that medical products have the identity, strength, quality and purity they are represented to possess.

Deviations
7.5 There should be standard operating procedures for handling deviations.

7.6 Any deviation from the standard operating procedures should be reported, properly investigated, recorded and justified.

7.7 Deviations should not be approved without the involvement of the quality control unit.

Charge-in of components
7.8 Standard operating procedures for production and control should include the following:

a. Batch formulated with the intention of providing not less than 100 percent of the labelled amount of active ingredients.

b. Components for manufacturing medicinal product weighed, measured, or subdivided as appropriate.

7.9.1 Where a component is removed from the original container to another, the new container should be identified with the following information:
a) Component name or identification number
b) Receiving or control number
c) Weight or measure in new container
d) Batch for which component was dispensed, including its product name,
strength, and lot number.

7.10 Weighing, measuring, or subdividing operations for components should be adequately supervised.

7.11 Each container of component dispensed for manufacturing should be examined by a second person to ensure that:
a) The component was released by the quality control unit
b) The weight or measure is correct as stated in the batch manufacturing records;
c) The containers are properly identified.

7.12 Each component should be added to the batch by one person and verified by a second person.

7.13 The identification of personnel performing each step of the process and of the person who checked each of these steps should be clearly stated and signatures appended.

Calculation of yield
7.14 a. Actual and theoretical yields should be determined at the conclusion of each appropriate phase of manufacturing, processing and packaging of the medicinal product.
b. Calculation of yields should be performed by one person and independently verified by a second person.

Equipment identification
7.15 All compounding and storage containers, processing lines, and major equipment used during the production of a batch of a medicinal product should be properly labelled at all times to indicate the product or material being processed, its strength (where applicable) batch number and, when necessary, the phase of processing of the batch.

7.16 Major equipment should be identified by a distinctive identification number or code that should be recorded in the batch manufacturing record to show the specific equipment used in the manufacture of each batch of a medicinal product.

7.17 Where only one of a particular type of equipment exists in a manufacturing facility, the name of the equipment may be used instead of a distinctive identification number or code.

Sampling and testing of in-process materials and medicinal products
7.18 To ensure batch uniformity and integrity of medicinal products, standard operating procedures that describe the in-process controls and tests, or examinations to be conducted on appropriate samples of in-process materials of each batch should be established and followed.

7.19 Control procedures should be established to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the medicinal product.

7.20 Valid in-process specifications should be consistent with medicinal product final specifications

7.21 In-process specifications should be derived from previous acceptable process average and process variability estimates where possible by applying suitable statistical procedures where appropriate.

7.22 Examination and testing of samples should ensure that the medicinal product and in process material conform to specifications.

7.23 In-process materials should be tested for identity, strength, quality, and purity as appropriate, approved or rejected by the quality control unit during the production process, for example, at commencement or completion of significant phases or after storage for long periods.

7.24 Rejected in-process materials should be identified and quarantined in restricted areas to prevent their use in manufacturing or processing operations.

Time limitations on production
7.25 When appropriate, time limits for the completion of each phase of production should be established to ensure the quality of the medicinal product.

7.26 Deviation from established time limits may be acceptable where such deviation does not compromise the quality of the medicinal product. Such deviation should be justified and documented.

Control of microbiological contamination
7.27 Standard operating procedures designed to prevent objectionable micro-organisms in medicinal products not required to be sterile, should be established and followed.

7.28 Standard operating procedures designed to prevent microbiological contamination of medicinal products purporting to be sterile, should be established and followed. Such procedures should include validation of any sterilization process.

Reprocessing
7.29 Standard operating procedures prescribing a system for reprocessing batches that do not conform to standards or specifications and the steps to be taken to ensure that the reprocessed batches would conform to all established standards, specifications and characteristics should be established and followed.

7.30 Reprocessing should not be performed without the review and approval of the quality control unit.

7.31 Rejected materials and products should be clearly marked as such and stored separately in restricted areas. They should either be returned to the suppliers or, where appropriate, reprocessed or destroyed. Whatever action is taken should be approved and recorded by authorised personnel.

7.32 The reprocessing of rejected products should be exceptional. It is only permitted if the quality of the final product is not affected, if the specifications are met and if it is done in accordance with a defined and authorised procedure after evaluation of the risks involved. Record should be kept of the reprocessing.

7.33 The recovery of all or part of earlier batches, which conform to the required quality by incorporation into a batch of the same product at a defined stage of manufacture should be authorised beforehand. This recovery should be carried out in accordance with adefined procedure after evaluation of the risks involved, including any possible effect on shelf life. The recovery should be recorded.

7.34 The need for additional testing of any finished product which has been reprocessed, or into which a recovered product has been incorporated, should be considered by the Quality Control Department.

7.35 Products returned from the market and which have left the control of the manufacturer should be destroyed unless without doubt their quality is satisfactory; they may be considered for re-sale, re-labelling or recovery with a subsequent batch only after they have been critically assessed by the Quality Control Department in accordance with a written procedure. The nature of the product, any special storage conditions it requires, its condition and history, and the time elapsed since it was issued should all be taken into account in this assessment. Where any doubt arises over the quality of the product, it should not be considered suitable for re-issue or re-use, although basic chemical reprocessing to recover active ingredients may be possible. Any action taken should be appropriately recorded.

8.0 Change Control

8.1 A formal change control system should be established to evaluate all changes that may affect the production and control of the medicinal product, intermediate or Active.

Pharmaceutical Ingredient
8.2 Written procedures should be in place to describe the actions to be taken if a change is proposed to a starting material, product component, process equipment, method of production, testing, site or any other change that may affect medicinal product quality or reproducibility of the process.

8.3 Sufficient data should be generated by change control procedures to demonstrate that the revised process will result in medicinal product of the desired quality, consistent with the approved specifications.

8.4 All changes that may affect medicinal product quality or reproducibility of the process should be formally requested, documented and approved by the appropriate organizational unit as well as the quality control unit.

8.5 All likely impact of change of facilities, systems and equipment on the medicinal product should be evaluated, including risk analysis.

9.0 Packaging and Labeling Control

Material examination and usage criteria
9.1 Standard operating procedures describing in sufficient detail the receipt, identification, storage, handling, sampling, examination, and/or testing of labeling and packaging materials should be established and followed.

9.2 Labeling and packaging materials should be representatively sampled, and examined or tested upon receipt and before use in packaging or labeling of a medicinal product.

9.3 Any labeling or packaging materials meeting appropriate written specifications may be approved and released for use.

9.4 Any labeling or packaging materials that do not meet specifications should be rejected to prevent their use in operations for which they are unsuitable.

9.5 Records should be maintained for each shipment received of each different labeling and packaging material indicating receipt, examination or testing, and whether accepted or rejected.

Packaging Materials
9.6 Containers should provide adequate protection against deterioration or contamination of the intermediate, API or finished medicinal product that may occur during transportation and recommended storage.

9.7 Containers should be clean and where indicated by the nature of the Intermediate, API or finished medicinal product, sanitized to ensure that they are suitable for their intended use.

