(2003; 148 pages)
15.10 Labels applied to containers, equipment or premises should be clear, unambiguous and in the company’s agreed format. It is often helpful in addition to the wording on the labels to use colours to indicate status (e.g. quarantined, accepted, rejected, clean).
15.11 All finished drug products should be identified by labelling, as required by the national legislation, bearing at least the following information:
(a) the name of the drug product;
(b) a list of the active ingredients (if applicable, with the INNs), showing the amount of each present and a statement of the net contents (e.g. number of dosage units, weight, volume);
(c) the batch number assigned by the manufacturer;
(d) the expiry date in an uncoded form;
(e) any special storage conditions or handling precautions that may be necessary;
(f) directions for use, and warnings and precautions that may be necessary;
(g) the name and address of the manufacturer or the company or the person responsible for placing the product on the market.
15.12 For reference standards, the label and/or accompanying document should indicate potency or concentration, date of manufacture, expiry date, date the closure is first opened, storage conditions and control number, as appropriate.
Specifications and testing procedures
15.13 Testing procedures described in documents should be validated in the context of available facilities and equipment before they are adopted for routine testing.
15.14 There should be appropriately authorized and dated specifications, including tests on identity, content, purity and quality, for starting and packaging materials and for finished products; where appropriate, they should also be available for intermediate or bulk products. Specifications for water, solvents and reagents (e.g. acids and bases) used in production should be included.
15.15 Each specification should be approved, signed and dated, and maintained by quality control, quality assurance unit or documentation centre. Specifications for starting materials, intermediates, and bulk, finished products and packaging meterials are referred to in sections 15.18 - 15.21.
15.16 Periodic revisions of the specifications may be necessary to comply with new editions of the national pharmacopoeia or other official compendia.
15.17 Pharmacopoeias, reference standards, reference spectra and other reference materials should be available in the quality control laboratory.
Specifications for starting and packaging materials
15.18 Specifications for starting, primary and printed packaging materials should provide, if applicable, a description of the materials, including:
(a) the designated name (if applicable, the INN) and internal code reference;
(b) the reference, if any, to a pharmacopoeial monograph;
(c) qualitative and quantitative requirements with acceptance limits.
Depending on the company’s practice other data may be added to the specification, such as:
(a) the supplier and the original producer of the materials;
(b) a specimen of printed materials;
(c) directions for sampling and testing, or a reference to procedures;
(d) storage conditions and precautions;
(e) the maximum period of storage before re-examination.
Packaging material should conform to specifications, and should be compatible with the material and/or with the drug product it contains. The material should be examined for compliance with the specification, and for defects as well as for the correctness of identity markings.
15.19 Documents describing testing procedures should state the required frequency for re-assaying each starting material, as determined by its stability.
Specifications for intermediate and bulk products
15.20 Specifications for intermediate and bulk products should be available. The specifications should be similar to specifications for starting materials or for finished products, as appropriate.
Specifications for finished products
15.21 Specifications for finished products should include:
(a) the designated name of the product and the code reference, where applicable;
(b) the designated name(s) of the active ingredient(s) (if applicable, with the INN(s));
(c) the formula or a reference to the formula;
(d) a description of the dosage form and package details;
(e) directions for sampling and testing or a reference to procedures;
(f) the qualitative and quantitative requirements, with acceptance limits;
(g) the storage conditions and precautions, where applicable;
(h) the shelf-life.
15.22 A formally authorized master formula should exist for each product and batch size to be manufactured.
15.23 The master formula should include:
(a) the name of the product, with a product reference code relating to its specification;
(b) a description of the dosage form, strength of the product and batch size;
(c) a list of all starting materials to be used (if applicable, with the INNs), with the amount of each, described using the designated name and a reference that 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;
(e) a statement of the processing location and the principal equipment to be used;
(f) the methods, or reference to the methods, to be used for preparing and operating the critical equipment, e.g. cleaning (especially after a change in product), assembling, calibrating, sterilizing, use;
(g) detailed step-wise processing instructions (e.g. checks on materials, pretreatments, sequence for adding materials, mixing times, temperatures);
(h) the instructions for any in-process controls with their limits;
(i) where necessary, the requirements for storage of the products, including the container, the labelling, and any special storage conditions;
(j) any special precautions to be observed.
15.24 Formally authorized packaging instructions should exist for each product, pack size and type. These should normally include, or make reference to:
(a) the name of the product;
(b) a description of its pharmaceutical form, strength and, where applicable, method of application;
(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 for each packaging material;
(e) where appropriate, an example or reproduction of the relevant printed packaging materials and specimens, indicating where the batch number and expiry date of the product have been marked;
(f) special precautions to be observed, including a careful examination of the packaging area and equipment in order to ascertain the line clearance before and after packaging operations;
(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
15.25 A batch processing record should be kept for each batch processed. It should be based on the relevant parts of the currently approved specifications on the record. The method of preparation of such records should be designed to avoid errors. (Copying or validated computer programmes are recommended. Transcribing from approved documents should be avoided.)
15.26 Before any processing begins, a check should be made that the equipment and work station are clear of previous products, documents, or materials not required for the planned process, and that the equipment is clean and suitable for use. This check should be recorded.
