INTRODUCTION:
·
Product
quality and consistency is ensured through total control strategy. In addition
to adherences to GXP, process validation, material control following are also
major contributors to this strategy:
o Product Characterization studies
o Testing and control of In-process Materials- Process
Control
o
Testing
and control of Intermediate Products- Process Control
o
Testing
and Control of Drug Substance (includes stability testing)
o
Testing
and Control of Drug Product (includes stability testing)
o Comparability exercise (if any additional
characteristic evaluated)
·
Product
characterization provides the data for setting the product specification.
Applicable analytical technologies are used to access below listed product
characteristics:
o Physicochemical Properties
o Biological Activity
o Immunochemical Properties
o Purity, impurity and contaminants
o Quantity
SELECTION OF A TEST METHOD:
·
Wherever
applicable a pharmacopeial method shall be selected for analysis.
·
If
pharmacopeia method is not available, an analytical method shall be selected
considering intended use and scope (assay used to test a defined characteristic
of the product, process control, product characterization, release based on
specification at each stage of product development). This shall reflect in
method development report.
·
The
selected test method shall then be developed.
DEVELOPMENT OF A TEST METHOD:
·
Method
development is a scientific exercise to demonstrate that the selected method is
fit for intended purpose and scope.
·
The aim
of method development is to develop a scientifically-sound, robust, and
transferrable analytic method that should be aligned with the drug development
stage.
·
Following
are the requirements for test method development:
o Development procedure shall follow proper
documentation and all data relating to these studies must be recorded in
laboratory notebook (LNB). Raw data, system generated printouts and calculation
sheets shall be attached to LNB.
o Wherever applicable, all the information with
respect to physicochemical properties of the analyte shall be collected before
start of activity.
o A representative sample shall be selected for each
test method.
o Information on sample matrix shall be collected.
o Parameters required to demonstrate the merit of the
method (performance characteristics) such as linearity, selectivity, range,
accuracy, precision, detection limits etc., shall be defined.
o Appropriate instrumentation setup shall be ensured
with appropriate qualification, calibration and operational procedure.
o Study plan with respect to each parameter explored
and evaluated shall be charted.
o Development and optimization of the method shall be
documented with analyte traceability. Wherever sample matrix has changed,
details shall be documented.
o Percent recoveries shall be demonstrated.
o Wherever reference standards, solutions, reagents
are used date of preparation/manufacturing and use before date/date of expiry
shall be recorded.
o Critical Reagents shall be defined.
·
Successful
method development shall ensure that laboratory resources are optimized,
sufficient confidence in results is achieved, method meets the required
objectives of development and suitable and reliable for specified purpose.
Here, the method can be claimed as “Fit for Use”.
·
All the
above requirements of the method development shall finally be captured in
method development report along with test data. Method development report shall
then finally conclude into proposed test method with assay validity/system
suitability criteria.
·
Based on
development report proposal the test method shall be defined and documented as
“SOP”.
·
SOP is
used for sample testing during initial phase of development.
·
SOP is
also used for method qualification.
QUALIFICATION OF TEST METHOD:
·
Once
method is developed, it is further qualified. Method Qualification is a
systematic approach targeted to verify that the method is able to meet the
design goal.
·
Note: Based on prior experience and platform
technologies handled, Oftentimes, test methods are not developed from the
ground up. Such methods can be optimized for particular product and product
matrix. In such cases, direct method qualification can be attempted. Reference
to suitable method development of similar platform technology/ product class is
required.
·
Method
shall be qualified using a preapproved Method Qualification Protocol (MQP).
·
Qualification
protocol shall provide the rational for selection of performance parameters
(such as specificity, linearity, accuracy, precision etc.) selected for
demonstration method performance.
·
Qualification
protocol shall also define the sample characteristics, sample matrices (and
changes if any from development phase), sample preparations, critical reagents,
reference standards, equipment’s/instruments, there qualification &
calibration requirements & status, data analysis, statistical functions and
other calculations employed.
·
Qualification
protocol may not have predefined method performance specifications, however
based on intended application of test method minimal performance capabilities
may be predefined.
