Good Manufacturing Practice Guidelines for Veterinary Drug and Product Manufacturers

December 8, 2005

DA ADMINISTRATIVE ORDER NO. 38-05

 

INTRODUCTION

This order is issued under the authority conferred upon the Secretary of Health and the Secretary of Agriculture by virtue of Section 26 (a) of Republic Act 3720 as amended.

Guidelines for current Good Manufacturing Practice (cGMP) are an important element in achieving acceptable standards for the manufacture and handling of products. These guidelines are an internationally accepted set of guidelines that describe proven systems and procedures for the production of quality products. They also contain the documentation requirements to provide a traceable history of the production and distribution of every batch of product produced. These cGMP guidelines are adopted to prescribe standards in the manufacture of veterinary drugs and products to ensure that no person or establishment shall manufacture veterinary drugs and products under substandard conditions.

The guidelines are presented in sections, each addressing a specific topic. In addition to the general matters of cGMP outlined in the succeeding ten sections of this Order, a series of annexes providing details about specific areas of activity is included.

For some manufacturing processes, different annexes will apply simultaneously. For example, the annexes on sterile preparations and on the manufacture of immunological veterinary medicinal products shall be consulted for the preparation of vaccines. cDCaHA

A glossary of some terms used in the guidelines has been incorporated after the annexes.

It is recognized that there are acceptable methods, other than those described in these guidelines, that are capable of achieving the principles of this Order. This Order is not intended to put any restraint upon the development of new concepts or new technologies that have been validated and provide a level of Quality Assurance at least equivalent to the standard set out in this Order.

License to manufacture veterinary drugs and products shall be issued only in compliance with current Good Manufacturing Practice guidelines.

SECTION 1. Quality Management. —

1.1 Principle

1.1.1 The holder of a manufacturing authorization shall manufacture veterinary medicinal products so as to ensure that they are fit for their intended use, comply with the requirements of the manufacturing authorization and do not place animals 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. It shall be fully documented and its effectiveness monitored. All parts of the Quality Assurance system shall be adequately resourced with competent personnel, and suitable and sufficient premises, equipment and facilities.

1.1.2 The basic concepts of Quality Assurance, Good Manufacturing Practice and Quality Control are interrelated. They are described here in order to emphasize their relationships and their fundamental importance to the production and control of veterinary medicinal products.

1.2 Quality Assurance

1.2.1 Quality Assurance is a wide-ranging concept that covers all matters that individually or collectively influence the quality of a product. It is the sum total of the organized arrangements made with the object of ensuring that 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 Order.

1.2.2 The system of Quality Assurance appropriate for the manufacture of products shall ensure that:

1.2.2.1 products are designed and developed in a way that takes account of the requirements of Good Manufacturing Practice (and Good Laboratory Practice);

1.2.2.2. managerial responsibilities production and control operations are clearly specified and Good Manufacturing Practice adopted;

1.2.2.3 arrangements are made for the manufacture, supply and use of the correct starting and packaging materials;

1.2.2.4 all necessary controls on intermediate products, and any other in process controls and validations are carried out;

1.2.2.5 the finished product is correctly processed and checked, according to the defined procedures;

1.2.2.6 products are not sold or supplied before an authorized person has documented that each production batch has been produced and controlled in accordance with the specifications of the manufacturing authorization and any other relevant regulations;

1.2.2.7 satisfactory arrangements exist to ensure, as far as possible, that the products are stored, distributed and subsequently handled so that quality is maintained throughout their shelf-life; and

1.2.2.8 there is a procedure for self inspection and/or quality audit that regularly appraises the effectiveness and applicability of the Quality Assurance system.

1.3 Good Manufacturing Practice for Veterinary Medicinal Products

1.3.1 Good Manufacturing Practice (GMP) is that part of Quality Assurance which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the manufacturing authorization.

1.3.2 Good Manufacturing Practice is concerned with both production and quality control. The basic requirements of GMP are that:

1.3.2.1 all manufacturing processes are clearly defined, systematically reviewed in the light of experience and shown to be capable of consistently manufacturing veterinary medicinal products of the required quality and complying with their specifications;

1.3.2.2 critical steps of manufacturing processes and significant changes to the process are validated;

1.3.2.3 all necessary facilities for GMP are provided including:

1.3.2.3.1 appropriately qualified and trained personnel;

1.3.2.3.2 adequate premises and space; TAcSaC

1.3.2.3.3 suitable equipment and services;

1.3.2.3.4 correct materials, containers and labels;

1.3.2.3.5 approved procedures and instructions; and

1.3.2.3.6 suitable storage and transport

1.3.2.4 instruction and procedures are written in an instructional form in clear" and unambiguous language, specifically applicable to the facilities provided;

1.3.2.5 operators are trained to carry out procedures correctly;

1.3.2.6 records are made, manually and/or by recording instruments, during manufacture which demonstrate that all the steps required by the defined procedures and instructions were in fact taken and that the quantity and quality of the product was as expected. Any significant deviations are fully recorded and investigated;

1.3.2.7 manufacturing records including distribution, which enable the complete history of a batch to be traced, are retained in a comprehensible and accessible form;

1.3.2.8 the distribution (wholesaling) of the product minimizes any risk to their quality;

1.3.2.9 a system is available to recall any batch of product from sale or supply; and

1.3.2.10 complaints about marketed products are examined, the causes of quality defects investigated, and appropriate measures taken in respect of the defective products and to prevent recurrence.

1.4 Quality Control

1.4.1 Quality Control is that part of Good Manufacturing Practice which is concerned with sampling, specifications and testing, and with the organization, documentation and release procedures which ensure that the necessary and relevant tests are actually carried out and that materials are not released for use, nor products released for sale or supply, until their quality has been judged to be satisfactory. lawscd06

1.4.2 The basic requirements of Quality Control are that:

1.4.2.1 adequate facilities, trained personnel and approved procedures are available for sampling, inspecting and testing starting materials, packaging materials, intermediate products, bulk products, and finished products, and where appropriate for monitoring environmental conditions for GMP purposes;

1.4.2.2 samples of starting materials, packaging materials, intermediate products, bulk products and finished products are taken by personnel and by methods approved by Quality Control.

1.4.2.3 test methods are validated;

1.4.2.4 records are made, manually and/or by recording instruments, which demonstrate that all the required sampling, inspecting and testing procedures were actually carried out. Any deviations are fully recorded and investigated;

1.4.2.5 the finished products contain active ingredients complying with the qualitative and quantitative composition of the manufacturing authorization, are of the purity required, and 'are enclosed within their proper container and correctly labeled;

1.4.2.6 records are made of the results of inspection and that testing of materials, intermediate, bulk, and finished products is formally assessed against specification. Product assessment includes a review and evaluation of relevant production documentation and an assessment of deviations from specified procedures;

1.4.2.7 no batch of product is released for sale or supply prior to documented approval by an authorized person that it is in accordance with the product specifications; and CEASaT

1.4.2.8 sufficient reference samples of starting materials and products are retained to permit future examination of the product if necessary and that the product is retained in its final pack unless exceptionally large packs are produced.

