WHO GUIDELINE FOR SAMPLING OF PHARMACEUTICAL PRODUCTS
SAMPLING: – Sampling comprises the operations designed to select a portion of a pharmaceutical product for a defined purpose. The sampling procedure should be appropriate to the purpose of sampling, to the type of controls intended to be applied to the samples and to the material to be sampled. The procedure should be described in writing.
CLASSES AND TYPES OF PHARMACEUTICAL PRODUCTS AND RELATED MATERIALS: The materials to be sampled may belong to the following classes:
- starting materials for use in the manufacture of finished pharmaceutical products.
- intermediates in the manufacturing process (e.g. bulk granule).
- pharmaceutical products (in-process as well as before and after packaging).
- primary and secondary packaging materials, and
- cleaning and sanitising agents, compressed gases and other processing agents.
- Preparation for sampling: –For the sampling of products, the responsible person should have at his or her disposal all the tools needed to open the containers (e.g. packages, barrels and others). Tools may include knives, pliers, saws, hammers, wrenches, implements to remove dust (preferably a vacuum cleaner), and material to reclose the packages (such as seal- ing tape), as well as self-adhesive labels to indicate that some of the contents have been removed from a package or container. Containers due to be sampled should be cleaned prior to sampling if necessary.
- Sampling of uniform starting materials does not require complicated tools. A variety of pipettes fitted with suction bulbs, cups or beakers, dippers and funnels are needed for liquids of low viscosity. The use of glass should be avoided. A suitable inert rod can be used for highly viscous liquid, and spatulas or scoops are needed for powdered and granular solids. Sterile pharmaceutical products should be sampled under aseptic conditions, and only when deemed absolutely essential, to avoid the risk of loss of sterility. All sampling tools and implements should be made of inert materials and kept scrupulously clean. After use or before reuse, they should be thoroughly washed, rinsed with water or suitable solvent, and dried. They should be stored in clean conditions. Adequate washing facilities should be provided in, or in close proximity to, the sampling area, otherwise samplers will need to bring separate clean sets of implements for sampling each product. The cleaning procedure used for all sampling tools and implements should be documented and recorded. The adequacy of the cleaning procedure for the material from which the sampling tool is made should be demonstrated. The use of disposable sampling materials has distinct advantages.
- Sampling operation and precautions: – There should be a written procedure describing the sampling operation. This should include details of the health and safety aspects of sampling. It should ensure that representative samples are taken in sufficient quantity for testing in accordance with specifications. Closures and labels should preferably be such that unauthorised opening can be detected. Samples should never be returned to the bulk.
- The sampling process should be appropriately supervised and documented.
- The sampling procedure should be such that non-uniformity of the material can be detected. During the sampling procedure, attention should be paid to any signs of nonconformity of the material.
- Signs of non-uniformity include differences in shape, size or colour of particles in crystalline, granular or powdered solid substances; moist crusts on hygroscopic substances; deposits of solid pharmaceutical product in liquid or semi-liquid products; and stratification of liquid products. Such changes, some of which may be readily reversible, can occur during prolonged storage or exposure to extreme temperatures during transportation. Homogeneous portions of the material or bulk such as those mentioned above should be sampled and tested separately from the rest of the material that has a normal appearance.
Pooling of the samples from the different portions should be avoided, because this can mask contamination, low potency or other quality problems.
Labelling of samples should provide appropriate details, including the batch number and, if known, the container number from which the sample was taken, the amount taken and for what purpose. Labels should be applied at the time of sampling. The container used to store the sample should also be properly labelled with appropriate details such as sample type, name of material, identification code, batch/lot number, code, quantity, date of sampling, storage conditions, handling precautions and container number.
For finished drug products, the sampling procedure should take account of the official and non-official tests required for the individual dosage form (e.g. tablets or parenteral preparations). Non-official tests could include testing for adulteration and counterfeiting.
The sampling procedure should also take account of past experience with the pharmaceutical product or related material and with the supplier, and of the number of sampling units in the consignment.
When a container is sampled outside the control of the consignee of the product, the following precautions should be taken. If the tamper proof seal is broken to obtain a sample, then the consignee of the product should be informed and the container resealed with an appropriate tamper-proof seal, and the consignee of the product informed of its type and its identification. If a bag has been punctured to take a sample, then the sampling hole should be appropriately closed and identified as a sampling hole made by an authorised sampler. Sampled containers should be identified, as they may no longer contain the quantity of product stated on the label. In accordance with national legislation there may be exceptions, e.g. during ongoing investigations of cases related to counterfeit pharmaceutical products.
- Storage and retention: – The container used to store a sample should not interact with the sampled material nor allow contamination. It should also protect the sample from light, air and moisture, as required by the storage directions for the pharmaceutical product or related material sampled. As a general rule the container should be sealed and preferably tamper-evident.
