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WHO good manufacturing practices: starting materials
Active pharmaceutical ingredients (bulk drug substances)
Pharmaceutical excipients

 

Active pharmaceutical ingredients (bulk drug
substances)

Explanation
General considerations
Personnel
Premises
Equipment
Sanitation
Documentation
Retention of records and reference samples
Production

Explanation

Since there are fundamental distinctions between the production of bulk active pharmaceutical ingredients and the formulation of finished pharmaceutical products, the strict application of GMP as set forth in the main part of this guide is not always practical or necessary. The present supplementary guidelines outline procedures and practices that manufacturers should employ to ensure that the methods, facilities, and controls used for the production of active pharmaceutical ingredients are operated or managed so that such products have the quality and purity appropriate for their use in finished pharmaceutical products.

General considerations

18.1 In the manufacture of active pharmaceutical ingredients, overall control is essential to ensure high quality. Haphazard operations cannot be permitted in the manufacture of substances that may be used to save life or to restore or promote health.18.2 Recommended practices for the manufacture of active pharmaceutical ingredients are set out below. Adherence to these practices, complementing the various control tests carried out from the beginning to the end of the production cycle, will contribute substantially to the production of consistently uniform batches of high-quality active pharmaceutical ingredients.18.3 The manufacturer must assume responsibility for the quality of the active pharmaceutical ingredients produced. The manufacturer alone can avoid mis-takes and prevent mishaps by exercising adequate care in both production and control procedures. Full evidence of compliance with GMP should be given from the step from which the processes or the starting materials used have a critical influence on the quality of the active pharmaceutical ingredient. This step should be determined in each individual case by agreement between the competent authority and the manufacturer.18.4 The good practices outlined below should be considered general guides; whenever necessary, they may be adapted to meet individual needs provided the established standards of quality of the active pharmaceutical ingredients are still achieved. The good practices are intended to apply to the manufacturing processes (including packaging and labelling) used in the production of active pharmaceutical ingredients.18.5 Sometimes several firms cooperate in the production (including packaging and labelling) of an active pharmaceutical ingredient. It may also happen that a finished, packed, and labelled active pharmaceutical ingredient is repacked and/or relabelled and given a new designation. Since such procedures constitute part of a manufacturing operation, they should be subject to the relevant guidelines set out below.

18.6 The practices outlined below are intended to apply to active pharmaceutical ingredients for both human and veterinary preparations.

Personnel

18.7 Each firm should employ personnel with the necessary qualifications and competence for the production and quality control of active pharmaceutical ingredients. There should be an adequate number of staff with appropriate education, technical knowledge, and practical experience related to the job they perform.18.8 The firm should have a defined organization represented in a chart. Individual responsibilities should be laid down in written instructions, to ensure that there are no gaps or overlaps. The responsibilities placed on any one individual should not be so extensive as to incur any risk to quality.18.9 Staff at all levels should be adequately trained for the tasks and responsibilities assigned to them.

18.10 Measures should be taken to ensure that no person affected by a disease in a communicable form or having open lesions on the exposed surface of the body is engaged in any production step involving direct contact with the active pharmaceutical ingredients.

Premises

18.11 Premises, including areas containing open tanks, should be of suitable construction. They should provide a suitable environment for manufacturing operations and should be adequately adapted to and of a sufficient size for their intended use. The premises should not contribute to actual or potential mix-ups or contamination of the active pharmaceutical ingredients. The arrangement should provide for a logical work flow.18.12 For special purposes, such as the production of sterile products and of certain antibiotics, hormones, and cytostatic substances, separate specifically designed enclosed areas with completely separate air-handling systems should be provided.

18.13 To maintain hygienic working conditions, the premises should include facilities for changing clothes, washing, and toilet purposes as well as for eating, drinking, and smoking.

Equipment

18.14 Manufacturing equipment should be designed, constructed, located, and maintained in such a way as to:

(a) be suitable for its intended use;(b) facilitate thorough cleaning;(c) minimize the risk of contamination of products and containers during production; and

(d) facilitate efficient and, if applicable, validated and reliable operation.