SECTION 2. Personnel. —

2.1 Principle

The establishment and maintenance of a satisfactory system of Quality Assurance and the correct manufacture of veterinary medicinal products relies upon people.

For this reason there must be sufficient qualified personnel to carry out all the tasks that are the responsibility of the manufacturer. Individual responsibilities shall be clearly understood by the individuals and recorded. All personnel shall be aware of the principles of Good Manufacturing Practice that affect-them, and undergo initial and continuing training, including hygiene instructions relevant to their needs.

2.2 General

2.2.1 The manufacturer shall have an adequate number of personnel with the necessary qualifications and practical experience. The responsibilities placed on anyone individual shall not be so extensive as to present any risk to quality.

2.2.2 The manufacturer must have an organizational chart. People in responsible positions shall 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 shall be no gaps or unexplained overlaps in the responsibilities of those personnel concerned with the application of GMP.

2.3 Key personnel

2.3.1 Key personnel include the head of Production, the head of Quality Control and, if at least one of these persons is not responsible for the release of products, the authorized person(s) designated for the purpose. Normally, key posts shall be occupied by full-time personnel.

2.3.2 The heads of Production and Quality Control must be independent from each other. In large organizations, it may be necessary to delegate some of the functions listed in 2.3.5, 2.3.6 and 2.3.7.

2.3.3 The production manager shall be a Professional Regulation Commission (PRC) registered qualified pharmacist or any other related profession.

2.3.4 The quality control manager shall be a PRC registered qualified pharmacist/chemist or any other related profession.

2.3.5 The Head of the Production Department generally has the following responsibilities:

2.3.5.1 to ensure that products are produced and stored according to the appropriate documentation in order to obtain the required quality;

2.3.5.2 to approve the instructions relating to production operations and to ensure their strict implementation;

2.3.5.3 to ensure that the production records are evaluated and signed by an authorized person before they are sent to the Quality Control Department;

2.3.5.4 to check the maintenance of the department, premises and equipment;

2.3.5.5 to ensure that the appropriate validations are done; and

2.3.5.6 to ensure that the required initial and continuing training of department personnel is carried out and adapted according to need.

2.3.6 The Head of the Quality Control Department generally has the following responsibilities:

2.3.6.1 to approve or reject, as appropriate, starting materials, packaging materials, and intermediate, bulk and finished products;

2.3.6.2 to evaluate batch records;

2.3.6.3 to ensure that all necessary testing is carried out;

2.3.6.4 to approve specifications, sampling instructions, test methods and other Quality Control procedures; CITcSH

2.3.6.5 to approve and monitor any contract analysis;

2.3.6.6 to check the maintenance of the department, premises and equipment;

2.3.6.7 to ensure that appropriate validations are done; and

2.3.6.8 to ensure that the required initial and continuing training of department personnel is carried out and adapted according to need.

2.3.7 The Heads of Production and Quality Control generally have some shared or jointly exercised responsibilities relating to quality. These may include:

2.3.7.1 the authorization of written procedures and other documents, including amendments;

2.3.7.2 the monitoring and control of the manufacturing environment;

2.3.7.3 plant hygiene, process validation, training;

2.3.7.4 the approval and monitoring of suppliers of materials and contract manufacturers;

2.3.7.5 the designation and monitoring of storage conditions for materials and products;

2.3.7.6 the monitoring of compliance with the requirements of GMP and retention of records; and

2.3.7.7 the inspection, investigation, and taking of samples, in order to monitor factors that may affect product quality.

2.4 Training

2.4.1 The manufacturer shall provide training for all the personnel whose duties take them into production areas or into quality control laboratories (including the technical, maintenance and cleaning personnel), and for other personnel whose activities could affect the quality of the product.

2.4.2 Besides the basic training on the theory and practice of Good Manufacturing Practice, newly recruited personnel shall receive training appropriate to the duties assigned to them. Continuing training programs shall be available, approved by either the head of production or the head of Quality Control, as appropriate. After training, the consequential employees' performance shall be appraised to determine their capability to meet the qualification requirement for the jobs. Records shall be kept. CAaEDH

2.4.3 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, shall be given specific training.

2.4.4 Visitors or untrained personnel shall, preferably, not be taken into the production and quality control areas. If this is unavoidable, they shall be given information in advance, particularly about personal hygiene and the prescribed protective clothing. They shall be closely supervised.

2.4.5 The concept of Quality Assurance and all the measures capable of improving its understanding and implementation shall be fully discussed during the training sessions.

2.5 Personal Hygiene

2.5.1 Detailed hygiene programs shall be established and adapted to the different needs within the factory. They shall include procedures relating to the health, hygiene practices and clothing of personnel. These procedures shall be understood and followed in a very strict way by every person whose duties take them into the production and control areas. Hygiene programs shall be promoted by management and widely discussed during training sessions

2.5.2 All personnel shall undergo medical examination upon recruitment. It must be the manufacturer's responsibility that there are instructions ensuring that health conditions that can be of relevance to the quality of products come to the manufacturer's knowledge. After the first medical examination, examinations shall be carried out when necessary for the work and personal health. STaAcC

2.5.3 Steps shall be taken to ensure as far as is practicable that no person affected by an infectious disease or having open lesions on the exposed surface of the body is engaged in the manufacture of medicinal products.

2.5.4 Every person entering the manufacturing areas shall wear protective garments appropriate to the operations to be carried out

2.5.5 Eating, drinking, chewing or smoking, or the storage of food, drink, smoking materials or personal medication in the production and storage areas shall be prohibited, h general, any unhygienic practice within the manufacturing areas or in any other area where the product might be adversely affected shall be forbidden.

2.5.6 Direct contact shall be avoided between the operator's hands and the exposed product as well as with any part of the equipment that comes into contact with the products.

2.5.7 Personnel shall be instructed to use the hand washing facilities. Signs to this effect shall be posted.

2.5.8 Any specific requirements for the manufacture of special groups of products, for example sterile preparations, are covered in the annexes.

SECTION 3. Premises. —

3.1 Principle

Premises and equipment must be located, designed, constructed, adapted and maintained to suit the operations to be carried out. Their layout and design must aim to minimize the risk of errors and permit effective cleaning and maintenance in order to avoid cross contamination, build up of dust or dirt and, in general, any adverse effect on the quality of products.

3.2 General

3.2.1 Premises shall be situated in an environment which, when considered together with measures to. protect the manufacture, presents minimal risk of causing contamination of materials or products.

3.2.2 Premises shall be carefully maintained, ensuring that repair and maintenance operations do not present any hazard to the quality of products. They shall be cleaned and, where applicable, disinfected according to detailed written procedures.

3.2.3 Lighting, temperature, humidity and ventilation shall be appropriate such that they do not adversely affect, directly or indirectly, either the medicinal products during their manufacture and storage, or the accurate functioning of equipment

3.2.4 Premises shall be designed and equipped so as to afford maximum protection against the entry of insects or other animals.

