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Pharmaceutical Technology REGULATORY SOURCEBOOK SEPTEMBER 2021 37 • notes on possible abnormalities or deviations • the name and signature of the operator. Second-person review should ensure traceability and compliance throughout this phase. High level structure for testing (Phase 2 and Phase 3). As noted earlier, there is a general consensus that there are two dis- tinct and independent generic processes involved in sam- pling and there is a point at which it ends (Phase 1) and testing begins (Phase 2). From Phase 2 onward, there is no longer any uncertainty contribution from sampling errors, only from analytical operational errors. The latter are both procedural and metrological in nature. However, there will be small error contributions from the within procedure analytical operations, for example, between portions, even if the analytical sample is representative. The generic testing process requires an input from an ana- lytical procedure for the required characteristic and is divided into three sub-processes: analytical operations, calculation protocol, and analytical record. The output from the analyt- ical procedure is the reportable value of the characteristic of the analytical sample. Analytical operations (Phase 2) The journey from the test sample to the analytical metrol- ogy will be technique specific. In addition, the analytical procedure will require compliance with system suitability tests as part of the analytical control strategy before any sample testing is carried out. However, there is a general scheme for a typical HPLC procedure illustrated in Figure 4, which covers nomenclature for sample preparation, rep- lication, and measurement. These operational and metro- logical steps form the input to the analytical record for the test sample. The preparation of reference standards is not included in this process f low for simplicity reasons but would follow the same logic as for the test sample. Table I. Proposed terms and definitions. ALCOA+ is attributable, legible, contemporaneous, original, and accurate, complete, consistent, enduring, and available. Term Definition Statistical sampling plan • A predetermined procedure for the selection, withdrawal, preservation, and preparation of the portions to be removed from a population as samples. • A sample is any portion of material selected from a larger quantity of material. The sample type is identified by specific qualifiers (e.g., random sample, with their own definitions) • The intent is to minimize the difference between the properties as estimated from a sample and the actual properties of the lot, and to limit or control the uncertainty generated by the sampling operation on a statistical basis, all within practical constraints. • The end point is a representative sample for testing that can be expected to adequately reflect the properties of interest (char- acteristics) of the parent population. Characteristic • A property or attribute of a material that is to be measured or observed. The ISO term is measurand. Sampling uncertainty (homogeneity) • That part of the error associated with using only a fraction of the material population to be sampled and extrapolating to the whole as distinct from analytical or testing error. It arises from a lack of homogeneity in the material population. • Sampling error may be determined by replication of sample increments and their multiple determinations or/and by reducing the particle size if appropriate. • Homogeneity is the degree to which a property, characteristic, or attribute is uniformly distributed throughout a quantity of material. The degree of heterogeneity (the opposite of homogeneity) is the determining factor of sampling error. Sampling process (definitions) Static sampling: The composition of the parent material can be considered as permanent with respect to position in space and stable in time such that the only variable is the sampling position within the space occupied by the consignment, lot or batch. Dynamic sampling: If the parent material is almost always changing with respect to time (dynamic) and the removal of a portion of the parent material at any instant reflects only a state at that time and at a particular site (e.g., in process control samples from a mixer) Sample increment: Each of the discrete, identifiable portions of material removed from a population, which can be individually tested, or combined Random sample: The sample so selected that any portion of the population has an equal (or known) chance of being chosen Representative sample: A sample resulting from a sampling plan Reference sample: A representative sample of a batch of starting material, packaging material, or finished product, which is stored for the purpose of being analyzed should the need arise during the shelf life of the batch concerned Retention sample: A sample of a fully packaged unit from a batch of finished product. It is stored for identification purposes. For example, presentation, packaging, labeling, patient information leaflet, batch number, and expiry date should the need arise during the shelf life of the batch concerned Stratified sample: A sample consisting of portions obtained from identified subparts (strata) of the parent population. Within each stratum, the samples are to be taken randomly. Sampling Procedure: The complete sampling operations to be performed on a defined material for a specific purpose Sampling Protocol: A detailed, written description of the sampling procedure to be carried out for a specific consignment, lot or batch Sampling record Documented evidence of the sampling operations carried out on a particular material for a defined purpose. The sampling record should contain the batch number, date, and place of sampling, reference to the sampling protocol used, a description of the containers and of the materials sampled, notes on possible abnormalities, together with any other relevant observations, and the name(s) and signature(s) of the sampler(s) in accordance with ALCOA+ principles.