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Bhenjaliya H, et al: Analytical Method Development and Validation: Requirements in Pharmaceutical Field
Review Article
Analytical Method Development and Validation: Requirements
in Pharmaceutical Field
Hetal Bhenjaliya, Rohan Barse*
Email: barserohan@gmail.com
Abstract
Analytical method validation needed during the production and manufacture of drugs and such analytical
procedure is sufficient for their intended purpose. The development of methods usually requires the collection
of method specifications and the decision on the type of instrumentation. This needs a system of analyzing
herbal products, new processes, and reactions, new compounds, active ingredients (macro analysis), residues
(microanalysis), impurity profiling, etc.
Key words: Analyte, Qualitative, Quantitative, Standard, Validation
Introduction 1. World Health Organization (WHO)
The creation of methods usually requires the 2. Pharmaceutical Inspection Cooperation Scheme
collection of method specifications and the types of (PIC/S)
instrumentation to be determined1. It includes an 3. United States Food and Drug Administration
analytical approach for herbal products, new processes (US FDA)
and reactions, new ingredients, active substances 4. The International Conference for Harmonization
(macro analysis), residues (microanalysis), impurity (ICH)
profiling, etc. This review article discusses the steps 5. Current Good Manufacturing Practice (cGMP)
involved in developing and validating a drug molecule regulations
2,3
analytical approach in the pharmaceutical field . 6. Good Laboratory Practice (GLP) regulations.
Analytical measurements are linked to every aspect 7. Pharmaceutical Inspection Cooperation Scheme
of society and there are countless explanations as to (PIC/S)
why these measurements are made. It is obviously
important to determine the correct outcome and to Reasons valid for developing new analytical
be able to demonstrate that it is accurate. process
Some of the prominent Quality Standards 1. Costly reagents and solvents required
5 current analytical procedures. It also requires
organizations are : burdensome extraction procedures and
1 2 separation.
Hetal Bhenjaliya , Rohan Barse 2. Existing methods may be unreliable.
1 Department of Pharmaceutics, Shree Dhanvantary Pharmacy
College, 3. A similar sample matrix may not contain a
Near Kim Railway Station (East), Kim, Surat-394110, Gujarat suitable method for a specific analyte.
State, India
2 Department of Quality Assurance, Shree Dhanvantary 4. Existing technologies could be too complicated,
Pharmacy College, cumbersome, not easily automated.
Near Kim Railway Station (East), Kim, Surat-394110, Gujarat 5. Current techniques may not have been
State, India
* Corresponding Author appropriately resilient.
Date of Submission: 25-07-2019, Date of Revision: 27-01-2020 6. Cannot consider analytical methods for
Date of Acceptance: 29-01-2019 quantifying the analyte in biological fluids
How to cite this article: Bhenjaliya H, Barse R. Analytical Method Development and Validation: Requirements in Pharmaceutical
Field. MJPS 2020; 6(1): 60-65.
60 Manipal Journal of Pharmaceutical Sciences | March 2020 | Volume 6 | Issue 1
Bhenjaliya H, et al: Analytical Method Development and Validation: Requirements in Pharmaceutical Field
Goals for a new or better theoretical process and materials publications for physicochemical
1. Direct transmission of qualitative or properties, synthesis, solubility, and correct
quantitative data to laboratory computers for analytical methods.
assessment, analysis, printing, and transmission • To decide if any analytical work on the
via a network to other locations. analyte has ever been carried out within the
2. Sample preparation reducing the time, energy, company, and if so, to collect data, findings,
materials and sample volume consumed by using records, memos, and publications.
simple quality assurance and quality control
procedures reduced costs per analysis. 4. Choosing a method
3. Qualitative description of special interest • If no methods are available to investigate the
analytes, with some structural details. analyte to be analyzed in the past.
4. Upon installation of the instrumentation • Adopt sample preparation and instrument
and consideration of analyte parameters, the conditions (e.g. HPLC) wherever possible
specifications should be used to further build, to take advantage of the latest methods and
refine and test the system. technologies.
