C H A P T E R 4 - DOCUMENTATION

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 Formulae and instructions, procedures, and records must be free from errors and available in writing. The legibility of documents is of paramount importance.
General
4.1. 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. Manufacturing Formulae, Processing and Packaging Instructions state all the starting materials used and lay down all processing and packaging operations. Procedures give directions for performing certain operations e.g. cleaning, clothing, environmental control, sampling, testing equipment operations. Records provide a history of each batch of product, including its distribution, and also of all other relevant circumstances pertinent for the quality of the final product.
4.2. Documents should be designed, prepared, reviewed and distributed with care. They should comply with the relevant parts of the manufacturing and marketing authorization dossiers.
4.3. Documents should be approved, signed and dated by appropriate and authorized persons.
4.4. Documents should have unambiguous contents; title, nature and purpose should be clearly stated. They should be laid out in an orderly fashion and be easy to check. Reproduced documents should be clear and legible. The reproduction of working documents from master documents must not allow any error to be introduced through the reproduction process.
4.5. Documents should be regularly reviewed and kept up-to-date. When a document has been revised, systems should be operated to prevent inadvertent use of superseded documents.
4.6. Documents should not be hand-written; although, where documents require the entry of data, these entries may be made in clear, legible, indelible handwriting. Sufficient space should be provided for such entries.
4.7. Any alteration made to the entry on a document should be signed and dated; the alteration should permit the reading of the original information. Where appropriate, the reason for the alteration should be recorded.
4.8. The records should be made or completed at the time each action is taken and in such a way that all significant activities concerning the manufacture of medicinal products are traceable. They should be retained for at least one year after the expiry date of the finished product.
4.9. Data may be recorded by electronic data processing systems, photographic or other reliable means, but detailed procedures relating to the system in use should be available and the accuracy of the records should be checked. If documentation is handled by electronic data processing methods, only authorized persons should be able to enter or modify data in the computer and there should be a record of changes and deletions; access should be restricted by passwords or other means and the result of entry of critical data should be independently checked. Batch records electronically stored should 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,.
Documents required
4.10. Specifications
There should be appropriately authorized and dated specifications for starting and packaging materials, and finished products; where appropriate, they should be also available for intermediate or bulk products.
Specifications for starting and packaging materials
4.11. Specifications for starting and primary or printed packaging materials should include, if applicable:
a) a description of the materials, including:
- the designated name and the internal code reference;
- the reference, if any, to a pharmacopoeial monograph;
- the approved suppliers and, if possible, the original producer of the products;
- a specimen of printed materials;
b) directions for sampling and testing or reference to procedures;
c) qualitative and quantitative requirements with acceptance limits;
d) storage conditions and precautions;
e) the maximum period of storage before re-examination.
Specifications for intermediate and bulk products
4.12. Specifications for intermediate and bulk products should be available if these are purchased or dispatched, or if data obtained from intermediate products are used for the evaluation of the finished product. The specifications should be similar to specifications for starting materials or for finished products, as appropriate.
Specifications for finished products
4.13. Specifications for finished products should include:
a) the designated name of the product and the code reference where applicable;
b) the formula or a reference to;
c) a description of the pharmaceutical form and package details;
d) directions for sampling and testing or a reference to procedures;
e) the qualitative and quantitative requirements, with the acceptance limits;
f) the storage conditions and any special handling precautions, where applicable;
g) the shelf-life.
Manufacturing Formula and Processing Instructions
Formally authorized Manufacturing Formula and Processing Instructions should exist for each product and batch size to be manufactured. They are often combined in one document.
4.14. The Manufacturing Formula should include:
a) the name of the product, with a product reference code relating to its specification;
b) a description of the pharmaceutical form, strength of the product and batch size;
c) a list of all starting materials to be used, with the amount of each, described using the designated name and a reference which is unique to that material; mention should be made of any substance that may disappear in the course of processing;
d) a statement of the expected final yield with the acceptable limits, and of relevant intermediate yields, where applicable.
4.15. The Processing Instructions should include:
a) a statement of the processing location and the principal equipment to be used;
b) the methods, or reference to the methods, to be used for preparing the critical equipment (e.g. cleaning, assembling, calibrating, sterilizing);
c) detailed stepwise processing instructions (e.g. checks on materials, pretreatments, sequence for adding materials, mixing times, temperatures);
d) the instructions for any in-process controls with their limits;
e) where necessary, the requirements for bulk storage of the products; including the container, labeling and special storage conditions where applicable;
f) any special precautions to be observed.