15.27 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 by the person responsible for the processing operations:
(a) the name of the product;
(b) the number of the batch being manufactured;
(c) dates and times of commencement, of significant intermediate stages, and of completion of production;
(d) the name of the person responsible for each stage of production;
(e) the initials of the operator(s) of different significant steps of production and, where appropriate, of the person(s) who checked each of these operations (e.g. weighing);
(f) the batch number and/or analytical control number and the quantity of each starting material actually weighed (including the batch number and amount of any recovered or reprocessed material added);
(g) any relevant processing operation or event and the major equipment used;
(h) the in-process controls performed, the initials of the person(s) carrying them out, and the results obtained;
(i) the amount of product obtained at different and pertinent stages of manufacture (yield), together with comments or explanations for significant deviations from the expected yield;
(j) notes on special problems including details, with signed authorization for any deviation from the master formula.
Batch packaging records
15.28 A batch packaging record should be kept for each batch or part batch processed. It should be based on the relevant parts of the approved packaging instructions, and the method of preparing such records should be designed to avoid errors. (Copying or validated computer programmes are recommended. Transcribing from approved documents should be avoided.)
15.29 Before any packaging operation begins, checks should be made 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. These checks should be recorded.
15.30 The following information should be recorded at the time each action is taken, and the date and the person responsible should be clearly identified by signature or electronic password:
(a) the name of the product, 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, the quantity actually obtained and the reconciliation;
(b) the date(s) and time(s) 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) the checks made 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, and, when necessary, the instructions for keeping the product unpacked or a record of returning product that has not been packaged to the storage area;
(g) whenever possible, samples of the printed packaging materials used, including specimens bearing the approval for the printing of and regular check (where appropriate) of the batch number, expiry date, and any additional overprinting;
(h) notes on any special problems, including details of any deviation from the packaging instructions, with written authorization by an appropriate person;
(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 product obtained to permit an adequate reconciliation.
Standard operating procedures (SOPs) and records
15.31 Standard operating procedures and associated records of actions taken or, where appropriate, conclusions reached should be available for:
(a) equipment assembly and validation;
(b) analytical apparatus and calibration; (c) maintenance, cleaning and sanitization;
(d) personnel matters including qualification, training, clothing and hygiene;
(e) environmental monitoring;
(f) pest control;
15.32 There should be standard operating procedures and records for the receipt of each delivery of starting material and primary and printed packaging material.
15.33 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) the date of receipt;
(d) the supplier’s name and, if possible, manufacturer’s name;
(e) the manufacturer’s batch or reference number;
(f) the total quantity, and number of containers received;
(g) the batch number assigned after receipt;
(h) any relevant comment (e.g. state of the containers).
15.34 There should be standard operating procedures for the internal labelling, quarantine and storage of starting materials, packaging materials and other materials, as appropriate.
15.35 Standard operating procedures should be available for each instrument and piece of equipment (e.g. use, calibration, cleaning, maintenance) and placed in close proximity to the equipment.
15.36 There should be standard operating procedures for sampling, which specify the person(s) authorized to take samples.
15.37 The sampling instructions should include:
(a) the method of sampling and the sampling plan;
(b) the equipment to be used;
(c) any precautions to be observed to avoid contamination of the material or any deterioration in its quality;
(d) the amount(s) of sample(s) to be taken;
(e) instructions for any required subdivision of the sample;
(f) the type of sample container(s) to be used, and whether they are for aseptic sampling or for normal sampling, and labelling;
(g) any specific precautions to be observed, especially in regard to the sampling of sterile or noxious material.
15.38 There should be a standard operating procedure describing the details of the batch (lot) numbering system, with the objective of ensuring that each batch of intermediate, bulk or finished product is identified with a specific batch number.
15.39 The standard operating procedures for batch numbering that are applied to the processing stage and to the respective packaging stage should be related to each other.
15.40 The standard operating procedure for batch numbering should ensure that the same batch numbers will not be used repeatedly; this applies also to reprocessing.
15.41 Batch-number allocation should be immediately recorded, e.g. in a logbook. The record should include at least the date of allocation, product identity and size of batch.
15.42 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.
15.43 Analysis records should include at least the following data:
(a) the name of the material or product and, where applicable, dosage form;
(b) the batch number and, where appropriate, the manufacturer and/or supplier;
(c) references to the relevant specifications and testing procedures;
(d) test results, including observations and calculations, and reference to any specifications (limits);
(e) date(s) and reference number(s) of testing;
(f) the initials of the persons who performed the testing;
(g) the date and initials of the persons who verified the testing and the calculations, where appropriate;
(h) a clear statement of release or rejection (or other status decision) and the dated signature of the designated responsible person.
15.44 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 an authorized person.
15.45 Records should be maintained of the distribution of each batch of a product in order, e.g. to facilitate the recall of the batch if necessary.
15.46 Records should be kept for major and critical equipment, as appropriate, of any validations, calibrations, maintenance, cleaning, or repair operations, including dates and the identity of the people who carried these operations out.
15.47 The use of major and critical equipment and the areas where products have been processed should be appropriately recorded in chronological order.
15.48 There should be written procedures assigning responsibility for cleaning and sanitation and describing in sufficient detail the cleaning schedules, methods, equipment and materials to be used and facilities and equipment to be cleaned. Such written procedures should be followed.