18.15 Production and testing equipment should be cleaned, sterilized when necessary, used, and maintained in accordance with specific written instructions. Before production of another product is started, multipurpose equipment used should be thoroughly cleaned and checked for cleanliness. Appropriate records of such procedures should be maintained.18.16 If necessary, equipment used for production and testing should have been shown to be capable of carrying out the processes for which it is intended.18.17 Process-monitoring systems should be available where necessary. Measuring, recording, and control equipment should be calibrated and checked at suitable intervals by appropriate methods. Appropriate records of such tests should be maintained.

18.18 Defective equipment should be labelled immediately as defective and repaired or removed as soon as possible. Technical maintenance and repair should be documented.

Sanitation

18.19 Written sanitation programmes should be available. These should include validated cleaning procedures for premises and equipment, a quality standard for water, instructions for hygiene when manufacturing and handling goods, and instructions relating to the health, hygienic practices, and clothing of personnel and the disposal procedures for waste materials and unusable residues.18.20 These programmes should be implemented; they should regularly be brought to the attention of the personnel involved and emphasized during continued staff training.18.21 Protective garments and other protective items appropriate to the processes being carried out should be worn.

18.22 Eating, smoking, and unhygienic practices should not be permitted in manufacturing areas.

Documentation

Master formulae

18.23 Written instructions covering each stage of production, storage, and quality control should be available, and they should be updated whenever necessary.18.24 There should be a master formula setting out in writing the starting materials and packaging materials (quality and quantity), as well as detailed production and quality control procedures for each active pharmaceutical ingredient. Wherever possible, the master formula should be prepared for standard batch sizes.18.25 Competent persons experienced in production and quality control should be responsible for the content and distribution within the firm of instructions and master formulae. These should be duly signed and dated.18.26 Outdated master formulae should be withdrawn but retained for reference. Copies of the master formula should be prepared in a manner that will eliminate any possibility of transcription error.

18.27 In certain circumstances, for example in the first production runs follow-ing pilot development, the master formula might need to be amended. Any amendments must be formally authorized and signed by competent person(s). The amended document should be replaced at the earliest opportunity by a newly prepared master formula.

Batch documentation

18.28 A batch manufacturing record should be completed during the production of each batch of intermediate products and of active pharmaceutical ingredients. It should contain the relevant parts of the master formula and should include the following:

(a) the name of the product (if applicable, the International Non-proprietary Name) or stage and the size and number of the batch;(b) the dates of the differents stages of production;(c) production details, including reference to the main equipment used and yields;(d) the batch or reference number (or analytical control number), if any, of starting materials used in the production;(e) a record of the in-process controls followed and the results obtained;(f) details of, and signed authorization for, any deviation from the master formula (any unplanned deviation being subject to investigation in relation to product quality);(g) any recovered materials, and procedures applied;(h) the initials of the operators and signature of the person responsible for the production operations and the date of signature;(i) all analytical records relating to the batch, or a reference that will permit their retrieval;(j) a decision for the release or rejection of the batch with the date and signature of the person responsible for the decision;

(k) the production record review (see section 16.15).

18.29 Where circumstances require the use of contract production and control facilities, this fact should be stated in the batch record.

18.30 Data may be recorded by electronic data-processing systems or by photographic or other reliable means. Master formulae and detailed standard operating 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 entry of critical data should be independently checked. Batch records electronically stored should be protected by back-up transfer on magnetic tape, microfilm, paper print-outs, or other means. It is particularly important that, during the period of retention, the data are readily available.

Retention of records and reference samples

18.31 Records should be kept in such a way that activities concerning the production and quality control of active pharmaceutical ingredients are traceable.

18.32 Records and reference samples of the active pharmaceutical ingredients, and where necessary of intermediate products, should be retained at least one year beyond the expiry date of the finished product or for a specified period if there is no expiry date.

Production

Processing procedures

18.33 Processing should be carried out in accordance with the master formula.18.34 Steps that are critical for the quality of the active pharmaceutical ingredient should be defined and the procedures applied should be validated.18.35 Processing should be supervised and performed by competent persons.18.36 During processing, vessels, containers, and significant equipment should be unambiguously labelled or identified with the name of the product and the batch number.

18.37 Information on the daily activities in each processing department should be available in addition to the batch documentation.

Starting materials

18.38 Starting materials should be received, quarantined, sampled, identified, examined for compliance with established specifications, released or rejected, stored, labelled, and dispensed in accordance with written instructions.