9.8 Containers should not be reactive, additive, or absorptive so as to alter the quality of the intermediate, API or finished medicinal product beyond the specified limits.

9.9 Where containers are re-used during production process, they should be cleaned in accordance with documented procedures and all previous labels should be removed.

Label Issuance and Control
9.10 Labels and other labeling materials for each different medicinal product, strength, dosage form, or quantity of contents should be stored separately with suitable identification.

9.11 Obsolete and outdated labels, labeling, and other packaging materials should be destroyed.

9.12 Use of gang printing of labeling for different medicinal products or different strengths or net contents of the same medicinal product, is prohibited unless the labeling from gangprinted sheets is adequately differentiated by size, shape, or color.

9.13 Where cut labeling is used, packaging and labeling operations should include one of the following special control procedures:

a) Dedication of labeling and packaging lines to each different strength of each different medicinal product.

b) Use of appropriate electronic or electromechanical equipment to conduct a 100- percent examination for correct labeling during or after completion of finishing operations; or

c) Use of visual inspection to conduct a 100- percent examination for correct labeling during or after completion of finishing operations for hand- applied labeling. Such examination shall be performed by one person and independently verified by a second person.

9.14 Printing devices on/or associated with, manufacturing lines used to imprint/overprint labeling upon the medicinal product unit label or case should be monitored to ensure that all imprinting/overprinting conform to the print specified in the batch manufacturing record.

9.15 Procedures should be used to reconcile the quantities of labels issued, used, and returned and to evaluate discrepancies found between the number of containers labelled and the number of labels issued. Such discrepancies should be investigated, documented and approved by the quality control unit(s).

9.16 All excess labeling bearing batch or control numbers should be destroyed.

9.17 Returned labeling should be maintained and stored in a manner to prevent mix-ups and provide proper identification.

Packaging and labeling operations
9.18 Standard operating procedures designed to ensure that correct labels, labeling, and packaging materials are used for medicinal products should be established and followed.

These procedures should incorporate the following features:
a) Designs to prevent mix-ups and cross-contamination by physical or spatial separation from operations involving other medicinal products.
b) Identification and handling of filled medicinal product containers that are set aside and held in unlabeled condition for future labeling operations to preclude mislabeling of individual containers, batches, or portions of batches. Identification need not be applied to each individual container but should be sufficient to determine name, strength, quantity of contents, and batch or control number of each container.

c) Identification of the medicinal product with a batch or control number that permits determination of the history of the manufacture and control of the batch.

d) Examination of packaging and labeling materials for suitability and correctness before packaging operations, and documentation of such examination in the batch manufacturing record.

e) Inspection of the packaging and labeling facilities immediately before use to ensure that all medicinal products have been removed from previous operations.

f) Inspection should also be made to ensure that packaging and labeling materials not suitable for subsequent operations have been removed. Results of inspection should be documented in the batch production records.

9.19 Holders of product license for medicinal products should obtain approval from the Agency for changes in packaging and labeling.

Tamper-resistant packaging
9.20 A medicinal product (except a dermatological, dentifrice, insulin, or throat lozenge product) for sale that is not packaged in a tamper-resistant package or that is not properly labelled as prescribed under this section should be considered adulterated.

9.21 The tamper- resistant packaging should be designed to and should remain intact when handled in a reasonable manner during manufacture, distribution, and retail display.

9.22 There should be a statement that is prominently placed so that consumers are alerted to the specific tamper-resistant feature of the package

9.23 The tamper- resistant labeling shall be so placed that it will be unaffected where the tamper-resistant feature of the package is breached or missing.

9.24 To reduce the likelihood of successful tampering and to increase the likelihood that consumers would discover where a product has been tampered with, tamper-resistant packaging should not be easily duplicated by the use of commonly available materials or through use of commonly available processes.

Expiration dating
9.25 To ensure that a medicinal product meets applicable standards of identity, strength, quality, and purity at the time of use, it should bear an expiration date determined by appropriate stability testing.

9.26 Expiration dates should be related to any storage conditions stated on the labeling, as determined by stability studies.

9.27 Where the medicinal product is to be reconstituted at the time of dispensing, its labeling should bear expiration information for both the reconstituted and un-reconstituted medicinal products.

9.28 Expiration dates should appear on labeling in accordance with the NAFDAC labeling regulations for medicinal products.

10.0 Storage and Distribution

Warehousing procedures
10.1 Storage areas should be of sufficient capacity to allow orderly storage of the various categories of materials and products: starting and packaging materials, intermediate, bulk and finished products, products in quarantine, released, rejected, returned or recalled.

10.2 Storage areas should be designed or adapted to ensure good storage conditions. In particular, they should be clean and maintained within acceptable temperature limits. Where special storage conditions are required (e.g. temperature, humidity) these should be provided, checked and monitored.

10.3 Receiving and dispatch bays should project materials and products from the weather. Receptions areas should be designed and equipped to allow containers of incoming materials to be cleaned where necessary before storage.

10.4 Where quarantine status is ensured by storage in separate areas, these areas must be clearly marked and their access restricted to authorised personnel. Any system replacing the physical quarantine should give equivalent security.

10.5 There should normally be a separate sampling area for starting materials. If sampling is performed in the storage area, it should be conducted in such a way as to prevent contamination or cross-contamination.

10.6 Segregated areas should be provided for the storage of rejected, recalled or returned materials or products.

10.7 Highly active materials or products should be stored in safe and secure areas.

10.8 Printed packaging materials are considered critical to the conformity of the medicinal products and special attention should be paid to the safe and secure storage of these materials.

10.9 Standard operating procedures describing the warehousing of medicinal products should be established and followed. They should include:

a) Quarantine of medicinal products before release by the quality control unit.

b) Storage of medicinal products under appropriate conditions of temperature, humidity, and light so that the identity, strength, quality, and purity of the medicinal products are not affected.

c) Monitoring of environmental conditions which should be documented

10.10 Records should be maintained of special storage conditions where required for some medicinal products.

Distribution procedures
10.11 Standard Operating Procedures for the distribution of medicinal products should be established, and followed. They should include:

a) A procedure whereby the oldest approved stock of a medicinal product is distributed first. Deviation from this requirement is permitted where such deviation is temporary, appropriate and documented.

b) A system by which the distribution of each batch of medicinal product could be traceable to facilitate its recall where necessary. Adequate documented should be done.

11.0 Quality Control

11.1 There should be quality control unit having the responsibility and authority to approve or reject all materials and medicinal products.

11.2 The quality control unit should have authority to review production records to ensure that no errors have occurred and where errors have occurred, that they have been fully investigated.

11.3 The quality control unit should be responsible for approving or rejecting medicinal products manufactured, processed, packed or held under contract by another company.

11.4 The quality control unit should have the responsibility for approving or rejecting all procedures or specifications impacting on the identity, strength, quality, and purity of the medicinal products.

11.5 The responsibilities and procedures applicable to the quality control unit should be in writing and followed.

11.6 Adequate laboratory facilities for the testing and approval or rejection of materials and medicinal products should be available to the quality control unit.