·
Qualification
studies shall be performed using qualified/ calibrated equipment’s and analyst
well versed with analytical technique under exploration.
·
All the
data shall be concurrently recorded and authenticated with signatures in
qualification records by analyst and supervisor (as and when required).
·
All the
raw data shall be attached in original and soft data archived for further
reference.
·
All
calculations and calculation printouts (if excel sheets are used) shall be
verified by supervisor.
·
Wherever,
the method fails to achieve the performance characteristic, it shall be
re-optimized to meet the performance characteristic required for its intended
application.
·
If still
it fails to achieve the required performance, the method shall be rejected for
intended application.
·
All the
activities and findings of method qualification shall be reported in a Method
Qualification Report (MQR). It shall include all the elements defined above and
shall provide a test method with control strategies.
·
When
deemed necessary, the SOP shall be revised to include the recommendations in
the method qualification report.
·
The data
generated during method qualification studies forms the basis for setting
acceptance criteria for method validation which shall be performed during late
stages of development lifecycle.
VALIDATION OF TEST METHOD:
·
Data
generated during method development, method qualification and subsequent
analysis and changes made in qualified method form the basis of method
validation.
·
Analytical
method validation is the process of demonstrating that an analytical procedure
is suitable for its intended purpose.
·
Method
shall be validated using a preapproved Method Validation Protocol (MVP).
·
Validation
protocol shall have predefined method performance specification which shall be
met at each trial run (replicate/repeat).
·
If the
validation experiment fails to meet the established specification, it can fail
the validation study unless a clear assignable cause (e.g. analyst error) is
found and corrected.
·
All
validation activities shall be performed using qualified
equipment’s/instruments, relevant calibrations shall be ensured, validated
calculation sheets shall be used, analyst shall be trained and all relevant
software should be validated.
·
Representative
samples shall be identified and selected. These samples shall be traceable to a
fixed manufacturing process to ensure correct matrices are used.
·
Critical
materials/reagents shall be identified and wherever applicable qualified e.g.
standards and reagents for purity, accurate amounts and sufficient stability.
·
Validation
protocol shall define suitable validation characteristics and performance
criteria. This shall be selected based on test method applicability with
reference to available regulatory guidance’s.
o Typical validation characteristics are:
o Specificity
o Linearity and Range
o Precision
§ Method precision (Repeatability)
§ Intermediate precision (Ruggedness)
o Accuracy
o Solution stability
o Limit of Detection (LOD)
o Limit of Quantification (LOQ)
o Robustness
·
During
validation experiments all the data shall be concurrently recorded and
authenticated with signatures in qualification records by analyst and
supervisor (as and when required).
·
All the
raw data shall be attached in original and soft data archived for further
reference.
·
All
calculations and calculation printouts (if excel sheets are used) shall be
verified by supervisor.
·
All the
activities and findings of method qualification shall be reported in a Method
Validation Report (MVR) along with deviations and changes made.
·
Method
validation report shall provide the recommended test procedure with controls,
and acceptance criteria. It shall also define the reasons for revalidation
which shall further be captured in standard test procedure.
STANDARD TEST PROCEDURE (A QUALITY
CONTROL ASSAY):
·
Test
method which passes the validation study becomes a ‘Quality Control Assay’ and
is documented as Standard Test Procedure (STP).
·
STP shall
define the scope and intended purpose of assay, provide details of test method,
reagents/materials/standard required, critical reagents identified, system
suitability defined, acceptance criteria defined along with situations which
require change in test method and subsequent validation/revalidation
requirements.
REVALIDATION:
·
A
revalidation is necessary whenever a method is changed, and the new parameter
lies outside the operating range defined in STP. This may also be required
where the source of the error cannot be traced back to the instruments or any
other cause.
·
Other
changes that may warrant revalidation (partial of full) study are listed below:
o new samples with new compounds or new matrices,
o new analysts with different skills,
o new instruments with different characteristics,
o new location with different environmental
conditions,
o new chemicals and/or reference standards and
o modification of analytical parameters.