3.2.5 Steps shall be taken in order to prevent the entry of unauthorized people.

Personnel who do not work in them shall not use production, storage and quality control areas as a right of way.

3.3 Production areas

3.3.1 In order to minimize the risk of a serious medical hazard due to cross-contamination, dedicated and self-contained facilities shall be available for the production of particular medicinal products, such as highly sensitizing materials (e.g. penicillin) or biological preparations (e.g. from live microorganisms).

The production of certain additional products, such as certain antibiotics, certain hormones, certain cytotoxics, certain highly active drugs and non-medicinal products shall not be conducted in the same facilities.

For those products, in exceptional cases, the principle of campaign working in the same facilities can be accepted provided that specific precautions are taken and the necessary validations are made. The manufacture of technical poisons, such as pesticides and herbicides, shall not be allowed in premises used for the manufacture of medicinal products. TDcAaH

3.3.2 Premises shall preferably be laid out in such a way as to allow the production to take place in areas connected in a logical order corresponding to the sequence of the operations and to the requisite cleanliness levels.

3.3.3 The adequacy of the working and in-process storage space shall permit the orderly and logical positioning of equipment and materials so as to minimize the risk of confusion between different medicinal products or their components, to avoid cross-contamination and to minimize the risk of omission or wrong application of any of the manufacturing or control steps.

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

3.3.5 Pipe work, light, fittings, ventilation points and other services shall be designed and sited to avoid the creation of recesses that are difficult to clean. As far as possible, for maintenance purposes, they shall be accessible from outside the manufacturing areas.

3.3.6 Drains shall be of adequate size, and have trapped gullies. Open channels shall be avoided where possible, but if necessary, they shall be shallow to facilitate cleaning and disinfection.

3.3.7 Production areas shall be effectively ventilated, with air control facilities (including temperature and, where necessary, humidity and filtration) appropriate both to the products handled, to the operations undertaken within them and to the external environment.

3.3.8 Weighing of starting materials usually shall be carried out in a separate weighing room designed for that use.

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

3.3.10 Premises for the packaging of medicinal products shall be specifically designed and laid out so as to avoid mix-ups or cross-contamination.

3.3.11 Production areas shall be well lit especially where visual on-line controls are carried out.

3.3.12 In-process controls may be carried out within the production area provided they do not carry any risk for the production.

3.4 Storage Areas

3.4.1 Storage areas shall 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.

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

3.4.3 Receiving and dispatch bays shall protect materials and products from the weather. Reception areas shall be designed and equipped to allow containers of incoming materials to be cleaned where necessary before storage.

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

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

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

3.4.7 Highly active materials or products shall be stored in safe and secure areas.

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

3.5 Quality Control Areas

3.5.1 Normally, quality control laboratories shall be separated from production areas. This is particularly important for laboratories for the control of biologicals, microbiologicals and radioisotopes, which shall also be separated from each other.

3.5.2 Control laboratories shall be designed to suit the operations to be carried out in them. Sufficient space shall be given to avoid mix-ups and cross-contamination.

There shall be adequate suitable storage space for samples and records.

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

3.5.4 Special requirements are needed in laboratories handling particular substances, such as biological or radioactive samples.

3.6 Ancillary Areas

3.6.1 Rest and refreshment rooms shall be separate from other areas.

3.6.2 Facilities for changing clothes, and for washing and toilet purposes, shall be easily accessible and appropriate for the number of users'. Toilets shall not directly communicate with production or storage areas.

3.6.3 Maintenance workshops shall as far as possible be separated from production areas. Whenever parts and tools are stored in the production area, they .shall be kept in rooms or, lockers .reserved for that use.

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

SECTION 4. Equipment. —

4.1 Principle

Equipment used in the manufacturing of veterinary drugs and products shall be of appropriate design and construction, adequate in size, suitably located in order to assure product quality and process reproducibility and facilitate easy cleaning and maintenance.

4.2 General

4.2.1 Manufacturing equipment shall be designed, located and maintained to suit its intended purpose.

4.2.2 Repair and maintenance operations shall not present any hazard to the quality of the products.

4.2.3 Manufacturing equipment shall be designed so that it can be easily and thoroughly cleaned. It shall be cleaned according to detailed and written procedures, and stored only in a clean and dry condition. IcTEaC

4.2.4 Washing and cleaning equipment shall be chosen and used in order not to be a source of contamination.

4.2.5 Equipment shall be installed in such a way as to prevent any risk of error or of contamination.

4.2.6 Production equipment shall not present any hazard to the products. The parts of the production equipment that come into contact with the product must not be reactive, additive or absorptive to such an extent that it will affect the quality of the product and thus present any hazard.

4.2.7 Balances and measuring equipment of an appropriate range and precision shall be available for production and control operations.

4.2.8 Measuring, weighing, recording and control equipment shall be calibrated and checked at defined intervals by appropriate methods. Adequate records of such tests shall be maintained.

4.2.9 Fixed pipe work shall be clearly labeled to indicate the contents and, where applicable, the direction of flow.

4.2.10 Distilled, de-ionized, and where appropriate, .other water pipes shall be sanitized according to written procedures that detail the action limits for microbiological contamination and the measures to be taken.

4.2.11 Defective equipment shall, if possible, be removed from production and quality control areas, or at least be clearly labeled as defective.

SECTION 5. Documentation. —

5.1 Principle

Good documentation constitutes an essential part of the Quality Assurance system. Clearly written documentation prevents errors from spoken communication and permits tracing of batch history. Specifications, manufacturing formulas and instructions, procedures, and records must be free from errors and available in writing. The legibility of documents is of paramount importance.

5.2 General

5.2.1 Specifications describe in detail the requirements with which the products or materials used or obtained during manufacture have to conform. They serve as a basis for quality evaluation.

5.2.2 Master Batch Production Record (manufacturing formula), Master Processing Record (processing) and Master Packaging Procedure (packaging instructions) state all the starting materials used and lay down all processing and packaging operations.

5.2.3 Procedures give directions for performing certain operations, e.g. cleaning, clothing, environmental control, sampling/testing, and equipment operations. cDCaHA

5.2.4 Records provide a history of each batch of product, including its distribution, and also of all other relevant circumstances pertinent to the quality of the final product.

5.2.5 Documents shall be designed, prepared, reviewed and distributed with care. They shall comply with the relevant parts of the manufacturing authorization.

5.2.6 Documents shall be approved, signed and dated by appropriate and authorized persons.

5.2.7 Documents shall have unambiguous contents; title, nature and purpose shall be clearly stated. They shall be laid out in an orderly fashion and be easy to check. Reproduced documents shall be clear and legible. The reproduction of working documents from master documents must not allow any error to be introduced through the reproduction process.

5.2.8 Documents shall be regularly reviewed and kept up-to-date. When a document has been revised, systems shall be operated to prevent inadvertent use of superseded documents.