Laboratory Controls
11.7 The establishment of any specifications, standards, sampling plans, test procedures, or other laboratory control mechanisms required by this section, including any change in such specifications, standards, sampling plans, test procedures, or other laboratory control mechanisms should be drafted by the appropriate organizational unit and reviewed and approved by the quality control unit.

11.8 The requirements in this section should be followed and should be documented at the time of performance.

11.9 Any deviation from the written specifications, standards, sampling plans, test procedures, or other laboratory control mechanisms should be recorded and justified.

11.10 Laboratory controls should include the establishment of scientific and appropriate specifications, standards, sampling plans, and test procedures designed to ensure that materials and medicinal products conform to appropriate standards of identity, strength, quality, and purity. Laboratory controls should include:

a) Determination of conformance to appropriate written specifications for theacceptance of each batch within each shipment of materials used in the manufacture, processing, packing of medicinal products.

b) Specifications describing the sampling and testing procedures used.

c) Samples which are representative and adequately identified.

d) Sampling and testing procedures requiring appropriate retesting of any material that is subject to deterioration.

e) Determination of conformance to written specifications and a description of sampling and testing procedures for in-process materials.

f) Determination of conformance to written descriptions of sampling procedures and appropriate specifications for medicinal products.

g) Calibration of instruments, apparatus, gauges, and recording devices at suitable intervals in accordance with an established written program containing specific directions, schedules, limits for accuracy and precision, and provisions for remedial action in the event accuracy and/or precision
limits are not met.

h) Instruments, apparatus, gauges, and recording devices not meeting established specifications should not be used.

Testing and release for distribution
11.11 For each batch of medicinal product, there should be appropriate laboratory determination of satisfactory conformance to final specifications for the medicinal product, including the identity and strength of each active ingredient, prior to release.

11.12 Where sterility and/or pyrogen testing are conducted on specific batches of short-lived radiopharmaceuticals, such batches may be released prior to completion of sterility and/or pyrogen testing, provided such testing should be completed as soon as possible.

11.13 There should be appropriate laboratory testing, as necessary, of each batch of medicinal product required to be free of objectionable microorganisms.

11.14 Standard operating procedures describing sampling and testing plans including the method of sampling and the number of units per batch to be tested, should be established and followed.

11.15 Acceptance criteria for the sampling and testing conducted by the quality control unit should be adequate to ensure that batches of medicinal products meet each appropriate specification and statistical quality control criteria as a condition for their approval and release.

11.16 Statistical quality control criteria should include appropriate acceptance levels and/or appropriate rejection levels.

11.17 The accuracy, sensitivity, specificity, and reproducibility of test methods employed should be established and documented.

11.18 Validation and documentation may be accomplished as follows:
a. A statement of each method used in the testing of the sample.

b. The statement should indicate the location of data establishing that the methods used in the testing of the sample meet proper standards of accuracy and reliability as applied to the product tested.

c. Where the method employed is in the current edition of a recognized standard reference (e.g. British Pharmacopoeia, United States Pharmacopoeia, International Pharmacopoeia), and the referenced method is not modified, a statement indicating the method and reference would suffice.
d. The suitability of all testing methods used should be verified under actual conditions of use.

11.19 Medicinal products failing to meet established standards or specifications and any other relevant quality control criteria should be rejected.

11.20 Reprocessing may be performed. Prior to acceptance and use, reprocessed material must meet appropriate standards, specifications, and any other relevant criteria.

Stability testing
11.21 There should be a written testing program designed to continuously assess the stability characteristics of medicinal products.

11.22 The results of such stability testing should be used in determining appropriate storage conditions and expiration dates.

11.23 The written program should be followed and should include:
a) Sample size and test intervals based on statistical criteria for each attribute
examined to ensure valid estimates of stability
b) Storage conditions for samples retained for testing
c) Reliable, meaningful, and specific test methods
d) Testing of the medicinal product in the same container-closure system as
that in which the medicinal product is marketed
e) Testing of medicinal products for reconstitution at the time of dispensing (as
directed in the labeling) as well as after they are reconstituted.

11.24 An adequate number of batches of each medicinal product should be tested to determine an appropriate expiration date and a record of such data should be maintained.

11.25 Accelerated studies, combined with basic stability information on the components, medicinal products, and container-closure system, may be used to support tentative expiration dates provided full shelf life studies are not available and are being conducted.

11.26 Where data from accelerated studies are used to project a tentative expiration date that is beyond a date supported by actual shelf life studies, there must be stability studies conducted, including medicinal product testing at appropriate intervals, until the tentative expiration date is verified or the appropriate expiration date determined.

11.27 For homeopathic medicinal products, the requirements of this section are as follows:
a) There should be a written assessment of stability based at least on testing or examination of the medicinal product for compatibility of the ingredients, and based on marketing experience with the medicinal product to indicate that there is no degradation of the product for the normal or expected period of use.

b) Evaluation of stability should be based on the same container-closure system in which the medicinal product is being marketed.

Special testing requirements
11.28 For each batch of medicinal product purporting to be sterile and/or pyrogen-free, there should be appropriate laboratory testing to determine conformance to such requirements. The test procedures should be in writing and should be followed.

11.29 For each batch of ophthalmic preparation, there should be appropriate testing to determine conformance to specifications regarding the presence of foreign particles and harsh or abrasive substances. The test procedures should be in writing and should be followed.

11.30 For each batch of controlled-release dosage form, there should be appropriate laboratory testing to determine conformance to the specifications for the rate of release of each active ingredient. The test procedures should be in writing and should be followed.

Retention Samples
11.31 An appropriately identified retention sample that is representative of each batch in each shipment of each active ingredient should be retained.

11.32 The retention sample consists of at least twice the quantity necessary for all tests required to determine whether the active ingredient meets its established specifications, except for sterility and pyrogen testing.

11.33 The retention time for an active ingredient is as follows:
i. The retention sample should be retained for 1 year after the expiration date of the medicinal product containing the active ingredient.

ii. The retention sample for an active ingredient in a radioactive medicinal product should be retained for:

a) Three months after the expiration date of the medicinal product containing the active ingredient where the shelf life of the medicinal product is 30 days or less
b) Six months after the expiration date of the medicinal product containing the active ingredient where the shelf life of the medicinal product is more than 30 days.

11.34 An appropriately identified retention sample that is representative of each batch of medicinal product should be retained and stored under conditions consistent with product labeling.

11.35 The retention sample should be stored in the same immediate container-closure system in which the medicinal product is marketed or in one that has essentially the same characteristics.

11.36 The retention sample consists of at least twice the quantity necessary to perform all the required tests, except those for sterility and pyrogens.

11.37 Except for those medicinal products described in section 12.32(ii) of this section, retention samples from representative sample batches selected by acceptable statistical procedures should be examined visually at least once a year for evidence of deterioration unless visual examination would affect the integrity of the retention sample.

11.38 The results of examination should be recorded and maintained with other stability data on the medicinal product.

11.39 Any evidence of medicinal product deterioration should be investigated and documented.

11.40 Retention samples of compressed medical gases need not be retained.

11.41 The retention time for a medicinal product is as follows:
i. The retention sample should be retained for 1 year after expiration date of the last batch of the medicinal product

ii. The retention sample of radioactive medicinal products should be retained for:
a) Three months after the expiration date of the medicinal product where the shelf life is 30 days or less

b) Six months after the expiration date of the medicinal product where the shelf life is more than 30 days.

