Specifications and Routine Tests

Starting materials, whether the active ingredient itself or an excipient used in the manufacture of the finished product, are controlled by a specification comprising a list of tests and associated limits. The substance must comply with these limits before a batch can be deemed of suitable quality for use in the manufacture of the proposed medicinal product. The information required differs according to whether or not a substance appears in a pharmacopoeia. 

Compliance with monographs of the European Pharmacopoeia (Ph Eur) applies to all substances appearing in it and, for other substances, national pharmacopoeias may be enforced. Thus, where a pharmacopoeial monograph for an active substance or pharmaceutical excipient employs NMR spectroscopy in a test method, the substance must comply with this test. However, a test other than the pharmacopoeial test may be used if proof is supplied that the starting material meets the quality requirements of the relevant pharmacopoeia. If a pharmacopoeial monograph is applicable to a substance, then there is no need for the applicant to provide full details of the analytical tests or their validation, as reference to the pharmacopoeia in question is deemed sufficient. 

However, where a starting materia has been prepared by a method liable to leave impurities not controlled by the monograph, these impurities and their maximum tolerance limits must be declared and a suitable test procedure described. For example, changing a route of synthesis might lead to different solvent impurities, catalysts or related substances. NMR techniques are, of course, particularly useful for identifying new organic impurities if they can be isolated in sufficient quantities. 

A competent authority is also at liberty to request more appropriate specifications if it considers that the monograph is insufficient to assure adequate qualify of the substance. Further to the examples given above which result fi om differences in the synthesis route, additional tests may be required for particle size, polymorphic form, microbial contamination and sterility as necesseury to ensure the correct performance of the starting material in the finished medicinal product. Limits which are tighter than the pharmacopoeial specification may be imposed if appropriate for the particular product in question. In addition, the competent authority will require stability data for active substances on which to base the storage conditions for the drug substance and its re-test period (the period of time for which it is expected to remain within specification and after which it must be re-tested for compliance and used immediately). 

These requirements also apply to drug substances for which a Certificate of Suitability has been issued by the European Pharmacopoeia This scheme was introduced in 1994 and certifies that the Ph Eur monograph for a substance is suitable for the control of that substance using a particular method of manufacture. Presentation of Certificates of Suitability are the preferred way for applicants to satisfy the guideline for such active substances (Table 2-2). A Certificate assures that the pharmacopoeial tests are adequate to 

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Table 3.7 CPMP Guideline III 9090, IIC3—packaging materials Specification and routine tests...

Packaging material (primary or immediate packaging) Specifications and routine tests, covering ... 

The adhesives are routinely tested for specific performance and compliance to many user specifications with different requirements. Government purchases are covered in the Mil Standard A-46050C (12). 

The best test for the suitability of the models is to develop their respec tive parameter estimates at one set of conditions and then test the accuracy of the models using measurements for other sets of conditions. The other conditions can be as relatively close to those used to establish the parameter estimates as might be experienced in routine operations. They may also be far different with different feed conditions and operating specifications. 

A team consists of two or more people that know the process technology, design, operating procedures, practices, alarms, emergency procedures, test and maintenance procedures, routine and non-routine tasks. They must consider authorization and procurement of parts and supplies, safety and health standards, codes, specifications and regulations. The team leader provides m.iriagcment and goals to the process the team and consultants construct and interpret the analyses. 

When all equipment has been listed, the total number of running feet needed can be added up. How much more will be required This will vary from one laboratory to another. In an industrial laboratory where both routine testing and product development work are to be performed, this figure can safely be multiplied by four for a realistic estimate. In some laboratories used exclusively for specific types of work with no other types contemplated, this figure may be lower. It should be kept in mind, however, that expanding an existing laboratory is an extremely expensive... 

RCM-related T-cell activity may be assessed in vitro by lymphocyte transformation test [19, 24]. In addition, CD69 upregulation (lymphocyte activation test) was observed in patients with a positive lymphocyte transformation test [24, 39]. These tests appear to be a promising tool to identify drug-reactive T cells in the peripheral blood of patients with RCM-induced drug-hypersensitivity reactions. However, the sensitivity and specificity remain unknown and, therefore, these tests cannot be recommended for routine use yet, but further research on the specificity and sensitivity is indicated. 

The commonly used hybridization technique (Kafatos et al. 1979, Martin 1985) for sequence-specific detection of DNA is sensitive to 10 pg of DNA. However, several factors render hybridization impractical for routine testing for DNA contaminants, since it is labor intensive, time consuming, and strongly semiquantitative and usually requires a radioisotope. In addition, the specificity of the method means that some contaminating DNA may be missed. 

Those aspects critical to the in vivo bioavailability of the product and routine control tests proposed to ensure that the product has consistent bioavailability from batch to batch. Where a product has low in vivo absorption, the evidence should be discussed and a conclusion reached as to whether this is due to intrinsic properties of the active ingredient(s) or whether it is related to the properties of the dosage form concerned. In the case of products intended to have a nonsystemic effect, the potential for systemic absorption may need to be considered. This may involve specific studies to determine the levels of the active ingredient(s) in the blood, plasma, urine, or feces and a discussion of the clinical significance of those results. 

Where there is a Ph Eur or national pharmacopeial specification for the excipient, this should be applied. Third country pharmacopeial specifications may also be acceptable. Routine tests and specifications should be stated. Function-related specifications should be included. 

For nonpharmacopeial materials a full specification should be included in the application. This should include appropriate tests and requirements for physical characteristics, identification, relevant purity tests, and performance-related tests. Characteristics likely to influence bioavailability of the finished product should be controlled. Routine tests and specifications should be described. Methods should be validated. The material should be fully characterized, with full data on the chemistry concerned and including consideration of the safety of the excipient. Any relevant European Directive requirements or other international specifications should be met, but additional requirements might apply depending on the intended use of the product—e.g., for materials to be used in sterile products. 

The homogeneity of the product should be addressed. The adequacy of mixing processes should be shown (and confirmed with appropriate process validation data) and potential segregation discussed (as affected by surface properties, crystallinity, particle size, etc.). The Ph Eur uniformity of content requirements should apply to the dosage forms and uniformity of distribution needs to be shown between batches and within batches. The need for appropriate routine tests as part of the release specification should be discussed. 

QA/QC laboratories. The QA/QC lab is responsible for the testing of feedstocks and raw materials, process intermediates, and finished goods, and may, in addition, be responsible for the development of standards for materials, processes, and procedures. The QA/QC lab is usually characterized by the routine, repetitive nature of its workload. Testing is primarily to specification and, where lot acceptance or rejection is involved, is often on a grade category or pass/fail basis. Data may be archived for compliance with regulatory directives and for analyses of trends In material or process performance. 

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