Packaging Instructions
4.16. There should be formally authorized Packaging Instructions for each product for pack size and type. These should normally include, or have a reference to, the following:
a) name of the product;
b) description of its pharmaceutical form, and strength where applicable;
c) the pack size expressed in terms of the number, weight or volume of the product in the final container;
d) 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;
e) 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;
f) special precautions to be observed, including a careful examination of the area and equipment in order to ascertain the line clearance before operations begin;
g) a description of the packaging operation, including any significant subsidiary operations, and equipment to be used;
h) details of in-process controls with instructions for sampling and acceptance limits.
Batch Processing Records
4.17. A Batch Processing Record should be kept for each batch processed. It should be based on the relevant parts of the currently approved Manufacturing Formula and Processing Instructions. The method of preparation of such records should be designed to avoid transcription errors. The record should carry the number of the batch being manufactured.
Before any processing begins, there should 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.
During processing, the following information should be recorded at the time each action is taken and, after completion, the record should be dated and signed in agreement by the person responsible for the processing operations:
a) the name of the product;
b) dates and times of commencement, of significant intermediate stages and of completion of production;
c) name of the person responsible for each stage of production;
d) 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);
e) 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);
f) any relevant processing operation or event and major equipment used;
g) a record of the in-process controls and the initials of the person(s) carrying them out, and the results obtained;
h) the amount of product yield obtained at different and pertinent stages of manufacture;
i) notes on special problems including details, with signed authorization for any deviation from the Manufacturing Formula and Processing Instructions.
Batch Packaging Records
4.18. A Batch Packaging Record should be kept for each batch or part batch processed. It should be based on the relevant parts of the Packaging Instructions and the method of preparation of such records should be designed to avoid transcription errors. The record should 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. Before any packaging operation begins, there should 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. The following information should be entered at the time each action is taken and, after completion, the record should be dated and signed in agreement by the person(s) responsible for the packaging operations:
a) the name of the product;
b) the date(s) and times of the packaging operations;
c) the name of the responsible person carrying out the packaging operation;
d) the initials of the operators of the different significant steps;
e) records of checks for identity and conformity with the Packaging Instructions including the results of in-process controls;
f) details of the packaging operations carried out, including references to equipment and the packaging lines used; g) whenever possible, samples of printed packaging materials used, including specimens of the batch coding, expiry dating and any additional overprinting;
h) notes on any special problems or unusual events including details with signed authorization for any deviation from the Manufacturing Formula and Processing Instructions;
i) 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.
Procedures and records
Receipt
4.19. There should be written procedures and records for the receipt of each delivery of each starting and primary and printed packaging material.
4.20. The records of the receipts should include:
a) the name of the material on the delivery note and the containers;
b) the "in-house" name and/or code of material (if different from a);
c) date of receipt;
d) supplier's name and, if possible, manufacturer's name;
e) manufacturer's batch or reference number;
f) total quantity, and number of containers received;
g) the batch number assigned after receipt;
h) any relevant comment (e.g. state of the containers).
4.21. There should be written procedures for the internal labeling, quarantine and storage of starting materials, packaging materials and other materials, as appropriate.
Sampling
4.22. There should 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 (see Chapter 6, Item 13).
Testing
4.23. There should be written procedures for testing materials and products at different stages of manufacture, describing the methods and equipment to be used. The tests performed should be recorded (see Chapter 6, Item 17).
Other
4.24 Written release and rejection procedures should 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.
4.25. Records should be maintained of the distribution of each batch of a product in order to facilitate the recall of the batch if necessary (see Chapter 8).
4.26. There should be written procedures and the associated records of actions taken or conclusions reached, where appropriate, for:
- validation;
- equipment assembly and calibration;
- maintenance, cleaning and sanitization;
- personnel matters including training, clothing, hygiene;
- environmental monitoring;
- pest control;
- complaints;
- recalls;
- returns.
4.27. Clear operating procedures should be available for major items of manufacturing and test equipment.
4.28. Log books should 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 these operations out.
4.29. Log books should also record in chronological order the use of major or critical equipment and the areas where the products have been processed.

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C H A P T E R 3 - PREMISES AND EQUIPMENT

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.
PREMISES
General
3.1. Premises should 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. Premises should be carefully maintained, ensuring that repair and maintenance operations do not present any hazard to the quality of products. They should be cleaned and, where applicable, disinfected according to detailed written procedures.
3.3. Lighting, temperature, humidity and ventilation should be appropriate and 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.
3.4. Premises should be designed and equipped so as to afford maximum protection against the entry of insects or other animals.