5.2.9 Documents shall not be handwritten, although, where documents require the entry of data, these entries may be made in clear, legible, indelible handwriting. Sufficient space shall be provided for such entries.

5.2.10 Any alteration made to the entry on a document shall be signed and dated; the alteration shall permit the reading of the original information. Where appropriate, the reason for the alteration shall be recorded. TSacAE

5.2.11 The records shall be made or completed at the time each action is taken and in such a way that all significant activities concerning the manufacture of products are traceable. They shall be retained for at least one year after the expiry date of the finished product.

5.2.12 Data may be recorded by electronic data processing systems, photographic or other reliable means, but detailed procedures relating to the system in use shall be available and the accuracy of the records shall be checked. If documentation is handled by electronic data processing methods, only authorized persons shall be able to enter or modify data in the computer and there shall be a record of changes and deletions; access shall be restricted by passwords or other means and the result of entry of critical data shall be independently checked. Batch records electronically stored shall be protected by back-up transfer on magnetic tape, microfilm, paper or other means. It is particularly important that the data are readily available throughout the period of retention.

5.3 Specification Documents Requirement

There shall be appropriately authorized and dated specifications for starting and packaging materials, and finished products; where appropriate, they shall also be available for intermediate or bulk products.

5.4 Specifications for Starting and Packaging Materials

5.4.1 Specifications for starting and primary or printed packaging materials shall include, if applicable:

5.4.1.1 a description of the materials, including:

5.4.1.1.1 the designated name and the internal code reference

5.4.1.1.2 the reference, if any, to a pharmacopoeia monograph;

5.4.1.1.3 the approved suppliers and, if possible, the original producer of the products; and

5.4.1.1.4 a specimen of printed materials.

5.4.1.2 directions for sampling and testing or reference to procedures;

5.4.1.3 qualitative and quantitative requirements with acceptance limits;

5.4.1.4 storage conditions and precautions; and

5.4.1.5 the maximum period of storage before re-examination.

5.5 Specifications for Intermediate and Bulk Products

5.5.1 Specifications for intermediate and bulk products shall be available if these are purchased or dispatched, or if data obtained from intermediate products are used for the evaluation of the finished product.

5.5.2 The specifications shall be similar to specifications for starting materials or for finished products, as appropriate.

5.6 Specifications for Finished Products

5.6.1 Specifications for finished products shall include:

5.6.1.1 the designated name of the product and the code reference where applicable;

5.6.1.2 the formula or a reference to it;

5.6.1.3 a description of the pharmaceutical form and package details;

5.6.1.4 directions for sampling and testing or a reference to procedures;

5.6.1.5 the qualitative and quantitative requirements, with the acceptance limits;

5.6.1.6 the storage conditions and any special handling precautions, where applicable; and

5.6.1.7 the shelf-life.

5.7 Master Batch Production Record and Master Processing Procedure (manufacturing formula and processing instructions)

5.7.1 Formally authorized manufacturing formula and processing instructions shall exist for each product and batch size to be manufactured. They are often combined in one document.

5.7.2 The manufacturing formula shall include:

5.7.2.1 the name of the product, with a product reference code relating to its specification;

5.7.2.2 a description of the pharmaceutical form, strength of the product and batch size;

5.7.2.3 a list of all starting materials to be used, with the amount of each, described using the designated name and a reference that is unique to that material; mention shall be made of any substance that may disappear in the course of processing; and

5.7.2.4 a statement of the expected final yield with the acceptable limits, and of relevant intermediate yields, where applicable.

5.7.3 The processing instructions shall include:

5.7.3.1 a statement of the processing location and the principal equipment to be used;

5.7.3.2 the methods, or reference to the methods, to be used for preparing the critical equipment (e.g. cleaning, assembling, calibrating, sterilizing); aETASc

5.7.3.3 detailed stepwise processing instructions (e.g. checks on materials, pre-treatments, sequence for adding materials, mixing time, temperatures);

5.7.3.4 the instructions for any in-process controls with their limits;

5.7.3.5 where necessary, the requirements for bulk storage of the products; including the container, labeling and special storage conditions where applicable; and

5.7.3.6 any special precautions to be observed.

5.8 Master Packaging Procedure or Packaging Instructions

5.8.1 There shall be formally authorized packaging instructions for each product, pack size and type. These shall normally include, or have a reference to me following:

5.8.1.1 name of the product;

5.8.1.2 description of its pharmaceutical form, and strength where applicable;

5.8.1.3 the pack size expressed in terms of the number, weight or volume of the product in the final container;

5.8.1.4 a complete list of all the packaging materials required for a standard batch size, including quantities, sizes and types. with the code or reference number relating to the specifications of each packaging material; EDCcaS

5.8.1.5 where appropriate, an example or reproduction of the relevant printed packaging materials, and specimens indicating where to apply batch number references, and shelf-life of the product;

5.8.1.6 special precautions to be observed including a careful examination of the area and equipment in order to ascertain the line clearance before operations begin;

5.8.1.7 a description of the packaging operation including any significant subsidiary operations and equipment to be used;

5.8.1.8 details of in-process controls with instructions for sampling and acceptance limits.

5.9 Batch Processing Records

5.9.1 A batch processing record shall be kept for each batch processed. It shall be based on the relevant parts of the currently approved manufacturing formula and processing instructions. The method of preparation of such records shall be designed to avoid transcription errors. The record shall carry the number of the batch being manufactured.

5.9.2 Before any processing begins, there shall be recorded 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.

5.9.3 During processing, the following information shall be recorded at the time each action is taken and after completion. The record shall be dated and signed in agreement by the person responsible for the processing operations:

5.9.3.1 the name of the product;

5.9.3.2 dates and times of commencement of significant intermediate stages and of completion of production;

5.9.3.3 name of the person responsible for each stage of production;

5.9.3.4 initials of the operator of different significant steps of production and where appropriate, of the person who checked each of these operations (e.g. weighing);

5.9.3.5 the batch number and/or analytical control number as well as the quantities of each starting material actually weighed (including the batch number and amount of any recovered or reprocessed material added); ECcTaH

5.9.3.6 any relevant processing operation or event and major equipment used;

5.9.3.7 a record of the in-process controls and the initials of the person(s) carrying them out, and the results obtained;

5.9.3.8 the product yield obtained at different and pertinent stages of manufacture; and

5.9.3.9 notes on special problems including details, with signed authorization for any deviation from the manufacturing formula and processing instructions.

5.10 Batch Packaging Records

5.10.1 A batch packaging record shall be kept for each batch or part batch processed. It shall be based on the relevant parts of the packaging instructions and the method of preparation of such records shall be designed to avoid transcription errors. The record shall carry the batch number and the quantity of bulk product to be packed, as well as the batch number and the planned quantity of finished product that will be obtained.