Samples of loose materials, whether solid or liquid, should be placed in one or more clean containers. Liquid samples should be transported in suitable bottles closed by screw tops with inert liners that provide a good vapour-proof (moisture-proof) seal for the contents. Suitable screw-top jars in exceptional cases only should be used for solid or semi-solid pharmaceutical products. The container should be inert. Light-sensitive materials should be protected by using amber glass containers or by wrapping colourless glass containers in foil or dark-coloured paper. Headspace should be kept to a minimum to minimise any possible degradation. Any special procedures, for example, nitrogen gassing, should be discussed with the consignee of the material and carried out as appropriate.
Solid dosage forms such as tablets or granules should be protected during transit, either by totally filling the container with the product or by filling any residual space with a suitable material. All containers should be sealed and labelled, and all samples should be packaged adequately and transported in such a way as to avoid breakage and contamination during transport.
For all containers that come apart (e.g. screw-capped jars or metal tins with separate lids) precautions should be taken to avoid any mix up when they are opened for examination, such as by labelling all parts of each container whenever possible.
If one sample is divided into several sample containers, they should be transported in a suitably sealed box, which should be labelled with the identity of the product, the consignment from which the sample was drawn, the size of the sample, the date and place of sampling, and the name of the inspector.
Security and adequate storage conditions should be ensured for the rooms in which samples are stored. Samples should be stored in accordance with the storage conditions as specified for the respective active pharmaceutical ingredient (API), excipient or drug product. Packaging materials similar to those in which the bulk is supplied should be used for long-term storage.
SAMPLING PLANS FOR STARTING MATERIALS, PACKAGING MATERIALS AND FINISHED PRODUCTS
Ideally each sampling unit should be examined to ensure that it is intact and also checked for possible damage to the container. The contents should be inspected for uniformity and appropriately tested for identity. Uniformity should be tested on selected layer samples at different points in the material without previous intermixing. However, in cases when this ideal procedure is not possible or justified by the purpose of sampling, a number of sampling units should be randomly selected for sampling. It is not prudent to open all containers of products, which are liable to deteriorate under the influence of moisture or oxygen when held in a transit warehouse. However, materials in damaged containers or those found to be non-uniform should either be rejected or individually sampled for a complete quality control. Unlabelled sampling units should be rejected.
For random sampling, whenever possible each sampling unit should be consecutively numbered and the required number of random sampling units selected using tables of random numbers.
Starting materials: – When sampling starting materials proper consideration has to be given to deciding on a sampling plan. The following are examples of sampling plans that could be used.
- The n plan: – The “n plan” should be used with great caution and only when the material to be sampled is considered uniform and is supplied from a recognised source. Samples can be withdrawn from any part of the container (usually from the top layer). The n plan is based on the formula n = 1 + square root N, where N is the number of sampling units in the consignment. The value of n is obtained by simple rounding. A minimum number of containers needs to be sampled, e.g. if N is less than or equal to 4, then every container is sampled. According to this plan, original samples are taken from n sampling units selected at random and these are subsequently placed in separate sample containers. The control laboratory inspects the appearance of the material and tests the identity of each original sample according to the relevant specification. If the results are concordant, the original samples are combined into a final, composite sample from which an analytical sample is prepared, the remainder being kept as a retention sample.
The n plan is not recommended for use by control laboratories of manufacturers who are required to analyse and release or reject each received consignment of the starting materials used to produce a drug product.
- The p plan: – The “p plan” may be used when the material is uniform, is received from a recognised source and the main purpose is to test for identity. The p plan is based on the formula p = 0.4 square root N, where N is the number of sampling units. The figures for p are obtained by rounding up to the next highest integer. According to this plan, samples are taken from each of the N sampling units of the consignment and placed in separate sample containers. These original samples are transferred to the control laboratory, visually inspected and tested for identity (a simplified method may be used). If the results are concordant, p final samples are formed by appropriate pooling of the original samples.
- The r plan:- The “r plan” may be used when the material is suspected to be non-uniform and/or is received from a source that is not well known. The r plan may also be used for herbal medicinal products used as starting materials. This plan is based on the formula r = 1.5 square root N, where N is the number of sampling units. The figures for r are obtained by rounding up to the next highest integer.
Samples are taken from each of the N sampling units of the consignment and placed in separate sample containers. These original samples are transferred to the control laboratory and tested for identity. If the results are concordant, r samples are randomly selected and individually subjected to testing. If these results are concordant, the r samples are combined for the retention sample.
Packaging materials and Finished products:- Sampling plans for packaging materials and finished product should be based on defined sampling standards, for example, British Standard BS 6001-1, ISO 2859 or ANSI/ASQCZ1.4-1993.
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