Laboratory animals
11.42 Animals used in testing components, in-process materials, or medicinal products for compliance with established specifications should be maintained and controlled in a manner that ensures their suitability for their intended use.

11.43 Laboratory animals should be identified, and adequate records showing the history of their use maintained.

Penicillin contamination
11.44 a. Where possibility exists that a non-penicillin medicinal product has been exposed to cross-contamination with penicillin, the non-penicillin medicinal product should be tested for the presence of penicillin.

b. The tested medicinal product should not be marketed where detectable levels of penicillin have been found

12.0 Records and Reports

General requirements
12.1 Records should provide appropriate history of each batch of medicinal product, including its distribution, and all other relevant circumstances pertinent to the quality of the final product.

12.2 The records should be made or completed at the time each operation is performed and in such a way that all significant activities concerning the manufacture of medicinal products are traceable.

12.3 All production, quality control and distribution records associated with a batch of medicinal product should be retained for at least 1 year after the expiration date of the batch.

12.4 Records should be maintained for all materials for at least 1 year after the expiration date of the medicinal product.

12.5 All records pertaining to medicinal products should be readily available for authorized inspection during the retention period at the establishment where the activities described in such records occurred.

12.6 All records pertaining to medicinal products should be subject to photocopying or other means of reproduction as part of authorized inspection.

12.7 Records that can be immediately retrieved from another location by computer or other electronic means, when appropriate, should be considered as meeting the requirements.

12.8 Records should be retained as original records.

12.9 True certified copies of the original records such as photocopies, microfilm, microfiche, or other accurate reproductions of the original records may also be retained.

12.10 Where reduction techniques, such as microfilming are used, suitable reader and photocopying equipment should be readily available.

12.11 Written records should be maintained so that data therein could be used for evaluating, at least annually, the quality standards of each medicinal product to determine the need for changes in medicinal product specifications, manufacturing or control procedures.

12.12 Standard operating procedures should be established and followed for evaluation of quality standards of medicinal products and should include provisions for:

a) Review of a representative number of batches, whether approved or rejected, and, where applicable, records associated with the batch.

b) Review of complaints, recalls, returned or recovered medicinal products, and investigations conducted as appropriate.

12.13 Procedures should be established to ensure that the responsible officials of the company, where they are not personally involved in or immediately aware, are notified in writing of:
a) Complaints, recalls, recovery or any investigation conducted in this respect.
b) Inspectional observations by the Agency or any regulatory action(s) relating to good manufacturing practices.

Equipment log book
12.14 Written records of major equipment validation, calibration, cleaning, maintenance (except routine maintenance such as lubrication and adjustments), repair and use should be included in individual equipment log book, as appropriate.

12.15 Equipment log book should also show date, time, product, number of each batch of medicinal product processed using the equipment and the areas where the product has been processed.

12.16 Where dedicated equipment is employed, the records of cleaning, maintenance and use should be part of the batch record.

12.17 Persons performing and double-checking validation, calibration, maintenance, repair or cleaning of equipment should date and sign or initial the log book indicating that the work was performed.

12.18 Entries in the log book should be in chronological order.

Materials records
12.19 Materials records should include:
a. Identity and quantity of each shipment of each batch of materials indicating:
i. Name of the supplier;
ii. Supplier’s batch number(s) where known;
iii. Distinctive code, batch or receipt number
iv. The date of receipt.

b. Name and location of manufacturer where different from supplier.

c. Results of any test or examination performed on the materials.

d. Individual inventory record of each material and record of reconciliation of the use of each batch of such component.

e. The inventory record containing sufficient information to allow determination of any
batch or lot of medicinal product associated with the use of each component, medicinal product container, and closure.

f. Documentation on the examination and review of labels and labeling for conformity with established specifications.

g. The disposition of rejected materials.

Master production and control records

12.20 To ensure uniformity from batch to batch, master production and control records for each medicinal product, including each batch size, should be prepared, dated, and signed (full signature, handwritten) by one person and independently checked, dated, and signed by a second person.

12.21 The preparation of master production and control records should be described in standard operating procedures and followed.

12.22 Master production and control records should include:
a) The name, strength of the product and dosage form

b) The weight or measure of the medicinal product.

c) Total weight or measure of dosage unit;

d) A complete list of components designated by names or codes sufficiently specific to indicate any special quality characteristic;

e) Accurate weight or measure of each component using the same weight or measure system for each component.

f) Variations may be permitted in the amount of components necessary for preparation of medicinal product provided they are justified in the master production and control records

g) A statement concerning any calculated excess of component;

h) A statement of theoretical weight or measure at appropriate phases of processing;

i) A statement of theoretical yield, including the maximum and minimum percentages of theoretical yield beyond which investigation is required.

j) A description of the medicinal product containers, closures, and packaging materials, including a specimen or copy of each label and all other labeling signed and dated by the person or persons responsible for approval of such labeling;

k) Complete manufacturing and control instructions, sampling and testing procedures, specifications, special notations, and precautions to be followed.

Batch production and control records
12.23 Batch production and control records should be prepared for each batch of medicinal product manufactured and should include complete information relating to the production and control of each batch.

12.24 Batch production and control records should include:
a. An accurate reproduction of the appropriate master production or control record, checked for accuracy, dated, and signed;

b. Documentation that each significant step in the manufacture, processing and packing of the batch was accomplished, including:

i. Date and time

ii. Identity of individual major equipment and lines used

iii. Checks that the equipment and work station are clear of previous products, documents or materials not required for the planned process, and that equipment is clean and suitable for use.

iv. Specific identification of each batch of component or in-process material used;

v. Weights or measures of components used in the course of processing;

vi. In-process and laboratory control results;

vii. Inspection of the packaging and labeling area before and after use;

viii. A statement of the actual yield and a statement of the percentage of theoretical yield at appropriate phases of processing;

ix. Complete labeling control records, including specimens or copies of all labeling used

x. Description of medicinal product containers and closures

xi. Any sampling performed

xii. Identification of the persons performing and directly supervising or checking each significant step in the operation

xiii. Any investigation carried out

xiv. Results of examinations of containers and packages for correct labelling as appropriate.

Production record review
12.25. All medicinal product production and control records, including those for packaging and labeling, should be reviewed and approved by the quality control unit to determine compliance with all established and approved standard operating procedures before a batch is released or distributed.

12.26 Any unexplained discrepancy (including a percentage of theoretical yield exceeding the maximum or minimum percentages established in master production and control records) or the failure of a batch or any of its components to meet any of its specifications should be thoroughly investigated, whether or not the batch has already been distributed.

12.27 The investigation should extend to other batches of the same medicinal product and other medicinal products that may have been associated with the specific failure or discrepancy.