6
Steps in the analytical method development 5. Instrument setup and initial studies
1. Analyte standard characterization • Installation, function and performance
• While analyzing multiple components in the evaluation of the instrumentation in respect
sample matrix, the number of components of laboratory standard operating procedures
that pose the data is noted, and normal shall be verified by defining the appropriate
usability is calculated. instrumentation
• Sample stability methods such as spectroscopic, • Starting with an accurate, proven norm is
high performance liquid chromatography essential, rather than a complex matrix of
(HPLC), gas chromatography (GC), mass samples.
spectrometry (MS), etc.
• Consider the availability of standards for 6. Optimization
degradation products, possible impurities • If initial analytical results are less than
and synthetic precursors. The purity of all optimal, start the optimization cycle, keeping
standards to be used in method development the method’s goal in mind. If necessary, using
should be established and documented. computer-based optimization tools.
2. Method requirements • Pay special attention to experimental design
• Find the aims or parameters of the analytical during optimization.
methods to be set and describe the figures of 7. Demonstration of investigative data of value
the analytical merit. with standards
• Additional criteria (time, energy, effort, time • First, give customized empirical merit
of analysis, available tools) tool limitations figures for the rule, before dealing with the
(pressure and solvents) and cost per analysis actual research. The norm can not meet the
3. Literature search and prior methodology required figures of empirical validity, and the
• Consider the objectives of the analytical
methods to be established and all literature study of the sample is futile.
information relating to the drug is checked • If the analytical merit figures are standardized
for relevant books, articles, United State and recorded, including standardization of
Pharmacopoeia/ National Formulary items such as integration parameters and any
(USP/NF), Association of analytical statistical data treatment (when necessary),
communitiesand American society for testing then sample analysis can start.
Manipal Journal of Pharmaceutical Sciences | March 2020 | Volume 6 | Issue 1 61
Bhenjaliya H, et al: Analytical Method Development and Validation: Requirements in Pharmaceutical Field
8. Evaluation of proven methods with actual is no SRM available, have one synthesized
samples: Derivation of figures of merit outside, contract laboratory that will guarantee
• Working with actual samples, conduct sample composition authenticity and identity.
preparation steps to ensure analyte peak 12. Preparation of written protocols and
detection capability apart from any other procedures
possible interferences and contaminants.
• Ideally, a “dilute and shoot” sample • Ensure that all necessary and sufficient
preparation will minimize the time and cost details of the method are stated so that other
of the overall analysis. At the same time, labs can reproduce, as closely as possible, the
one must remember to provide an injection experimental conditions.
solution that is compatible with the HPLC/ • Provide specific suppliers, addresses, catalog
MS system. numbers, batch numbers, purity levels, and
any other unique identifying features that
9. Validation of figures of merit will ensure that other analysts obtain the
• Validate the method once it has been developed exact items to duplicate the method.
and optimized. Regulatory laboratories (FDA)
perform method validation by evaluating and 13. Transfer of method technology to outside
documenting the USP. laboratories: Interlaboratory collaborative
• The eight parameters of method validation studies
namely accuracy, linearity, range, limit of • Continue method validation (ruggedness)
detection (LOD), limit of quantification outside the original laboratory by performing
(LOQ), specificity, ruggedness and sturdiness. interlaboratory collaborative studies.
10. Determination of percentage of sample interlaboratory studies can be accomplished
recovery and quantitative sample analysis by splitting known, authenticated samples
• An average percentage of the recovery in a and dispensing them to other laboratories
sample matrix of spiked, genuine standard while providing them with a complete
drug that contains no analyte. Recovery procedure of the overall, final method.
optimization has to be shown from sample 14. Comparison of interlaboratory studies
to sample for reproducibility (average ± • Summarize and statistically compare
standard deviation) validation results from interlaboratory
11. Method validation collaborative studies to demonstrate whether
• Perform zero blind studies to demonstrate that the method can be transferred to other
known levels can be accurately and precisely facilities and provide similar accuracy and
determined in a real sample. precision of the quantitative results.