·
Any
changes in process shall also be evaluated for impact on test method and its
validity.
·
Note: All the changes shall follow change control
procedure.
METHOD VERIFICATION:
·
Compendial
procedures are also subject to regulations that require demonstration of
suitability under actual conditions of use.
·
The
verification process for compendial test procedures is the assessment of
whether the procedure can be used for its intended purpose, under the actual
conditions of use for a specified drug substance and/or drug product matrix.
·
Relevant
regulatory/pharmacopeial guidance shall be referred for verification
of compendial procedures that are being performed for the first time
to yield acceptable results utilizing the personnel, equipment, and reagents
available.
GLOSSARY & TERMS:
·
Analyte: A substance whose chemical constituents
are being identified and measured.
·
Analytical Technologies: ‘Test Methods’ which measures and represent the
product characteristic in terms of test results during product processing/ batch manufacturing and
shelf life are considered as analytical technologies.
·
Characterization: Characterization refers to the broad and general process by which a material's
structure and properties are probed and measured. It is carried out using
appropriate, state-of-the-art biochemical, biophysical and biological
analytical techniques. For the active ingredient(s) (i.e. the desired
product), details should be provided on primary and higher-order structure,
post-translational modifications (including, but not limited to, glycoforms),
biological activity, purity, impurities, product-related (active) substances
(variants), and immunochemical properties, where relevant.
·
Comparability: Head-to-head comparison of a biotherapeutic
product with a licensed originator product with the goal of establishing similarity in
quality, safety and efficacy. Products should be compared in the same study
using the same procedures.
·
Drug Product: A pharmaceutical product type that contains a drug substance, generally in
association with excipients.
·
Drug Substance: The active pharmaceutical ingredient and
associated molecules that may be subsequently formulated, with excipients, to
produce the drug product. It may be composed of the desired product, product-related substances, and
product- and process-related impurities. It may also contain other components
such as buffers.
·
In-process samples: This represents the samples generated during
product processing and results demonstrate degree of process control.
·
Intermediate: This represents the product manufactured at
different stages of manufacturing process and intermediate of one stage is
starting material of the next stage. These intermediate products have a
predefined attributes which at times forms the specification. Few intermediates
can be stored / held at specified conditions for defined duration before
proceeding for next step.
·
Life Cycle-Analytical Technologies: Identification of test method, subsequent
development, qualification and validation to finally accept it as quality
control method.
·
Life Cycle-Product: Product Life cycle includes following technical
activities for new and existing products: (1) Product Development (Preclinical
and clinical), (2) Technology Transfer, (3) Commercial Manufacturing, (4) Product Discontinuation.
·
Method Qualification: A protocol based scientific study to determine
method performance capabilities as required for an intended purpose. There are no or minimal predefined
method performance specification.
·
Method Validation: A protocol based scientific study with predefined performance
specification performed to establish, by laboratory studies, that the
performance characteristics of the procedure meet the requirements for the
intended analytical applications.
·
Quality Control Assay: An assay which is used for testing and release of
material post method validation (can be established during Clinical
Manufacturing or Commercial Manufacturing based on strategic approach adopted).
It is represented as standard test procedure (STP).
·
Reference Biologic: A reference biologic (biotherapeutic) product is
used as the comparator for head-to-head comparability studies with the similar
biotherapeutic product in order to show similarity in terms of quality, safety
and efficacy. Only an originator product that was licensed on the basis of a full registration
dossier can serve as an RBP. The term does not refer to measurement standards
such as international, pharmacopoeial or national standards or reference
standards.
·
Specification: A specification is defined as a list of tests,
references to analytical procedures, and appropriate acceptance criteria which
are numerical limits, ranges, or other criteria for the tests described. It establishes the set of criteria
to which a drug substance, drug product or materials at other stages of its
manufacture should conform to be considered acceptable for its intended use.
·
Test Result: The value of a characteristic obtained by carrying out a
specified ‘Test Method’.
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Sunday 11 March 2018
Methods: Development & Validation
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