5.10.2 Before any packaging operation begins, there shall be recorded checks that the equipment and work station are clear of previous products, documents or materials not required for the planned packaging operations, and that equipment is clean and suitable for use. ISCcAT

5.10.3 The following information shall be entered at the time each action is taken and, after completion, the record shall be dated and signed in agreement by the person(s) responsible for the packaging operations:

5.10.3.1 the name of the product;

5.10.3.2 the date(s) and time(s) of the packaging operations;

5.10.3.3 the name of the responsible person carrying out the packaging operation;

5.10.3.4 the initials of the operators of the different significant steps;

5.10.3.5 records of checks for identity and conformity with the packaging instructions including the results of in-process controls;

5.10.3.6 details of the packaging operations carried out, including references to equipment and the packaging lines used;

5.10.3.7 whenever possible, samples of printed packaging materials used, including specimens of the batch coding, expiry dating and any additional overprinting;

5.10.3.8 notes on any special problems or unusual events including details with signed authorization for any deviation from the manufacturing formula and processing instructions; and SITCEA

5.10.3.9 the quantities and reference number or identification of all printed packaging materials and bulk product issued, used, destroyed or returned to stock and the quantities of obtained product, in order to provide for an adequate reconciliation.

5.11 Procedures and Records Receipt

5.11.1 There shall be written procedures and records for the receipt of each delivery of each starting, primary and printed packaging material.

5.11.2 The records of the receipts shall include:

5.11.2.1 the name of the material on the delivery note and the containers;

5.11.2.2 the 'in-house' name and/or code of material if different from;

5.11.2.3 date of receipt;

5.11.2.4 supplier's name and, if possible, manufacturer's name;

5.11.2.5 manufacturer's batch or reference number;

5.11.2.6 total quantity, and number of containers received;

5.11.2.7 the batch number assigned after receipt; and

5.11.2.8 any relevant comment (e.g. state of the containers).

5.11.3 There shall be written procedures for the internal labeling, quarantine and storage of starting materials, packaging materials and other materials, as appropriate.

5.12 Sampling

There shall be written procedures for sampling, which include the person(s) authorized to take samples, the methods and equipment to be used, the amounts to be taken and any precautions to be observed to avoid contamination of the material or any deterioration in its quality.

5.13 Testing

There shall be written procedures for testing materials and products at different stages of manufacture, describing the methods and equipment to be used. The tests performed shall be recorded.

5.14 Others

5.14.1 Written release and rejection procedures shall be available for materials and products, and in particular for the release for sale of the finished product by the authorized person(s) designated for the purpose.

5.14.2 Records shall be maintained of the distribution of each batch of a product in order to facilitate the recall of the batch if necessary.

5.14.3 There shall be written procedures and the associated records of actions taken or conclusions reached, where appropriate, for

5.14.3.1 validation;

5.14.3.2 equipment assembly and calibration;

5.14.3.3  maintenance, cleaning and sanitization;

5.14.3.4 personnel matters including training, clothing, hygiene;

5.14.3.5 environmental monitoring;

5.14.3.6 pest control;

5.14.3.7 complaints;

5.14.3.8 recalls; and

5.14.3.9 returns.

5.15 Clear operating procedures shall be available for major items of manufacturing and test equipment

5.16 Log books shall be kept for major or critical equipment recording, as appropriate, any validations, calibrations, maintenance, cleaning or repair operations, including the dates and identity of people who carried out these operations.

5.17 Log books shall also record in chronological order the use of major or critical equipment and the areas where the products have been ' processed.

SECTION 6. Production. —

6.1 Principle

Production operations must follow clearly defined procedures; they must comply with the principles of Good Manufacturing Practice in order to obtain products of the requisite quality and be in accordance with the relevant manufacturing and marketing authorizations.

6.2 General

6.2.1 Production shall be performed and supervised by competent people.

6.2.2 All handling of materials' and products, such as receipt and quarantine, sampling, storage, labeling, dispensing, processing, packaging and distribution shall be done in accordance with written procedures or instructions and, where necessary, recorded.

6.2.3 All incoming materials shall be checked to ensure that the consignment corresponds to the order. Containers shall be cleaned where necessary and labeled with the prescribed data.

6.2.4 Damage to containers and any other problem, which might adversely affect the quality of a material shall be investigated, recorded and reported to the Quality Control Department ACaDTH

6.2.5 Incoming materials and finished products shall be physically or administratively quarantined immediately after receipt or processing, until they have been released for use or distribution.

6.2.6 Intermediate and bulk products purchased as such shall be handled on receipt as though they were starting materials.

6.2.7 All materials and products shall be stored under the appropriate conditions established by the manufacturer and in an orderly fashion to permit batch segregation and stock rotation.

6.2.8 Checks on yields and reconciliation of quantities shall be carried out as necessary to ensure that there are no discrepancies outside acceptable limits.

6.2.9 Operations on different products shall not be earned out simultaneously or consecutively in the same room unless there is no risk of mix-up or cross-contamination.

6.2.10 At every stage of processing, products and materials shall be protected from microbial and other contamination.

6.2.11 When working with dry materials and products, special precautions shall be taken to prevent the generation and dissemination of dust. This applies particularly to the handling of highly active or sensitizing materials. ESITcH

6.2.12 At all times during processing, all materials, bulk containers, major items of equipment and rooms used shall be labeled or otherwise identified with an indication of the product or material being processed, its strength (where applicable) and batch number. Where applicable, this indication shall also mention the stage of production.

6.2.13 Labels applied to containers, equipment or premises shall be clear, unambiguous and in the company's agreed format. It is often helpful in addition to the wording on the labels to use colors to indicate status (e.g. quarantined, accepted, rejected, and clean).

6.2.14 Checks shall be carried out to ensure that pipelines and other pieces of equipment used for the transportation of products from one area to another are connected in a correct manner.

6.2.15 Any deviation from instructions or procedures shall be avoided as far as possible. If a deviation occurs, it shall be approved in writing by a competent person, with the involvement of the Quality Control Department when appropriate

6.2.16 Access to production premises shall be restricted to authorized personnel.

6.2.17 Normally, the production of non-veterinary medicinal products shall be avoided in areas and with the equipment destined for the production of veterinary medicinal products

6.3 Prevention of Cross-Contamination in Production

Contamination of a starting material or of a product by another material or product must be avoided. This risk of accidental cross-contamination arises from the uncontrolled release of dust, gases, vapors, sprays or organisms from materials and products in process, from residues on equipment, and from operators' clothing.

The significance of this risk varies with the type of contaminant and of product being contaminated. Among the most hazardous contaminants are highly sensitizing materials, biological preparations containing living organisms, certain hormones, cytotoxics, and other highly active materials. Products in which contamination is likely to be most significant are those administered by injection, those given in large doses and/or over a long time.

