Nov. 16, 2017
As indicated in the previous article, five batch analyses are the backbone of a dossier of technical material and any gaffe in the application procedure - from filling templates and providing confidential and non-confidential information - may delay the registration timeline. Proposed specification by manufacturer/s producing separate technical material, if deviated from guidelines of the FAO/WHO specifications/manual, should include a clause with proper justification, coupled with the supporting data and argument.
Manufacturing process: It is an obligatory requirement from the regulatory bodies. It provides insinuation about the expected number and nature of impurities during reaction process. Brief description, including starting material %age purity, wherever applicable or essential and their source/s, stages of formation, of impurities along with conditions of the reaction, gives an insight for better understanding about impurities. Details about intermediate and impurity stability help analytical laboratory in developing suitable analytical methods for the screening of batches. Evidence, on nature of catalyst and solvent system, used during workups and purification steps, is an additional source of information, helps analytical chemists and regulatory personnel to draw a picture of impurities expected and actually present.
Type of impurities and challenges in the analysis: Once information on manufacturing process in depth available, prediction of impurities becomes much easier, which is further validated by screening the batches using a suitable analytical technique. The impurities could be unused starting materials, their carryovers, side products, degradants, intermediates, rearranged products, solvents, catalyst used during the manufacturing process, inorganic salts, etc. Screening a test substance or a batch with so many presumptions is quite challenging and becomes much more difficult with regulatory requirements of identifying and quantifying all impurities available at or above 1g/kg. Challenges are not only limited to organic or inorganic nature of impurities but also to their toxicological relevance. The guideline also suggests identifying and quantifying all relevant impurities present at or below 1g/Kg. Another challenge is to identify a suitable analytical technique and method for defined level detection. Selection of technique again depends on the nature of impurities. For impurities with conjugated double bonds are easier to detect on HPLC-UV, while other organic impurities without any chromophore needed ELSD or RI detector. Gas chromatography is another option if molecules are volatile enough to be detected by various detectors like FID, ECD, and NPD. Nature of moieties in the volatile molecules helps in selection of appropriate detector to be coupled with the GC instrument. A mass detector, when coupled with the HPLC or GC instrument, provides additional useful information on the molecular weight of the impurity. To take it further, ion trap or triple quadrupole analyzer in the mass spectrometer gives an additional hand in structure elucidation of impurity.
The number of techniques and method required for screening 5 batch analyses: It is defined by nature and number of impurities. All chromophoric impurities, with similar polarity and similar water solubility, require HPLC-UV or LCMS/MS. Volatile impurities require gas chromatograph to be analyzed and if residual solvent than Head space, coupled with GC-FID, is the relevant option. Inorganic ions need ion chromatograph or ICP-OES technique. To know the %age of moisture, Karl fisher or GC-FID using specific column can be employed. The titrimetric method is another option for some impurities like chloride analysis. Thermal analysis is a supplementary tool to check the purity of the technical material as well to know if any polymorph exists in the test substance. One of the major challenges is related with isomeric impurities. These impurities could be achiral isomers or chiral isomers. For chirality determination, special columns and specific analytical methods are required, while for achiral isomers, in general, longer run times are good enough to resolve different geometrical or positional isomers. Developing a method to resolve isomers is another challenge and time-consuming process and needs expertise in the domain.
Preliminary Screening of five batches for impurity profile and purity %age of technical material: In general, screening of five relevant batches to make sure that each and every method developed is robust and reproducible. All impurities, above 0.1 %age, are identified and quantified. All relevant impurities are identified, quantified and characterized well. Once the profile of five batches meets the FAO/WHO specifications, in terms of technical material as well as impurity profile, next step is to validate all the methods and analyze five representative batches. It is mandatory to carry out complete analysis in a laboratory with GLP accreditation with a defined archiving period. The test item and all the documents including raw data, instrumental data, report, and communication details have to be retained for a defined period for future use, if any.
Report format: It has to be in the specific format based on the country of registration.
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