5 Batch Analysis

R & D Centre - Torrent Pharmaceuticals

Torrent Research Centre, Vill Bhat, Dist. Gandhinagar,, AHMEDABAD (gujarat)

Drkrishnasarmapathy, Dr S.Nadkarni Dr A .Mohan. Hasmukh patel.

Received: 30/03/2010; Accepted: 17/07/2011

Guidance to the manufacturer and the testing laboratories

The term 5 batch analysis originates from the US EPA guidelines for testing of pesticides. The term is
accepted now by most regulatory bodies like EEC, Indian registration authorities namely CIB & RC and
other countries as well. There are no guidelines of OECD for this study. The study is essential to
determine the composition of the product with respect to the active ingredient and its associated
impurities.

Background
In the early framing of the guidelines for the composition of the technical grade pesticides ( With respect
.to) the active ingredient and its associated impurities up to the level of 0.01% were suggested by US
EPA. However, industries showed their inability to comply with this and suggested 0.1% levels for
impurities. For toxic impurities ( like dioxins, nitroso amines ) the levels will be lower be than this. For
impurities that cannot be characterized easily a gross description is accepted. E.g. polymeric impurities
containing carbon, nitrogen, hydrogen and oxygen. The main concern is the consistency of the product
that should be maintained by the manufacturer of the technical grade pesticide.

Introduction
The 5 batch analysis is that first step in determining the composition of a technical grade product of a
manufacturer. The study is useful in setting up the specification of the impurity levels ( at least maximum
content ). The report of the study are also required for registration of a technical grade pesticide.

Performing the 5-Batch Analysis

6-9
The 5-batch analysis may be performed while registering a new product developed by a manufacturer or
for an existing product of another manufacturer made by still another manufacturer. The second case is
commonly required for a generic product (the product that is out of patent validity period ). There are me too
registrations permitted in most countries. In this case, one has also to match the composition wrt to the
composition of the material that is previously registered. The data may be generated on the 5-batches of the
final process developed in R&D. It is preferable to use pilot plant batches to the development samples from
R&D.

ISSN: 1306-3057, Moment Publication 2012

One of the batches can also be used for physic chemical properties and the safety(toxicity) data generation.
It is still better to use the manufacturing plant bathes for this purpose. The data needs to be generated again
if there are changes in the process, equipment or raw material quality that can result in different composition
e.g., the Dow had a process of Chlorpyrifos Technical based on the chlorination of pyridine forming the
penultimate intermediate 3,5,6-Trichloropyridin-2-ol(TCP). That process in now replaced with acrylonitrile
and trichloroacetyl chloride telomerisation process for the penultimate intermediate TCP.

Selection of Batches for the 5 Batch Analysis Study

The selection of the five batches of a technical grade pesticide is from the manufacturing produced by the
standard process using the raw materials supplied by the approved vendors and passing the specifications.
The pilot plant or R&D batches(that are standardized and finalized) may also be used in the development
Phases. For a continuous process the lots produced at different time may be used.

5 BATCH ANALYSIS
Guidance to the Manufactures and the Testing laboratories

Developing the method of Analysis for the 5-Batch Analysis

The methods of analysis of the 5-Batches are one that are selective and specific to the contents. Different
complementary methods may be used e.g. HPLC with UV or preferably a DAD (PDA) detector with
complementary LC-MS/MS or GC with FID/ECD/NPD/FPD with complementary GC-MS/MS, ICP with
complementary ICP-MS Techniques like HPTLC have their use in many analyses where non-eluting
impurities like residual solvent and decomposition products that are volatile in nature. At least two methods
are to be used for identification and quantitation of the components.

In developing the methods of 5-Bathc analysis it is necessary t ensure that all the possible impurities can be
analysed by the methods should be preferably complementary like GC-FID and GC-MS-MS or GC-
ECD(Complementary ) and HPLC UV-VIS(DAD) complimented by LC-MS-MS.

A PRODUCT LIKE Chlorpyrifos Technical can be analysed by GC- FID because all impurities are stable to
heat and volatile enough to be analysed. An HPLC UV (300nm)method of CIPAC can be used with the
advantage for the same analysis but a toxicologically very significant imparity like sulfotep is not UV active at
300nm. It is then possible to use an LC-MS/MS method for analysis of this impurity at low levels(less than
0.3% w/w) using similar LC conditions. An excellent GC method is already published for determination of
sulfotep in Chorpyrifos by the international organizations.