12.28 A written record of the investigation including conclusions and follow-up should be made.

Laboratory records
12.29 Laboratory records should include complete data derived from all tests necessary to ensure compliance with established specifications and standards, including examinations and assays, as follows:

a) A description of the sample received for testing with identification of source (that is, location from where sample was obtained), quantity, batch number or other distinctive code, date sample was taken, and date sample was received for testing.

b) A statement of each method used in the testing of the sample

c) Statement indicating location of data establishing that the methods used in the testing of the sample meet proper standards of accuracy and reliability as applied to the product tested.

d) The method and reference employed which will suffice if the method is in the current edition of a recognized standard reference (e.g. British Pharmacopoeia, United States Pharmacopoeia, International Pharmacopoeia) and the referenced method has not been modified.

e) The suitability of all testing methods used and verified under actual conditions of use.

f) A statement of the weight or measure of sample used for each test, where appropriate.

g) A complete record of all data secured in the course of each test, including all graphs, charts, and spectra from laboratory instrumentation, properly identified to show the specific component, medicinal product container, closure, in-process material, or medicinal product, and batch tested.

h) A record of all calculations performed in connection with the test, including units of measure, conversion factors, and equivalency factors.

i) A statement of the results of tests and how the results compare with established standards of identity, strength, quality, and purity for the component, medicinal product container, closure, in-process material, or medicinal product tested.

j) The initials or signature of the person who performs each test and the date(s) the tests were performed.

k) The initials or signature of a second person showing that the original records have been reviewed for accuracy, completeness, and compliance with established standards.

12.30 Complete records should be maintained of any modification of an established method employed in testing.

12.31 Records of modification of established methods should include the reason for the modification and data to verify that the modification produced results that are at least as accurate and reliable for the material being tested as the established method.

12.32 Complete records should be maintained of all out-of-specification investigations carried out.

12.33 Complete records should be maintained of any testing and standardization of laboratory reference standards, reagents, and standard solutions.

12.34 Complete records should be maintained of the periodic calibration of laboratory instruments, apparatus, gauges, and recording devices done in accordance with an established written program.

12.35 Complete records should be maintained of all stability testing performed.

Distribution records
12.36 Distribution records should contain the following:
a) Name and strength of the medicinal product

b) Description of the dosage form,

c) Name, address and telephone number(s) of the consignee

d) Date and quantity supplied

e) Batch number of the medicinal product.

Complaint files
12.37 Standard operating procedures describing the handling of all written and oral complaints regarding a medicinal product should be established and followed.

12.38 The standard operating procedure should include:
a) Provisions for review of any complaint of failure of medicinal product to meet any of its specifications by the quality control unit

b) The need of the quality control unit to investigate medicinal product failure to comply with any of its specifications

c) Provisions for review to determine whether the complaint represents a serious and unexpected adverse drug event to be reported to the Agency.

12.39 Written record of each complaint should be maintained in a file designated for medicinal product complaints.

12.40 The file regarding medicinal product complaints should be maintained at the establishment where the medicinal product involved was manufactured, processed, or packed, or such file may be maintained at another facility where the written records in such files are readily available for inspection at that other facility.

12.41 Written records involving a medicinal product should be maintained until at least 1 year after the expiration date of the medicinal product, or 1 year after the date that the complaint was received, whichever is longer.

12.42 The written record should include the following information where known:
i. Name and strength of the medicinal product

ii. Batch number

iii. NAFDAC registration number

iv. Name and address of complainant

v. Nature of complaint, and

vi. Reply to complainant.

12.43 Where an investigation is conducted, the written record should include the findings of the investigation and follow-up.

12.44 The record or copy of the record of the investigation should be maintained at the establishment where the investigation was conducted.

12.45 Where an investigation is not conducted, the written record should include the reason why an investigation was not necessary and the name of the responsible person making such a determination.

Recall records
12.46 All medicinal product recall activities whether voluntarily or directed by the Agency should be carried out promptly and the records kept.

12.47 There should be standard operating procedure describing medicinal product recall.

12.48 The standard operating procedure should define the circumstances under which recall of medicinal product should be considered.

12.49 The standard operating procedures for medicinal product should be regularly checked and updated when necessary.

12.50 The recall procedure should designate:
i. Who should be involved in evaluating the information

ii. How a recall should be initiated

iii. Who should be informed about the recall, and

iv. How the recalled material should be treated.

12.51 In the event of a voluntarily recall or serious and/ or potentially life-threatening situation, local, national, and/or international authorities should be informed.

12.52 Appropriate investigation of the reason for recall should be conducted.

12.53 Where an investigation is not conducted, the written record should include the reason why an investigation was not considered necessary and the name of the responsible person making such determination.

12.54 The distribution records should be readily available to the person(s) responsible for recalls and should contain sufficient information on consignees.

12.55 The progress of recall process should be recorded and a final report issued, including reconciliation between supplied and recovered quantities of the medicinal product.

13.0 Returned and Recovered Medicinal Products

Returned medicinal products
13.1 Returned medicinal products should be identified as such and held.

13.2 Where there are doubts on the safety, identity, strength, quality or purity of the returned medicinal product, the product should be destroyed unless examination, testing or other investigations prove that the medicinal product meets appropriate standards of safety, identity, strength, quality or purity.

13.3 A medicinal product may be reprocessed provided the subsequent medicinal product meets appropriate standards, specifications, and characteristics.

13.4 Records of returned medicinal products indicating the following should be maintained:
a) Name

b) Labeled potency of the medicinal product

c) Dosage form

d) Batch number or control number

e) Reason for the return

f) Quantity returned

g) Date of disposition of the returned medicinal product.

13.5 Where the reason for a medicinal product being returned implicates associated batches, an appropriate investigation shall be conducted.

13.6 Standard operating procedures for testing, reprocessing and storage of returned medicinal products should be in writing and followed.

Medicinal product recovery

13.7 Medicinal products which have been subjected to improper storage conditions including extremes in temperature, humidity, smoke, fumes, pressure, age, expiry, or radiation due to natural disasters, fires, accidents, or equipment failures should not be recovered and returned to the marketplace.

13.8 Whenever there is doubt whether medicinal products have been subjected to such conditions, recovery operations may be conducted only where there is:

a) Evidence from laboratory tests and assays (including animal feeding studies where applicable) that the medicinal products meet all applicable standards of identity, strength, quality, and purity and

b) Evidence from inspection of the premises that the medicinal products and their associated packaging were not subjected to improper storage conditions as a result of the disaster or accident.

13.9 Organoleptic examinations should be acceptable only as supplementary evidence that the medicinal products meet appropriate standards of identity, strength, quality, and purity.

13.10 Records including name, batch number, and disposition should be maintained as appropriate.

14.0 Contract Manufacture and Analysis
General
14.1 Contract manufacture and analysis must be correctly defined, agreed and controlled in order to avoid misunderstandings which could result in a medicinal product or work of unsatisfactory quality.
14.2 There must be a written contract between the contract giver and the contract acceptor which clearly establishes the duty of each party
14.3 All arrangements for contract manufacture and analysis including any proposed changes in technical or other arrangements should be in accordance with the marketing authorisation for the medicinal product concerned.