6.3.1 Cross-contamination shall be avoided by appropriate technical or organizational measures, for example:

6.3.1.1 production in segregated areas (required for products such as penicillin, live vaccines, live bacterial preparations and some other biological), or by campaign (separation in time) followed by appropriate cleaning; EDcICT

6.3.1.2 providing appropriate air-locks and air extraction;

6.3.1.3 minimizing the risk of contamination caused by re-circulation or reentry of untreated or insufficiently treated air;

6.3.1.4 keeping protective clothing inside areas where products with special risk of cross contamination are processed;

6.3.1.5 using cleaning and decontamination procedures of known effectiveness, as ineffective cleaning of equipment is a common source of cross-contamination;

6.3.1.6 using closed systems' of production;

6.3.1.7 testing for residues and use of cleaning status labels on equipment.

6.3.2 Measures to prevent cross-contamination and their effectiveness shall be checked periodically according to set procedures.

6.4 Validation

6.4.1 Validation studies shall reinforce Good Manufacturing Practice and be conducted in accordance with defined procedures. Results and conclusions shall be recorded.

6.4.2 When any new manufacturing formula or method of preparation is adopted, steps shall be taken to demonstrate its suitability for routine processing. The defined process, using the materials and equipment specified, shall be shown to yield a product consistently of the required quality.

6.4.3 Significant amendments to the manufacturing process, including any change in equipment or materials, which may affect product quality and/or the reproducibility of the process shall be validated.

6.4.4 Processes and procedures shall undergo periodic critical re-validation to ensure that they remain capable of achieving the intended results.

6.5 Starting Materials

6.5.1 The purchase of starting materials is an important operation, which shall involve staff that has a particular and thorough knowledge of the suppliers.

6.5.2 Starting materials shall be purchased only from approved suppliers named in the relevant specification and, where possible, directly from the producer, it is recommended that the specifications established by the manufacturer for the starting materials be discussed with the suppliers. It is of benefit that all aspects of the production and control of the starting material in question, including handling, labeling and packaging requirements, as well as complaints and rejection procedures, are discussed with the manufacturer and the supplier.

6.5.3 For each delivery, the containers shall be checked for integrity of package and seal and for correspondence between the delivery note and the supplier's labels.

6.5.4 If one material delivery is made up of different batches, each batch must be considered as separate for sampling, testing and release."

6.5.5 Starting materials in the storage area shall be appropriately labeled. Labels shall bear at least the following information:

6.5.5.1 the designated name of the product and the internal code reference where applicable;

6.5.5.2 a batch number given at receipt; where appropriate, the status of the contents (e.g. in quarantine, on test, released, rejected);

6.5.5.3 where appropriate, an expiry date or a date beyond which retesting is necessary; and

6.5.5.4 When fully computerized storage systems are used, all the above information shall not necessarily be in a legible form on the label.

6.5.6 There shall be appropriate procedures or measures to assure the identity of the contents of each container of .starting material. Bulk containers from which samples have been drawn shall be identified. cISAHT

6.5.7 Only starting materials that have been released by the Quality Control Department and that are within their shelf-life shall be used.

6.5.8 Starting materials shall be dispensed only by designated persons, following a written procedure, to ensure that the correct materials are accurately weighed or measured into clean and properly labeled containers.

6.5.9 Each dispensed material and its weight or volume shall be independently checked and the check recorded.

6.5.10 Materials dispensed for each batch shall be kept together and conspicuously labeled as such.

6.6 Processing Operations: Intermediate and Bulk Products

6.6.1 Before any processing operation is started, steps shall be taken to ensure that the work area and equipment are clean and free from any starting materials, products, product residues or documents not required for the current operation.

6.6.2 Intermediate and bulk products shall be kept under appropriate conditions.

6.6.3 Critical processes shall be validated (see Validation' in this Section).

6.6.4 Any necessary in-process controls and environmental controls shall be carried out and recorded. IcDCaS

6.6.5 Any significant deviation from the expected yield shall be recorded and investigated.

6.7 Packaging Materials

6.7.1 The purchase, handling and control of primary and printed packaging materials shall be accorded attention similar to that given to starting materials.

6.7.2 Particular attention shall be paid to printed materials. They shall be stored in adequately secure conditions such as to exclude unauthorized access.

Cut labels and other loose printed materials shall be stored and transported in separate closed containers so as to counters or similar devices are operating correctly avoid mix-ups. Packaging materials shall be issued for use only by authorized personnel following an approved and documented procedure.

6.7.3 Each delivery or batch of printed or primary packaging material shall be given a specific reference number or identification mark.

6.7.4 Outdated or obsolete primary packaging material or printed packaging material shall be destroyed and this disposal recorded.

6.8 Packaging Operations

6.8.1 When setting up a program for the packaging operations, particular attention shall be given to minimizing the risk of cross-contamination, mixups or substitutions. Different products shall not be packaged in close proximity unless there is physical segregation. IcaHTA

6.8.2 Before packaging operations are begun, steps shall be taken to ensure that the work area, packaging lines, printing machines and other equipment are clean and free from any products, materials or documents previously used, if these are not required for the current operation. The line-clearance shall be performed according to an appropriate checklist.

6.8.3 The name and batch number of the product being handled shall be displayed at each packaging station or line.

6.8.4 All products and packaging materials to be used shall be checked on delivery to the packaging department for quantity, identity and conformity with the packaging instructions.

6.8.5 Containers for filling shall be clean before filling. Attention shall be given to avoiding and removing any contaminants such as glass fragments and metal particles.

6.8.6 Normally, filling and sealing shall be followed as quickly as possible by labeling. If it is not the case, appropriate procedures shall be applied to ensure that no mix-ups or mislabeling can occur.

6.8.7 The correct performance of any printing operation (e.g. code numbers, expiry dates) to be done separately or in the course of the packaging shall be checked and recorded. Attention shall be paid to printing by hand which shall be re-checked at regular intervals. aADSIc

6.8.8 Special care shall be taken when using cut-labels and when overprinting is carried out off-line. Roll-feed labels are normally preferable to cut-labels to avoid mix ups.

6.8.9 Checks shall be made to ensure that any electronic code readers label counters or similar devices are operating correctly.

6.8.10 Printed and embossed information on packaging materials shall be distinct and resistant to fading or erasing.

6.8.11 On-line control of the product during packaging shall include at least checking the following:

6.8.11.1 general appearance of the packages;

6.8.11.2 whether the packages are complete;'

6.8.11.3 whether the correct products and packaging materials are used;

6.8.11.4 whether any over-printing is correct; and

6.8.11.5 correct functioning of line monitors;

6.8.12 Samples taken away from the packaging line shall not be returned.

6.8.13 Products that have been involved in an unusual event shall be reintroduced into the process only after special inspection, investigation and approval by authorized personnel. Detailed records shall be kept of this operation. HEacAS

6.8.14 Any significant or unusual discrepancy observed during reconciliation of the amount of bulk product and printed packaging materials and the number of units produced shall be investigated and satisfactorily accounted for before release.

6.8.15 Upon completion of a packaging operation, any unused batch-coded packaging materials shall be destroyed and the destruction recorded. A documented procedure shall be followed if uncoded printed materials are returned to stock.