3.5. Steps should be taken in order to prevent the entry of unauthorized people. Production, storage and quality control areas should not be used as a right of way by personnel who do not work in them.
Production Area
3.6. In order to minimize the risk of a serious medical hazard due to cross-contamination, dedicated and self-contained facilities must be available for the production of particular medicinal products, such as highly sensitizing materials (e.g. penicillins) or biological preparations (e.g. from live micro-organisms). The production of certain additional products, such as certain antibiotics, certain hormones, certain cytotoxics, certain highly active drugs and non-medicinal products should 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, should not be allowed in premises used for the manufacture of medicinal products.
3.7. Premises should 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.
3.8. The adequacy of the working and in-process storage space should 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.
3.9. 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 and should permit easy and effective cleaning and, if necessary, disinfection.
3.10. Pipe work, light fittings, ventilation points and other services should be designed and sited to avoid the creation of recesses which are difficult to clean. As far as possible, for maintenance purposes, they should be accessible from outside the manufacturing areas.
3.11. Drains should be of adequate size, and have trapped gullies. Open channels should be avoided where possible, but if necessary, they should be shallow to facilitate cleaning and disinfection.
3.12. Production areas should 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.
3.13. Weighing of starting materials usually should be carried out in a separate weighing room designed for that use.
3.14. In cases where dust is generated (e.g. during sampling, weighing, mixing and processing operations, packaging of dry products), specific provisions should be taken to avoid cross-contamination and facilitate cleaning.
3.15. Premises for the packaging of medicinal products should be specifically designed and laid out so as to avoid mix-ups or cross-contamination.
3.16. Productions areas should be well lit, particularly where visual on-line controls are carried out.
3.17. In-process controls may be carried out within the production area provided they do not carry any risk for the production.
Storage Areas
3.18. 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.
3.19. Storage areas should be designed or adapted to ensure good storage conditions. In particular, they should be clean and dry and maintained within acceptable temperature limits. 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 products from the weather. Receptions areas should be designed and equipped to allow containers of incoming materials to be cleaned where necessary before storage.
3.21. 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 should give equivalent security.
3.22. 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.
3.23. Segregated areas should be provided for the storage of rejected, recalled or returned materials or products.
3.24. Highly active materials or products should be stored in safe and secure areas.
3.25. 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.
Quality Control Areas
3.26. Normally, Quality Control laboratories should be separated from production areas. This is particularly important for laboratories for the control of biologicals, microbiologicals and radioisotopes, which should also be separated from each other.
3.27. Control laboratories should be designed to suit the operations to be carried out in them. Sufficient space should be given to avoid mix-ups and cross-contamination. There should be adequate suitable storage space for samples and records.
3.28. Separate rooms may be necessary to protect sensitive instruments from vibration, electrical interference, humidity, etc.
3.29. Special requirements are needed in laboratories handling particular substances, such as biological or radioactive samples.
Ancillary Areas
3.30. Rest and refreshment rooms should be separate from other areas.
3.31. Facilities for changing clothes, and for washing and toilet purposes should be easily accessible and appropriate for the number of users. Toilets should not directly communicate with production or storage areas.
3.32. Maintenance workshops should as far as possible be separated from production areas. Whenever parts and tools are stored in the production area, they should be kept in rooms or lockers reserved for that use.
3.33. Animal houses should be well isolated from other areas, with separate entrance (animal access) and air handling facilities.
EQUIPMENT
3.34. Manufacturing equipment should be designed, located and maintained to suit its intended purpose.
3.35. Repair and maintenance operations should not present any hazard to the quality of the products.
3.36. Manufacturing equipment should be designed so that it can be easily and thoroughly cleaned. It should be cleaned according to detailed and written procedures and stored only in a clean and dry condition.
3.37. Washing and cleaning equipment should be chosen and used in order not to be a source of contamination.
3.38. Equipment should be installed in such a way as to prevent any risk of error or of contamination.
3.39. Production equipment should 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.
3.40. Balances and measuring equipment of an appropriate range and precision should be available for production and control operations.
3.41. Measuring, weighing, recording and control equipment should be calibrated and checked at defined intervals by appropriate methods. Adequate records of such tests should be maintained.
3.42. Fixed pipe-work should be clearly labeled to indicate the contents and, where applicable, the direction of flow.
3.43. Distilled, deionized and, where appropriate, other water pipes should be sanitized according to written procedures that detail the action limits for microbiological contamination and the measures to be taken.
3.44. Defective equipment should, if possible, be removed from production and quality control areas, or at least be clearly labeled as defective.
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