The contract
14.4 A contract should be drawn up between the contract giver and contract acceptor which specifies their respective responsibilities relating to the manufacture and control of medicinal products.

14.5 All arrangements for manufacture and analysis should be in accordance with the marketing authorisation and agreed by both parties.

14.6 The contract should describe clearly who is responsible for purchasing materials, testing and releasing materials, undertaking production and quality controls, including in-process controls, and who has responsibility for sampling and analysis.

14.7 Manufacturing, analytical and distribution records, and retention samples should be kept by, or be available to, the contract giver.

14.8 Any record relevant to assessing the quality of a medicinal product in the event of complaints or a suspected defect should be accessible and specified in the defect/recall procedures of the contract giver.

14.9 The contract should permit the contract giver to visit the facilities of the contract acceptor

Contract Giver

14.10 The contract giver is responsible for assessing the competence of the contract acceptor to carry out successfully the work required and for ensuring that the principles and guidelines of GMP are followed.

14.11 The contract giver should provide the contract acceptor with all the information necessary to carry out the contracted operations correctly in accordance with the marketing authorisation and any other legal requirements.

14.12 The contract giver should ensure that the contract acceptor is fully aware of any problems associated with the product or the work which might pose a hazard to his premises, equipment, personnel, other materials or other products.

14.13 The contract giver should ensure that all processed products and materials delivered to him by the contract acceptor comply with approved specifications.

Contract Acceptor

14.14 The contract acceptor must have adequate premises, equipment, knowledge, experience, and competent personnel to carry out satisfactorily the work ordered by the contract giver.

14.15 Contract manufacture should be undertaken by a manufacturer who is a holder of a marketing authorisation

14.16 The contract acceptor should ensure that all products or materials delivered to him are suitable for their intended purpose.

14.17 The contract acceptor should not pass to a third party any of the work entrusted to him under the contract without the contract giver’s prior evaluation and approval of the arrangements.

14.18 Arrangements made between the contract acceptor and any third party should ensure that the manufacturing and analytical information is made available in the same way as between the original contract giver and contract acceptor.

14.19 The contract acceptor should refrain from any activity which may adversely affect the quality of the medicinal product manufactured and/or analysed for the contract giver.

15.0 Complaints and Recall

15.1 A person should be designated to handle complaints and decide the measures to be take together with sufficient supporting staff to assist him.

15.2 There should be written procedures describing the actions to be taken, including the need to consider a recall, in the case of a complaint concerning a possible product defect.

15.3 Any complaint concerning a product defect should be recorded with all the original details and thoroughly investigated. The person responsible for quality control should normally be involved in the study of such problems.

15.4 If a product defect is discovered or suspected in a batch, consideration should be given to checking other batches in order to determine whether they are also affected.

15.5 All the decisions and measures taken as a result of a complaint should be recorded and referenced to the corresponding batch records.

15.6 Complaint records should be reviewed regularly for any indication of specific or recurring problems requiring attention and possibly the recall of marketed medicinal products.

15.7 Special attention should be given to establishing whether complaint was caused by counterfeiting or not.

15.8 The Agency should be informed if a manufacturer is considering action following safety, faulty manufacture, medicinal product deterioration, detection of counterfeiting or any other serious quality problems with a medicinal product.

15.9 The following information should be included in your recall submission:

i. PRODUCT INFORMATION:
a. Product name (include brand name and generic name)
b. Description of the product

  • Include if product is powder, liquid, tablet, capsule, etc.
  • Include the intended use or indications.
  • If the product is perishable, include the expected shelf life.
  • Include type of packaging (i.e. box, flexible plastic, glass).

c. Labelling

  • Product labelling
  • Individual package label
  • Case label (photocopy acceptable)
  • Package Inserts
  • Directions for Use
  • Promotional Material (if applicable)

d. Additional information for Drug recalls

1 Indicate if prescription or OTC

2 Strength

3 Route of Administration

4 NAFDAC Registration Number

5 Lot/Batch/Unit Numbers
(NOTE: If “all batches” are involved or the product is not coded, explain how nonrecalled, or reintroduced product may be distinguished from product subject to recall. Provide an explanation of your batch number coding system.)

6 Expiration date(s) or Use by date(s) or Expected shelf life of product.

e. Recalling Firm:

Firm name and location address.
Identify firm type (i.e. manufacturer, importer or distributor)

CONTACTS for Recalling Firm:
Name/title/phone/fax number/e-mail address for RECALL contact

Name/title/address/phone/fax number of the most responsible individual for the recalling firm Name/title/phone/fax number/e-mail address for public contact

f. Manufacturer:

  •   Firm name, address, city, state

ii. REASON FOR THE RECALL:

  • Explain in detail how product is defective and/or violative.
  • Explain how the defect affects the performance and safety of the product.
  • If the recall is due to the presence of a foreign object, describe the foreign objects’ size, composition, hardness, and sharpness.
  • If the recall is due to the presence of a contaminant (cleaning fluid, machine oil, paint vapors), explain level of contaminant in the product. Provide labeling, a list of ingredients and the Material Safety Data Sheet for the contaminant.
  • If the recall is due to failure of the product to meet product specifications, provide the specifications and report all test results. Provide copies of any sample analysis.
  • If the recall is due to a label/ingredient issue, provide and identify the correct and incorrect label(s), description(s), and formulation(s).
  • Please explain how the problem occurred and the date(s) it occurred.
  •   Explain how the problem was discovered and the date discovered.
  • Please explain if the problem/defect affects ALL units subject to recall, or just a portion of the units in the lots subject to recall.
  • Explain why this problem affects only those products/lots subject to recall.
  •   Provide detailed information on complaints associated with the product/problem:

1. Date of complaint
2. Description of complaint -include details of any injury or illness
3. Lot Number/Serial Number/Batch Number involved

iii. DISTRIBUTION PATTERN:

  •   Number of customers you sell directly to by type, for example:

1. wholesalers/distributors
2. manufacturers
3. retail/pharmacy/veterinarian
4. users (medical devices – hospitals, clinics, laboratories)
5. Federal Government Agencies/Ministries
6. Foreign consignees in the case of exported products (specify whether they
are wholesale distributors, retailers or users)

  • Geographic areas of distribution, including foreign countries.

iv. RECALL STRATEGY:

  •   Indicate the level in the distribution chain to which you are extending the recall. (i.e. wholesale/retail/pharmacy/medical user) If your recall only extends to the wholesale/distributor level, we recommend thatyou explain your rationale for not recalling to retail/pharmacy level.
  •   Indicate the method of notification (i.e. mail, phone, facsimile, e-mail). It is advisable to include a written notification so customers will have a record of the recall and your instructions.
  • Indicate how letters will be sent to customers (e.g. overnight mail, first class mail, certified mail, facsimile)
  • If initial notification is by phone, provide a copy of the phone numbers to NAFDAC
  • If you have a web site, you should consider posting the recall notification on the web site as an additional method of recall notification. (Note: This is not recommended as a sole means of customer notification.)
  • Report on what you have instructed customers to do with the recalled product.
  • It is helpful for recalling firms to know the name and title of the Recall Contact for each of its consignees. Addressing a recall notification letter to a recall contact will expedite the recall process and reduce the potential for the notification letter to get misdirected.
  • If product is to be returned, explain the standard operating procedure of the process.
  • Explain if this recall will create a market shortage that will impact on the consumer.
  • Report on recall effectiveness check strategy. Include your actions for nonresponders.
  • Determine and provide your course of action for out-of-business distributors.
  • Provide a proposed standard procedure for the destruction process, if applicable.
  • If the product is to be “reconditioned”, explain how and where the reconditioning will take place. Please provide details of the reconditioning plan to NAFDAC before implementation. All reconditioning must be conducted under any applicable CGMPs.
  • Describe how reconditioned product will be identified so it is not confused with recalled (pre-reconditioned) product.