Methods of Analysis of Complementary Supplementary methods Remarks

Active and Impurities methods
HPLC UV photo diode LC-MS-MS GC-FID/ECD; HS-GC/ Thermally unstable
array GC-MS ingredients
GC- FID GC-MS-MS HPLC; HPTLC All thermally stable
ingredients
HPLC-UV photo diode LC-MS-MS HPTLC; TLC - MS Polymeric non-elutable (
array in small pore size
column ) impurities
X ray fluorescence ion ICP; ICP-MS ASS Flame photometer For inorganics like AIP,
chromatography CuSo4.5H2O

Analysis of Cypermethrim technical for 5- batches poses different issues. The normal phase HPLC UV
method published for Cypermethrin cannot resolve the enantiomers. The 4 pairs of diastereomers are
separated on the normal phase silica column using non polar solvent along with some polar solvents like
propan -2 ol- or diisopropyl ether and many such solvent systems. However, it can not resolve the isomers
fully. Chiral column are needed for the resolution. The methods are available for the same. The volatile
solvent can be analysed by HS- GC or HS-GC-MS/MS.GC methods are also suitable for diastereomers and
impurities. The molecular peaks of the active isomers and the impurities are usually small and need to be
indentified carefully subtracting the background. The major fragments in GC give lot of information about the
impurity structure. HPTLC is a useful technique for determining the polymeric impurities in Cypermethrin
technical and arriving at the mass balance. Recently mass spectrometry is being used with HPTLC.

Analytical Method Validation (AMV) for the 5 Batch Analysis

The methods used are validated using SANCO 3030 rev.42000 guidelines. Other guidelines can be used on
merit.

5 BATCH ANALYSIS
Guidance to the Manufactures and the Testing laboratories

Identification of the A.I. and the impurities in 5- Batch Analysis

Identification of the impurities can be done by matching the retention time of A.I and other parameters like
the UV spectrum in the PDA or mass spectrum in GC-MS/MS and LC- MS/MS or high resolution mass
matching.

If the certified reference materials ( traceable to some national or international standard ) are available then
the confirmation of the a new impurity the chemical structure can be determined using the standards
spectroscopic methods like UV- VIS, FTIR, NMR, Mass Spectra, Single Crystal X- ray and Elemental
Analyses or empirical formula derived by high resolution GC/LC/MS.

Determination of A.I. in the 5 Batch Analysis

The active ingredients are analysed preferably by a known published method of analysis. The standard
Method like CIPAC and AOAC methods can be used without validation provided that the specificity wrt
impurity interference is passing the test. Chiral methods should be used to quantify the enantiomers, if a new
method is developed and used the method needs to be validated

Determination of impurities in the 5-Batch Analysis

The method for A.I. may be suitable for the impurities. However, the methods are developed as per the
properties of the impurities. The low level impurities can be analysed by trace analysis methods. Adequate
sampling and enrichment are suggested for determining the trace level toxic impurities. If a new method is
developed for impurities and used then the method to be validated.

Other parameters for ascertaining the quality of the technical material

The parameters of quality control like acidity/alkalinity, insoluble material, ash content, moisture content,
melting point and appearance by using the standard methods.

Reporting the result

The data of the analysis of the 5 Batches are to be presented in the report with appropriate uncertainty
associated with the measurement. The data should be rounded using significant rules; Summarized data
should be presented with statistical evaluation as appropriate. The mass balance to be achieved should
meet the 98-102% criterion.
Conclusions form the 5 Batch Analysis

Result need to be presented in such a way that it will help th manufacture prepared the composition of the
technical material. The specifications of the product can be laid down using the data.

Setting Up limits of A.I and impurities

The certified limits can be proposed in the report to help the sponsor or the manufacture of the material for
its registration. Due consideration is to be given the stability of A.I during the storage and the possible
degradation products.

5 BATCH ANALYSIS
Guidance to the Manufactures and the Testing laboratories

References

1. Office of prevention, Pesticides and toxic Substance; United states environmental Protection Agency,
Prevention, Pesticides and Toxic Substance OPPTS NO.830.1770 Preliminary Analysis (TS-7101)
EPA712-C-96-011 August 1996.
2. OPPTS NO.8301550 Products identity and composition,(TS-7101)EPA 712 C-96-006 August 1996.
3. OPPTS No.830.1750 Certified limits(TS-7101) EPA 712-96-012 Aug 1996.
4. OPPTS No.830.1750 Enforcement Analytical Method (TS-7101) EPA 712-96-013 Aug 1996.
5. Oficio Cirular CTA, Brasila, 21 de sete de 2011.Orientacao sobre procedilmentos tecnicas e
administrativos entreproductos tecnios . Servico public federal comitetecnico de assessoramento para
agrotomaxicosta.
6. Guidance on application for technical equivalence: guidance on regulation (EU) No. 528/2012
concerning the making available on the market and use of biocidal products version 1.0 august 2013.
7. New Source guidance guidelines concerning the requirements for technical specification of active
ingredients in non-agricultural pesticides products Updated : 29 April 2005.: Documents product by BPU
( HSE)
8. Guidance on the generation and submission of chemistry data in support of the approval of non-
agricultural pesticides control of pesticides regulation ( COPR) 1986 HSEs Biocides and pesticides
assessment unit ( BPAU) to support the approval of non agricultural pesticides under COPR.
9. Technical material and preparation : Guidance for generating and reporting mrthods of analyisi in
support of pre and post registration for Annes-II( Part A, Section 4) and Annex III ( Part A, Section 5 ) of
directive 91/414 working document directorate general health and consumer protection
SANCO/3030/99 rev.4 11/07/2000.