• Perform double-blind studies to further 15. Preparation of summary report on overall
demonstrate the quantitative accuracy and method validation results
precision of the overall method. • Prepare a summary report that includes
• Demonstrate repeatability of analytical results, results from all laboratories where the
within a single laboratory. method was employed, with qualitative and
• Demonstrate analytical figures of merit quantitative results statistically treated.
reproducibility (ruggedness), from lab to lab,
analyst to analyst, instrument to instrument, 16. Summary report of final method procedures
and so on, as required. and results, and preparation of journal article
• Carry out additional analysis using the analyte’s for submission.
credible sample matrix selected reaction Sampling collection for the development of an
monitoring (SRM)of major interest. If there analytical tool
62 Manipal Journal of Pharmaceutical Sciences | March 2020 | Volume 6 | Issue 1
Bhenjaliya H, et al: Analytical Method Development and Validation: Requirements in Pharmaceutical Field
Make the quantification of impurities accurate at instrumentation, reagent, and expertise the cost of
low levels which is essential in defining the quality the study is quite high. Such methods are reliable
of pharmaceutical products. To that end, a great and consistent with good reproducibility, but the
deal of time is devoted to developing methods to pharmaceutical analyst also takes into consideration
meet these needs. The first step of this development a situation where concentration of one or more
project must be to define and gather a set of samples substances is required in samples known to contain
containing any potential and actual impurities other absorbent substances that may interfere with
that need to be assessed by the purity method. the assay.
With this set in hand, subsequent development If the sampling method is known, the interfering
experiments can assure that a method or methods material’s identity and concentration is known, and
can accurately and completely determine the purity the degree of interference may be measured in the
of a pharmaceutical product. study. The analyst has a number of modifications to
This paper provides detailed guidance in selecting the basic spectrophotometric technique which can
the set of samples that contain the compounds eliminate some sources of interference and allow all
of interest that must be quantified at low levels absorbing components to be measured accurately.
for a pharmaceutical product. A list of potential Some changes to the basic procedure can be made
components and their sources is provided. Guidance if certain criteria are met. The basis of all the
is given on sample-screening techniques and spectrophotometric techniques for multicomponent
when to eliminate samples that are redundant or samples is the possessions that at all wavelengths:
unnecessary. Finally, techniques are outlined to • The sum of absorption of the individual
enrich and combine samples in order to minimize components is the absorption of a solution.
the sample set. or
7 • Precise absorption is the difference between the
Method Development in Chromatography
Problems in method development overall absorption of the sample cell solution
1. Stored samples are initially accurate but slowly and that of the reference cell solution.
become inaccurate with low bias There are various spectrophotometric methods
2. Absorption issue: A serially diluted curve available that can be used to test a mixture sample.
is concave. The response factors drop with They can be used according to methods:
decreasing concentration. An increased • Difference spectrophotometry
exposure due to the number of dilutions, surface • Derivative spectrophotometric method
area contact, and time may cause this problem • Method for absorbing the ratio (Q-Absorbance
3. Homogeneity: The sample to be analyzed gets method)
partitioned. • Simultaneous equation method
The detector must then be selected to provide the Assay bias and factor for the response of analytes
required sensitivity, the necessary. These are some All analytical procedures are associated with a
of the basic options, but there are many others to number of biases, particularly biological assays,
make, such as an internal or external standard, the that test for biopharmaceutical purity, potency, and
sampling process, the need for gradient elution or molecular interactions. Adequate reference criteria
temperature programming, sensitivity to detectors, may also not be readily available, as the commodity
etc. The efficient implementation of the system may be one of a kind. The most difficult part of the
includes expertise in chromatographic science and production and testing process can be determining
comprehensive practical experience. the accuracy and bias of the assay. Comparing the
Spectrophotometric methods findings of the new method with those of the old
These approaches are reliable and consistent method often only makes sense when controlling for
with good reproducibility but due to costly bias in the test.
Manipal Journal of Pharmaceutical Sciences | March 2020 | Volume 6 | Issue 1 63
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