15.10 In a situation where the product may pose a significant health hazard and recalled product is in the hands of consumers, a press release is usually appropriate. Issuance of a press release should be the highest priority and it should be issued promptly.

Evaluation of the Recall
15.11 It is the recalling firm’s responsibility to assure that the recall is effective. Therefore, we recommend that you consider effectiveness checks for every recall. The purpose of an effectiveness check is to verify your recall notification letter was received by the customer, that the customer read and understood the letter and followed the recall instructions. The effectiveness check should also verify your recall reached the appropriate level in the distribution chain. The effectiveness check is your means of evaluating the effectiveness of your recall. If your effectiveness checks indicate that the recall notification was not received, read and/or instructions followed, then you should take necessary steps to make the recall effective. These steps may involve sending out a follow up notification that better identifies the product, better explains the problem and/or provides better instructions to customers.

Note: In addition to the effectiveness checks conducted by recalling firms, NAFDAC may also contact a percentage of your customers (referred to as audit checks) as a means of assuring the recalling firm and its consignees are carrying out their recall responsibilities. If NAFDAC audit checks determine the recall to be ineffective, the recalling firm (or sub recalling firm if such is the case) will then be asked by to take appropriate actions, including re-issuing recall notifications.

15.12 You will be asked to provide Recall Status Reports after initiating a recall (usually on a monthly basis but more frequently when indicated) to the nearest NAFDAC office. The reports requested will usually include the following information:
– Dates customers notified
– Number of customers notified
– Number of customers responding
– Quantity of RECALLED product returned or accounted for
– Details of your recall effectiveness checks

15.13 The root cause of the problem that resulted in the recall is to be provided to the NAFDAC office in your locality once it has been established. It is important to establish the root cause of the problem so that appropriate preventative measures can be taken.

15.14 We recommend that you explain the corrective actions planned or underway and provide standard operating procedures that will prevent a similar problem from re-occurring.

15.15 We recommend that you evaluate your recall for termination when all possible customer responses have been received and it is reasonable to assume that the recalled product has been recovered, corrected, reconditioned, or destroyed. A final status report and documentation of recalled product disposition should be provided to NAFDAC before formal termination of the recall action.

Recalls

15.16 A person should be designated as responsible for execution and coordination of recalls.

15.17 In the event of a voluntarily recall or serious and/ or potentially life-threatening situation, local, national, and/or international authorities should be informed.

15.18 Appropriate investigation of the reason for recall should be conducted.

15.19 Recalled products should be identified and stored in a restricted and secure area while awaiting a decision on their fate.

16.0 Self inspection

16.1 Self inspections should be conducted in order to monitor the implementation and compliance with good manufacturing practice principles and to propose necessary corrective measures.

16.2 Personnel matters, premises, equipment, documentation, production, quality control, distribution of the medicinal products, arrangements for dealing with complaints and recalls, and self inspection, should be examined at intervals following a pre-arranged program in order to verify their conformity with the principles of quality assurance.

16.3 Self inspections should be conducted in an independent and detailed manner by designated competent persons(s) from the company. Independent audits by external experts may also be useful.

16.4 All self inspections should be documented.

16.5 Reports of self inspection should contain all the observations made during the inspections and where applicable, proposals for corrective actions.

16.6 Corrective actions taken following self inspection should also be documented.

Medicinal product inspection
16.7 Packaged and labeled medicinal products should be examined during finishing operations to provide assurance that containers and packages in the batch have the correct label.

16.8 A representative sample of units should be collected at the completion of finishing
operations and should be visually examined for correct labeling.
16.9 Results of these examinations should be recorded in the batch manufacturing or control records.

17.0 Penalty

a. A person who contravenes a provision of these regulations is guilty of an offence and liable on conviction:-
i. in the case of an individual, to imprisonment for a term not exceeding two years or to a fine not exceeding N50,000 or to both imprisonment and fine.
ii. In the case of body corporate, to a fine not exceeding N100,000.
b. Where an offence under these Regulations is committed by a body corporate or firm or other association of individuals:-
i. every director, manager, secretary or other similar officer of the body
corporate; or
ii. every partner or officer of the firm; or
iii. every trustee of the body concerned; or
iv. every person concerned in the management of the affairs of the association; or
v. every person who was purporting to act in a capacity referred to in paragraphs (i) to (iv), is severally guilty of that offence and liable to be proceeded against and punished for that offence in the same manner as if he had himself committed the offence unless he proves that the act or omission constituting the offence took place without his knowledge, consent or connivance.

Interpretations
In these regulations, unless the context otherwise requires the following terms shall have the meanings specified:

Acceptance/rejection criteria
The product specifications and acceptance/rejection criteria, such as acceptable quality level and unacceptable quality level, with an associated sampling plan, that are necessary for making a decision to accept or reject a lot or batch (or any other convenient subgroups of manufactured units).

Act

The NAFDAC Decree 1993 as amended

Active ingredient

Any component that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or other animals. The term includes those components that may undergo chemical change in the manufacture of the medicinal product and be present in the medicinal product in a modified form intended to furnish the specified activity or effect.

Active pharmaceutical ingredients (API) (or Medicinal Substances)
Any substances or mixture of substances intended to be used in the manufacture of a drug (medicinal) product and that, which when used in the production of a drug, becomes an active ingredient of the medicinal product. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the
structure and function of the body.

Actual yield

The quantity that is actually produced at any appropriate phase of manufacture, processing, or packing of a particular medicinal product.

Agency

National Agency for Food and Drug Administration and Control

Aseptic area

A zone or zones within a clean area where grade A or B conditions are maintained.

Aseptic process

A method of producing a sterile product in which sterile bulk drug or sterile raw materials are compounded and assembled with sterile packaging components under grade A or B conditions.

Authorized person

The person recognised by the Agency as having the necessary basic scientific and technical background and experience; and who is responsible for ensuring that each batch of finished product has been manufactured, tested and approved for release in compliance with the laws and regulations in force in that country.

Batch (or lot)

A batch of a medicinal product that comprises all the units of a drug form which are made from the same initial mass of material and have undergone a single series of manufacturing operations or a single sterilization operation or, in the case of a continuousproduction process, all the units manufactured in a given period of time during the same cycle of manufacture. A lot can also be a batch, or a specific identified portion of a batch, having uniform character and quality within specified limits.

