Why it is required?
The five-batch analysis is required for the registration of any new/generic product by the manufacturer. By conducting five-batch analyses, the manufacturer proves the chemical equivalence to the reference specifications, as per the Food and Agriculture Organization of the United Nations (FAO) and the World Health Organization (WHO).
The aim of the analysis is to quantify significant impurities ≥0.1% w/w, borderline impurities ≥ 0.06% w/w and toxicological relevant impurities. All other impurities in the< 0.06% w/w category, need to be identified and characterized, whenever and wherever possible or feasible.
Selection of five manufacturing batches
The random selection of true five batches has to be at a point in the production process, after which no further chemical reaction (designed to produce or purify the substance) is intended.
A number of guidelines are available to be followed for the enforcement of the analytical method. A few of them are ABNT, US-EPA, SENASA, COFEPRIS etc. FAO and IUPAC provide information on toxicological relevant impurities. There is little variation in the requirements of the regulatory bodies in different countries, with a common objective of quality and the safety of the product in the market.
Analytical method development
Details of manufacturing process, with enough information on key starting materials, their impurities and intermediates play an important role in the selection of appropriate techniques for the method development process. Even a laboratory with the state-of-the-art facility is prone to shoddy analysis unless they are armed with correct information from the manufacturer.
A careful study of the manufacturing process will help in identifying the nature of impurities and selection of suitable analytical techniques for analysis. The presence of non-chromophoricimpurities would need a RI/ELSD detector if they are not heat-labile and non-volatile. Analysis of volatiles would need GC-FID/NPD/ ECD detectors depending upon attached moieties or functional groups.
Before initiating the method development, the analytical chemist has to think about the country of submission of dossier for which five-batch analyses are intended. Compliance with the country centric guidelines will ease the process of registration. If a manufacturer wishes to submit a dossier to Brazilian authorities for one of the thiocarbamates, it will have to conform to the Brazilian requirements of 3D (see picture 1 and 2) analysis, but thiocarbamates do not have any chromophore, so 3D HPLC analysis is not feasible using as such molecule. Development of a selective derivatization procedure for the chromophore to the molecule can make 3D analysis feasible.
Once the technique/s is/are selected, the optimization of various parameters, such as the polarity of a column or phase of column, column temperature, mobile phase composition, flow rate, monitoring wavelength etc. completes the method development path. The combined set of optimized parameters, which gives a desired resolution of all impurities (picture 3), proper peak shapes, peak purities and acceptable run time will be defined as a suitable method for the next step of preliminary screening of five batches.
The preliminary screening of five batches for the percentage of AI and impurities (by products, carry over, salts etc.)
This screening of samples could be non-GLP. It includes qualitative or semi-quantitative analysis of active ingredients and impurities in the technical grade material. If the molecule is organic and has a chromophore, LC-MS and or GC-MS is/are right techniques for the screening purpose. The outcomes of this analysis are a percent area of all identified and resolved peaks along with their retention times, m/z ions and fragmentation pattern. The mass balance has to meet 98 to 102 percent criterion. Before going for method validation, a characterization of active ingredients for all known and unknown impurities using 1H NMR, Mass and FTIR would certify the respective structures.
The method validation has to be performed to satisfy SANCO 3030/99 rev 4, ABNT NBR 14029:2005, 2016, OCSPP 830.1800 in accordance to 40 CFR part 158.
For method validation, the parameters that need to be covered are linearity, LOQ, LOQ, accuracy and precision. Once the method is validated, the method is used to analyze the target five batches, which are randomly selected and are true representatives of the manufacturing process.
At JRF, we have completed more than 350 five-batch analyses. The reports generated for 2D or 3D analysis are accepted by all regulatory authorities. We have a team of highly experienced and self-motivated five batch analysts. One of them has completed more than 100 five batch analyses. JRF has 39 years of rich experience of data generation thus supporting manufacturers worldwide, in meeting with their commitments of a timely submission of dossiers. JRF is capable of handling inorganic compounds for five-batch analyses, such as phosphides, sulfates etc., which completes the bandwidth of existing molecules.
5 Batch Study Team of JRF
References: Guidelines (ABNT, OCSPP, SANCO, SENASA, COFEPRIS) and EC regulations
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