6.9 Finished Products

6.9.1 Finished products shall be held in quarantine until their final release under conditions established by the manufacturer.

6.9.2 The evaluation of finished products and documentation that is necessary before' release of product for sale are described in Section 6 (Quality Control).

6.9.3 After release, finished products shall be stored as usable stock-under conditions established by the manufacturer.

6.10 Rejected, Recovered and Returned Materials

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

6.10.2 The reprocessing of rejected products shall be exceptional. It is permitted only 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 authorized procedure after evaluation of the risks involved. Records shall be kept of the reprocessing.

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

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

6.10.5 Products returned from the market and which have left the control of the manufacturer shall be destroyed unless without doubt their quality is satisfactory; they may be considered for resale, re-labeling 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 shall all be taken into account in this assessment. Where any doubt arises over the quality of the product, it shall not be considered suitable for reissue or reuse, although basic chemical reprocessing to recover active ingredients may be possible. Any action taken shall be appropriately recorded.

SECTION 7. Quality Control. —

7.1 Principle

Quality Control is concerned with sampling, specifications and testing as well as the organization, documentation and release procedures which ensure that the necessary and relevant tests are carried out, and that materials are-not released for use, nor products released for sale or supply, until their quality has been judged satisfactory. Quality Control is not confined to the laboratory operations, but must be involved in all decisions that may concern the quality of the product The independence of Quality Control from Production is considered fundamental to the satisfactory operation of Quality Control.

7.2 General

7.2.1 Each holder of a manufacturing authorization/license to operate shall have a Quality Control Department. This department shall be independent from other departments, and under the authority of a person with appropriate qualifications and experience, who has one or several control laboratories as their disposal. Adequate resources must be available to ensure that all the quality control arrangements are effectively and reliably carried out. STcEIC

7.2.2 The principal duties of the head of Quality Control are summarized in Section 2. The Quality Control Department as a whole will also have other duties, such as to establish, validate and implement all quality control procedures, keep the reference samples of materials and products, ensure the correct labeling of containers of materials and products, ensure the monitoring of the stability of the products, participate in the investigation of complaints related to the quality of the product, etc. All these operations shall be carried out in accordance with written procedures and, where necessary, recorded.

7.2.3 Finished product assessment shall embrace all relevant factors, including production conditions, results of in-process testing, a review of manufacturing (including packaging) documentation, compliance with finished product specification, and examination of the final finished pack.

7.2.4 Quality control personnel shall have access to production areas for sampling and investigation as appropriate.

7.3 Good Quality Control Laboratory Practice

7.3.1 Control laboratory premises and equipment shall-meet the general and specific requirements for Quality Control areas given in Section 3. HcACST

7.3.2 The personnel, premises, and equipment in the laboratories shall be appropriate to the tasks imposed by the nature and the scale of the manufacturing operations. The use of outside laboratories, in conformity with the principles detailed in Section 8 (Contract Analysis), can be accepted for particular reasons, but .this shall be stated in the Quality Control records.

7.4 Documentation

7.4.1 Laboratory documentation shall follow the principles given in Section 5. An important part of this documentation deals with Quality Control and the following details shall be readily available to the Quality Control Department:

 

7.4.1.1 specifications;

7.4.1.2 sampling procedures;

7.4.1.3 testing procedures and records;

7.4.1.4 analytical reports and/or certificates; and

7.4.1.5 data from environmental monitoring, where required; validation records of test methods, where applicable; procedures for and records of the calibration of instruments and maintenance of equipment.

7.4.2 Any Quality Control documentation relating to a batch record shall be retained for one year after the expiry date of the batch and at least five years after the date of manufacture for products with no expiry date. TADCSE

7.4.3. For some kinds of data (e.g. analytical tests results, yields, and environmental controls) it is recommended that records be kept in a manner permitting trend evaluation.

7.4.4 In addition to the information that is part of the batch record, other original data such as laboratory notebooks and/or records shall be retained and be readily available.

7.5 Sampling

7.5.1 The sampling shall be done in accordance with approved written procedures that describe:

7.5.1.1 the method of sampling and amount of sample to be taken;

7.5.1.2 the equipment to be used;

7.5.1.3 instructions for any required subdivision of the sample;

7.5.1.4 the type and condition of the sample container to be used;

7.5.1.5 the identification of containers sampled;

7.5.1.6 any special precautions to be observed, especially with regard to the sampling of sterile or noxious materials; CTcSAE

7.5.1.7 the storage conditions; and

7.5.1.8 instructions for the cleaning and storage of sampling equipment

7.5.2 Reference samples shall be representative of the batch of materials or products from which they are taken. Other samples may also be taken to monitor the most stressed part of a process (e.g. beginning or end of a process).

7.5.3 Sample containers shall bear a label indicating the contents, with the batch number, the date of sampling and the containers from which samples have been drawn.

7.5.4 Reference samples from each batch of finished products shall be retained till one year after the expiry date. Finished products shall usually be kept in their final packaging and stored under the recommended conditions.

7.5.5 Samples of starting materials (other than solvents, gases and water) shall be retained for at least two years after the release of the product if their stability allows.' This period may be shortened if their stability, as mentioned in the relevant specification, is shorter. Reference samples of materials and products shall be of a size sufficient to permit at least a full re-examination. CSDcTH

7.6 Testing

7.6.1 Analytical methods shall be validated. All testing operations described in the marketing authorization shall be carried out according to the approved methods.

7.6.2 The results obtained shall be recorded and checked to make sure that they are consistent with each other. Any calculations shall be critically examined.

7.6.3 The tests performed shall be recorded and the records shall include at least the following data:

7.6.3.1 name of the material or product and, where applicable, dosage form;

7.6.3.2 batch number and, where appropriate, the manufacturer and/or supplier;

7.6.3.3 references to the relevant specifications and testing procedures;

7.6.3.4 test results, including observations .and calculations, and reference to any certificates of analysis;

7.6.3.5 dates of testing;

7.6.3.6 initials of the persons who performed the testing; CHIEDS

7.6.3.7 initials of the persons who verified the testing and the calculations;

7.6.3.8 a clear statement of release or rejection (or other status decision) and the dated signature of the designated responsible person.

7.6.4 All the in-process controls, including those made in the Production area by Production personnel, shall be performed according to methods approved by Quality Control and the results recorded.

7.6.5 Special attention shall be given to the quality of laboratory reagents, volumetric glasswares and solutions, reference standards and culture media. They shall be prepared in accordance with written procedures.

7.6.6 Laboratory reagents intended for prolonged use shall be marked with the preparation date and the signature of the person who prepared them. The expiry date of unstable reagents and culture media shall be indicated on the label, together with specific storage conditions. In addition, for volumetric solutions, the last date of standardization and the last current factor shall be indicated.

7.6.7 Where necessary, the date of receipt of any substance used for testing operations (e.g. reagents and reference standards) shall be indicated on the container. Instructions for use and storage shall be followed. In certain cases it may be necessary to carry out an identification test and/or other testing of reagent materials upon receipt or before use. ECTIcS

7.6.8 Animals used for testing components, materials or products, shall, where appropriate, be quarantined before use. They shall be maintained and controlled in a manner that assures their suitability for the intended use.