Bulk product

Any product which has completed all processing stages up to, but not including, final packaging.

Calibration

The set of operations which establish, under specified conditions, the relationship between values indicated by a measuring instrument or measuring system, or values represented by a material measure and the corresponding known values of a reference standard.

Component

Any ingredient intended for use in the manufacture of a medicinal product, including those that may not appear in such medicinal product.

Computer system

A group of hardware components and associated software, designed and assembled to perform a specific function or group of functions.

Computerised system

A system including the input of data, electronic processing and the output of information to be used either for reporting or automatic control.

Contamination

The undesired introduction of impurities of a chemical or microbiological nature, or of foreign matter, into or on to a starting material, intermediate or finished product during production, sampling, packaging or repackaging, storage or transport.

Cross contamination

Contamination of a material or product with another material or product.

Fiber

Any particulate contaminant with a length at least three times greater than its width.

Finished product

A finished dosage form that has undergone all stages of manufacture, including packaging in its final container and labelling.

Gang-printed labeling

Labeling derived from a sheet of material on which more than one item of labeling is printed.

Inactive ingredient

Any component other than an “active ingredient.”

In-process material

Any material fabricated, compounded, blended, or derived by chemical reaction that is produced for, and used in, the preparation of the medicinal product.

Intermediate product

Partly processed material which must undergo further manufacturing steps before it becomes a bulk product.

Lot number, control number, or batch number
Any distinctive combination of letters, numbers, or symbols, or any combination of them, from which the complete history of the manufacture, processing, packing, holding, and distribution of a batch or lot of medicinal product or other material can be determined.

Manufacture, processing, packing, or holding of a medicinal product
Includes packaging and labeling operations, testing, and quality control of medicinal products.

Manufacturer

A company that carries out operations such as production, packaging, repackaging, labelling and re-labelling of pharmaceuticals.

Marketing authorization (product license, registration certificate)
A legal document issued by the competent drug regulatory authority that establishes the detailed composition and formulation of the product and the pharmacopoeial or other recognized specifications of its ingredients and of the final product itself, and includes details of packaging, labelling and shelf-life.

Master formula

A document or set of documents specifying the starting materials with their quantities and the packaging materials, together with a description of the procedures and precautions required to produce a specified quantity of a finished product as well as the processing instructions, including the in-process.

Master record

A document or set of documents that serve as a basis for the batch documentation (blank batch record).

Materials

A general term used to denote components, raw materials (starting materials, reagents, solvents), process aids, intermediates, APIs, product containers, closures, packaging and labeling materials and in-process materials.

Medicinal product

Any substance or combination of substances which may be administered to human beings or animals with a view to preventing diseases, making a medical diagnosis or restoring, correcting or modifying physiological functions in human beings or in animals.

Non-fiber-releasing filter

Any filter, which after any appropriate pretreatment such as washing or flushing, will not release fibers into the component or medicinal product that is being filtered. All filters composed of asbestos are deemed to be fiber-releasing filters.

Packaging

All operations, including filling and labelling, which a bulk product has to undergo in order to become a finished product.

Note: Filling of a sterile product under aseptic conditions or a product intended to be terminally sterilized, would not normally be regarded as part of packaging

Packaging material

Any material employed in the packaging of a medicinal product, excluding any outer packaging used for transportation or shipment. Packaging materials are referred to as primary or secondary according to whether or not they are intended to be in direct contact with the product.

Percentage of theoretical yield
The ratio of the actual yield (at any appropriate phase of manufacture, processing, or packing of a particular medicinal product) to the theoretical yield (at the same phase), stated as a percentage.

Production

All operations involved in the preparation of a medicinal product, from receipt of materials, through processing and packaging, to its completion as a finished product.

Qualification

Action of proving that any premises, systems and items of equipment work correctly and actually leads to the expected results. The word validation is sometimes widened to incorporate the concept of qualification.

Quality assurance (QA)

The sum total of the organised arrangements made with the object of ensuring that all medicinal products are of the quality required for their use and that quality systems are maintained.

Quality control (QC)

Quality Control is the part of GMP that is concerned with sampling, specifications, testing, documentation, and release procedures which ensures that materials are not released for use, and that medicinal products are not released for sale or supply, until their quality has been deemed satisfactory.

Quality control unit

An organizational unit independent of production designated by the firm to be responsible for the duties relating to both quality control and quality assurance functions. This can be in the form of separate QA and QC units or a single individual or group, depending upon the size and structure of the organization.

Quality unit(s)

An organizational unit independent of production which fulfills both Quality Assurance and Quality Control responsibilities. This can be in the form of separate QA and QC units or a single individual or group, depending upon the size and structure of the organization.

Quarantine

The status of starting or packaging materials, intermediate, bulk or finished products isolated physically or by other effective means whilst awaiting a decision on their release or refusal.

Recovery

The introduction of all or part of previous batches of the required quality into another batch at a defined stage of manufacture.

Regulatory action

Includes but not limited to product hold, recall, forfeiture, or destruction, sealing of manufacturing line or facility, withdrawal of GMP certificate or product license/registration certificate, prosecution

Representative sample

A sample that consists of a number of units that are drawn based on rational criteria such as random sampling and intended to ensure that the sample accurately portrays the material being sampled.

Reprocessing

The reworking of all or part of a batch of product of an unacceptable quality from a defined stage of production so that its quality may be rendered acceptable by one or more additional operations.

Retention or Reserve sample

Retained sample of each batch of starting materials and finished medicinal product and that is representative of the batch.

Signed (signature)

The record of the individual who performed a particular action or review. This record can be initials, full handwritten signature, personal seal, or authenticated and secure electronic signature.

Specifications

A list of detailed requirements with which the products or materials used or obtained during manufacture have to conform. They serve as a basis for quality evaluation.

Standard operating procedures (SOP)
An authorized written procedure giving instructions for performing operations not necessarily specific to a given product or material (example equipment operation, maintenance and cleaning; validation; cleaning of premises and environmental control; sampling and inspection). Certain SOPs may be used to supplement product-specific master and batch production documentation.

Starting material

Any substance used in the production of a medicinal product excluding packaging materials.

Strength

1. The concentration of the drug substance (for example, weight/weight, weight/volume, or unit dose/volume basis), and/or

2. The potency, that is, the therapeutic activity of the medicinal product as indicated by appropriate laboratory tests or by adequately developed and controlled clinical data (expressed, for example, in terms of units by reference
to a standard).

System

A regulated pattern of interacting activities and techniques which are united to form an organised whole.

Tamper-resistant package

A package having one or more indicators or barriers to entry which, where breached or missing, can reasonably be expected to provide visible evidence to consumers that tampering has occurred. A tamper-resistant package may involve an immediate-container and closure system or secondary- container or carton system or any combination of systems intended to provide a visual indication of package integrity.

Theoretical yield

The quantity that would be produced at any appropriate phase of manufacture, processing, or packing of a particular medicinal product, based upon the quantity of components to be used, in the absence of any loss or error in actual production.

Validation

A documented program that provides a high degree of assurance that a specific process, method, or system will consistently produce a result meeting pre-determined criteria.

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