16. Good Practices In Production:
16.1 Principle. Production operations must follow clearly defined procedures in accordance with manufacturing and marketing authorizations, with the objective of obtaining products of the requisite quality.
General:
16.2 All handling of materials and products, such as receipt and cleaning, quarantine, sampling, storage, labelling, dispensing, processing, packaging and distribution should be done in accordance with written procedures or instructions and, where necessary, recorded.
16.3 Deviation from instructions or procedures should be avoided as far as possible. If deviations occur, they should be in accordance with an approved procedure. The authorization of the deviation should be approved in writing by a designated person, with the involvement of the QC department, when appropriate.
16.4 Checks on yields and reconciliation of quantities should be carried out as necessary to ensure that there are no discrepancies outside acceptable limits.
16.5 Operations on different products should not be carried out simultaneously or consecutively in the same room or area unless there is no risk of mix up or cross-contamination.
16.6 At all times during processing, all materials, bulk containers, major items of equipment, and, where appropriate, the rooms and packaging lines being used, should be labelled or otherwise identified with an indication of the product or material being processed, its strength (where applicable) and the batch number. Where applicable, this indication should also mention the stage of production. In some cases it may be useful to also record the name of the previous product that has been processed.
16.7 Access to production premises should be restricted to authorized personnel.
16.8 Normally, non-medicinal products should not be produced in areas or with equipment destined for the production of pharmaceutical products.
16.9 In-process controls are usually performed within the production area. The performance of such in-process controls should not have any negative effect on the quality of the product or another product (e.g. cross-contamination or mix up).
Prevention Of Cross-Contamination and Bacterial Contamination During Production:
16.10 When dry materials and products are used in production, special precautions should be taken to prevent the generation and dissemination of dust. Provision should be made for proper air control (e.g. supply and extraction of air of suitable quality).
16.11 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, particles, vapours, sprays or organisms from materials and products in process, from residues on equipment, from intruding insects, and from operators’ clothing, skin, etc. The significance of this risk varies with the type of contaminant and of the product being contaminated. Among the most hazardous contaminants are highly sensitizing materials, biological preparations such as living organisms, certain hormones, cytotoxic substances, and other highly active materials. Products in which contamination is likely to be most significant are those administered by injection or applied to open wounds and those given in large doses and/or over a long time.
16.12 Cross-contamination should be avoided by taking appropriate technical or organizational measures, for example:
(a) Carrying out production in dedicated and self-contained areas (which may be required for products such as penicillins, live vaccines, live bacterial preparations and certain other biologicals);
(b) Conducting campaign production (separation in time) followed by appropriate cleaning in accordance with a validated cleaning procedure;
(c) Providing appropriately designed airlocks, pressure differentials, and air supply and extraction systems;
(d) Minimizing the risk of contamination caused by recirculation or reentry of untreated or insufficiently treated air;
(e) Wearing protective clothing where products or materials are handled;
(f) Using cleaning and decontamination procedures of known effectiveness;
(g) Using a “closed system” in production;
(h) Testing for residues;
(i) Using cleanliness status labels on equipment.
16.13 Measures to prevent cross-contamination and their effectiveness should be checked periodically according to SOPs.
16.14 Production areas where susceptible products are processed should undergo periodic environmental monitoring (e.g. for microbiological and particulate matter, where appropriate).
WHO Good Manufacturing Practices For Pharmaceutical Products: Main Principles
(Annex 2, WHO Technical Report Series 986, 2014)