18.39 Some starting materials may not be tested for compliance because of the hazards involved (e.g., phosphorus pentachloride and dimethyl sulfate). This is acceptable when a batch certificate of analysis is available from the vendor and when there is a reason based on safety or other valid considerations.

Intermediate products

18.40 Intermediate products should, where necessary, be tested in accordance with the specifications and should be conspicuously labelled/identified and properly stored.

Active pharmaceutical ingredients

18.41 Each batch of finished active pharmaceutical ingredient must meet established specifications for quality, purity, identity, and potency, including, where applicable, specifications for tests and limits for residues of solvents and other reactants.

18.42 For the production of sterile active pharmaceutical ingredients, section 17 ("Sterile pharmaceutical products") may be applicable to the steps at which the process may have a critical influence on the quality attributes of the finished pharmaceutical product.

Packaging

18.43 Care should be exercised when packaging materials are selected for active pharmaceutical ingredients. The materials should have no detrimental effect on the substance, and should give adequate protection against external influences and potential contamination. Suitable written specifications should be available.18.44 Attention should be directed at all stages to the prevention of packaging errors. Sound procedures must be employed to protect the quality of the product when it is packaged and to ensure that the correct labels are applied to the containers.18.45 The containers should be conspicuously marked with the following information:

(a) the name of the product;(b) its quality, if specified;(c) the batch number;(d) the expiry or retest date, if specified;(e) warnings, if required;(f) storage conditions, if specified; and

(g) the names of the manufacturer and the supplier.

Quality control

18.46 Every manufacturer should have an independent quality control unit, the head of which is directly responsible to the management of the firm. The principal duties of the quality control unit are listed below.

(a) It should approve:

(i) specifications and testing methods for starting materials, intermediate products and, if required, packaging materials and active pharmaceutical ingredients;

(ii) sampling procedures;(iii) instructions regarding sanitation and hygiene;(iv) reprocessing procedures for rejected batches or recovered materials;(v) other instructions related to the quality of the product.

(b) It should be responsible for the release or rejection of starting materials, active pharmaceutical ingredients, packaging materials, and, if required, intermediate products.(c) It should ensure that the stability of active pharmaceutical ingredients is monitored.

(d) It should be responsible for the investigation of complaints related to the quality of active pharmaceutical ingredients.

18.47 Every manufacturer should have access to a control laboratory. The laboratory should be staffed and fully equipped for performing all quality control tests required. The tests should be performed in accordance with written and validated procedures. Instruments should be calibrated at suitable intervals and reagents should be of appropriate quality.

18.48 Where circumstances require the use of outside laboratories, this fact should be stated in the analytical records.

Stability studies

18.49 A written stability-testing programme should be established for active pharmaceutical ingredients. Stability-indicating methods should be used.18.50 Samples should be stored in suitable containers and in simulated market containers at room temperature or the recommended temperature and under stress conditions.

18.51 Expiry dates do not usually need to be set for active pharmaceutical ingredients. If testing does not indicate a reasonable shelf-life, e.g., two years or more under anticipated storage conditions, then the product can be labelled with an appropriate arbitrary expiry date and should be retested on or before that date.

Self-inspection and quality audits

18.52 In order to maintain strict adherence to GMP and to all manufacturing procedures and prescribed controls, it is advisable for a firm to designate an expert or a team of experts to conduct regular independent inspections of its overall production and control procedures. Such experts should be as independent as possible in their inspection of production and control procedures.

18.53 Self-inspections and audits (see section 9) should be recorded.

Storage

18.54 Active pharmaceutical ingredients should be stored under conditions established by the manufacturer on the basis of stability studies.

18.55 Records should be maintained on the distribution of each batch of an active pharmaceutical ingredient in order to facilitate the recall of the batch if necessary, according to written procedures.

Complaints and defects

18.56 The manufacturer should maintain written instructions for dealing with complaints and defects concerning the quality of active pharmaceutical ingredients.18.57 All necessary action should be taken promptly, the complaints thoroughly investigated, and all facts recorded.

18.58 The manufacturer should have a system to allow review of all products that may have been affected by a repetitive error or a failure in the procedures of the firm.

Rejected materials

18.59 The manufacturer should maintain written instructions concerning the handling of rejected materials, whether starting materials, intermediate products, packaging materials, or active pharmaceutical ingredients. Rejected materials should be conspicuously identified as such and stored in a controlled manner pending destruction, reprocessing, or return to the supplier.

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