They shall be identified, and adequate records shall be maintained, showing the history of their use.

SECTIONS 8. Contract Manufacture And Analysis. —

8.1 Principle

Contract manufacture and analysis must be correctly defined, agreed and controlled in order to avoid misunderstandings that could result in a product or work of unsatisfactory quality. There must be a written contract between the contract giver and the contract acceptor that clearly establishes the duties of each party. The contract must clearly state the way in which the authorized person releasing each batch of product for sale exercises his/her responsibility.

8.2 General

8.2.1 There shall be a written contract covering the manufacture and/or analysis arranged under contract and any technical arrangements made in connection with it.

8.2.2 All arrangements for contract manufacture and analysis, including any proposed changes in technical or other arrangements, shall be in accordance with the marketing authorization for the product concerned. IaAEHD

8.3 The Contract Giver (Trader)

8.3.1 The contract giver is responsible for assessing the competence of the contract acceptor to carry out successfully the work required and for ensuring by means of the contract that the principles and guidelines of cGMP as interpreted in this guide are followed.

8.3.2 The contract giver shall provide the contract acceptor with all the information necessary to carry out the contracted operations correctly in accordance with the marketing authorization/Certificate of Product Registration (CPR) processed products and materials delivered to them by the contract acceptor comply with their specifications or that the products have been released by an authorized person.

8.4 The Contract Acceptor (Toll Manufacturer)

8.4.1 The contract acceptor must have adequate premises and equipment, knowledge and experience, and competent personnel to carry out satisfactorily the work ordered by the contract giver. Contract manufacture may be undertaken only by an approved manufacturer.

8.4.2 The contract acceptor shall ensure that all products or materials delivered to them are suitable for their intended purpose.

8.4.3 The contract acceptor shall not pass to a third party any of the work entrusted to them under the contract without the contract giver's prior evaluation and approval of the arrangements. Arrangements made between the contract acceptor and any third party shall ensure that the manufacturing and analytical information is made available in the same way as between the original contract giver and contract acceptor.

8.4.4 The contract acceptor shall refrain from any activity that may adversely affect the quality of the product manufactured and/or analyzed for the contract giver.

8.5 Contract

8.5.1 A contract shall be drawn up between the contract giver and the contract acceptor which specifies their respective responsibilities relating to the manufacturer and control of the product. Technical aspects of the contract shall be drawn up by competent persons suitably knowledgeable in pharmaceutical technology, analysis and cGood Manufacturing Practice. All arrangements for manufacture and analysis must be in accordance with the manufacturing authorization and agreed by both parties.

8.5.2 The contract shall specify the way in which the authorized person releasing the batch for sale ensures that each batch has been manufactured and checked for compliance with the requirements of manufacturing authorization.

8.5.3 The contract shall 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. In the case of contract analysis, the contract shall state whether or not the contract acceptor shall take samples at the premises of the manufacturer. TACEDI

8.5.4 Manufacturing, analytical and distribution records, and reference samples shall be kept by, or be available to, the contract giver. Any records relevant to assessing the quality of a product in the event of complaints or a suspected defect must be accessible and specified in the defect/recall procedures of the contract giver.

8.5.5 The contract shall permit the contract giver to visit the facilities of the contract acceptor.

8.5.6 In case of contract analysis, the contract acceptor shall understand that they are subject to inspection by the competent authorities (BAI).

SECTION 9. Complaints and Product Recall. —

9.1 Principle

All complaints and other information concerning potentially defective products must be reviewed carefully according to written procedures. In order to provide for all contingencies, a system shall be designed to recall promptly and effectively, if necessary, products known or suspected to be defective from the market.

9.2 Complaints

9.2.1 A person shall be designated responsible for handling the complaints and deciding the measures to be taken, together with sufficient supporting staff to assist If this person is net the authorized person, the. latter shall be made aware of any complaint, investigation or recall.

9.2.2 There shall be written procedures describing the action to be taken, including the need to consider a recall, in the case of a complaint concerning a possible product defect.

9.2.3 Any complaint concerning a product defect shall be recorded with all the original details and thoroughly investigated. The person responsible for Quality Control shall normally be involved in the study of such problems.

9.2.4 If a product defect is discovered or suspected in a batch, consideration shall be given to checking other batches in order to determine whether they are also affected. In particular, other batches that may contain reworks of the defective batch shall be investigated.

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

9.2.6 Complaints records shall be reviewed regularly for any indication of specific or recurring problems requiring attention and possibly the recall of marketed products.

9.2.7 The regulatory authority shall be informed if a manufacturer is considering action following possibly faulty manufacture, product deterioration, or any other serious quality problems with a product.

9.3 Recalls

9.3.1 A person shall be designated as responsible for execution and coordination of recalls and shall be supported by sufficient staff to handle all the aspects of the recalls with the appropriate degree of urgency. This responsible person shall normally be independent of the sales and marketing organization. If this person is not the authorized person, the latter shall be made aware of any recall operation.

9.3.2 There shall be established written procedures, regularly checked and updated when necessary, in order to organize any recall activity.

9.3.3 Recall operations shall be capable of being initiated promptly and at any time.

9.3.4 All regulatory authorities of all countries to which products may have been distributed shall be informed promptly if products are intended to be recalled because they are, or are suspected of being, defective.

9.3.5 The distribution records shall be readily available to the persons) responsible for recalls, and shall contain sufficient information on wholesalers and directly supplied customers (with addresses, phone and/or fax numbers inside and outside working hours, batches and amounts delivered), including those for exported products and medical samples. DSCIEa

9.3.6 Recalled products shall be identified and stored separately in a secure area while awaiting a decision on their fate.

9.3.7 The progress of the recall process shall be recorded and a final report issued, including a reconciliation between the delivered and recovered quantities of the products.

9.3.8 The effectiveness of the arrangements for recalls shall be evaluated from time to time.

SECTION 10. Self Inspection. —

Principle

10.1 Self inspections shall be conducted in order to monitor the implementation and compliance with Good Manufacturing Practice principles and to propose necessary corrective measures.

10.2 Personnel matters, premises, equipment, documentation, production, quality control, distribution of the medicinal products, arrangements for dealing with complaints and recalls, and self inspection, shall be examined at intervals following a prearranged program in order to verify their conformity with the principles of Quality Assurance.

10.3 Self inspections shall be conducted in an independent and detailed way by designated competent person(s) from the company. Independent audits by external experts may also be useful.

10.4 All self inspections shall be recorded. Reports shall contain all the observations made during the inspections and, where applicable, proposals for corrective measures. Statements on the actions subsequently taken shall also be recorded.

(SGD.) DOMINGO F. PANGANIBANSecretary

Recommending Approval:

DAVINIO P. CATBAGAN, DVMOfficer-in-Charge