ICH guideline

Guidance on specifications is divided into universal tests/criteria which are considered generally applicable to all new substances/products and specific tests/criteria which may need to be addressed on a case-by-case basis when they have an impact on the quality for batch control. Tests are expected to follow the ICH guideline on analytical validation (Section 13.5.4). Identification of the drug substance is included in the universal category, and such a test must be able discriminate between compounds of closely related structure which are likely to be present. It is acknowledged here that optically active substances may need specific identification testing or performance of a chiral assay in addition to this requirement. 

Table 5.3 Suggested headings for an Investigator s Brochure according to ICH guidelines.

ICH Guideline Q7 Good Manufacturing Practice for Active Pharmaceutical Ingredients, www.ich.org. 

ICH Guideline Q2 Validation of Analytical Procedures Text and Methodology. www.ich.org. 

Storage under stress conditions according to ICH Guidelines,i.e. 25°C/60% RH, 30765% RH, or 40°C/75% RH (Conditions I, II, resp. Ill temperature controlled to within 2°C, relative humidity to within 5%), with sampling intervals of 2 weeks or 1 month. 

Australia has a formal process for adopting European guidelines for drug development and evaluation, including the ICH guidelines. It also has bilateral agreements with a number of countries, and its membership of the Pharmaceutical Inspection Convention allows it to exchange GMP information with other members. 

Non-specific absolute assay methods, e.g. volumetric titration, can be applied to avoid the establishment of a reference substance. This is only appropriate, however, when the monograph describes a separation test for related substances. This approach is certainly valid for the determination of the content of pharmaceutical raw materials but less acceptable for the assay of content of pharmaceutical preparations where the employment of specific assay methods is recommended (ICH Guideline 1994) to take account of decomposition of the active ingredient during the shelf life of the product and to avoid possible interference from excipients. 

A pharmacopoeial reference substance is intended for the determination of the main component of a substance or for the active ingredient of a pharmaceutical formulation which is usually present at a high proportion of the total. The reference substance is to be used as a primary standard in a specific method validated as prescribed in the ICH Guideline Validation of Analytical Procedure Methodology" (Technical Guide for the Elaboration of Monographs 1996 ICH Guideline 1997). the reproducibility of which is known. This is taken into account when the limits of acceptance (tolerance) for the substance or product are fixed (Daas and Miller 1997,1998). 

ICH Guideline (1994) Validation of analytical methods (Definition and Terminology). IFPMA, Geneva. 

ICH Guideline (1997) Validation of analytical procedure methodology. IFPMA, Geneva, (ref. 31)... 

Since the final product is a pharmaceutical, high purity of the product is definitely required. Furthermore, the amount of any impurities in the final product has to be rigorously regulated under ICH guidelines. Rejection of impurities related to cyclopropylacetylene (37) was difficult throughout this whole process [28]. Thus, not only the isolated yield but the impurity profile of 37 was critical. 

Initially, 50 was converted into the benzoxazinone 51 by reaction with phosgene in the presence of triethylamine and 51 was isolated in 95% yield upon crystallization from methanol. Deprotection of the pMB group from 51 was accomplished with ceric ammonium nitrate (CAN) in aqueous acetonitrile. Efavirenz was isolated in 76% yield after crystallization from EtOAc-heptane (5 95), as shown in Scheme 1.19. There were two issues identified in this route. First, lequiv of ani-saldehyde was generated in this reaction, which could not be cleanly rejected from product 1 by simple crystallization to an acceptable level under the ICH guideline. Anisaldehyde was removed from the organic extract as a bisulfite adduct by washing with aqueous Na2S205 twice, prior to the crystallization of 1. Secondly,... 

The objective for Process Chemistry is to establish clean cost-effective manufacturing processes for new medicines identified by Medicinal Chemistry in a timely manner. At an absolute minimum, the reproducibility of the process and the quality of the final products has to meet established standards, such as the ICH guidelines. 

Just as there is an adverse event form, there is usually a serious adverse event (SAE) form. Note here that serious as defined by the FDA is different from severe on the adverse event form. A patient can have a severe headache that may not be considered serious. The ICH guideline (also in ICH E3) entitled Clinical Safety Data Management Definitions and Standards for Expedited Reporting defines serious adverse events as follows ... 

Where toxic gases or solvents have been used in the manufacturing process, validation data on their removal and relevant release and shelf life specifications and acceptance limits should be included in the dossier (taking into account the ICH guidelines on residual solvents and the CPMP guideline on ethylene oxide usage). These can be discussed in the development pharmaceutics section or elsewhere. 

The formation of ethylcellulose nanoemulsions by a low-energy method for nanoparticle preparation was reported recently. The nanoemulsions were obtained in a water-polyoxyethylene 4 sorbitan monolaurate-ethylcellulose solution system by the PIC method at 25 °C [54]. The solvent chosen for the preparation of the ethylcellulose solution was ethyl acetate, which is classed as a solvent with low toxic potential (Class 3) by ICH Guidelines [78]. Oil/water (O/W) nanoemulsions were formed at oil/ surfactant (O/S) ratios between 30 70 and 70 30 and water contents above 40 wt% (Figure 6.1). Compared with other nanoemulsions prepared by the same method, the O/S ratios at which they are formed are high, that is, the amount of surfactant needed for nanoemulsion preparation is rather low [14]. For further studies, compositions with volatile organic compound (VOC) contents below 7 wt% and surfactant concentrations between 3 and 5 wt% were chosen, that is, nanoemulsions with a constant water content of 90% and O/S ratios from 50 50 to 70 30. 

Carcinogenicity Studies. Carcinogenicity studies are covered in Guidelines SI A, SIB, and SIC. The guidelines are almost more philosophical than they are technical. In comparison to the EPA guidelines for example, the ICH guidelines contain little in... 

While they were not quite as sweeping in approach as the aforementioned guidelines, a toxicologist working in pharmaceutical safety assessment should become familiar with the all the other ICH Guidelines in the S series. 

TABLE 2.13. Comparison of Traditional and ICH Guidelines for Reproductive and Developmental Toxicology... 

ICH guidelines specifically require three genotoxicity assays for all devices (see Table 6.2). The assays should preferably evaluate DNA effects, gene mutations and chromosomal aberrations, and two of the assays should preferably use mammalian cells. Guidance for providing tests for selection to meet these needs are the OECD guidelines, which include 8 in vitro and 7 in vivo assays. 

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