P R Pote Patil College Of Pharmacy, Amravati

PHARMACEUTICAL
VALIDATION

Presented by Guided by
Manohar S Kasdekar Dr. Dipti Ruikar Mam
1. INTRODUCTION

 The process validation was developed in the 20 th century in order to

improve the quality of pharmaceutical products.
 Validation is a systematic process that involves gathering and
analysing data to establish documented evidence that systems,
instruments, processes, and facilities do what they are intended to
do.
 Validation can help organizations increase productivity, reduce
costs, and ensure consistent operations.
1.1 DEFINITION

Validation
Validation is a systematic approach to
collecting and analysing sufficient data
to give reasonable assurance and
documented evidence that a process or
an analytical method will, when
operated within specified parameters,
consistently produce results within
predetermined specifications..
https://www.totalpharmaceuticaltopics.com/2020/08/process-validation-study-
types-of.html?m=1#google_vignette
Qualification
Qualification is described as the
action of proving that any
premises, systems and items of
equipment work correctly and
actually lead to the expected
results.

https://www.icqconsultants.com/services/qualification/
calibration
 Calibration is a process or action that
compares the measurement values of
a measuring device or equipment
against a reference standard and
certifies the measurement accuracy.

https://www.inspiredpharma.com/2017/09/12/gmp-measuring-
instrument-calibration/
1.2 Scope of Calibration
To determine the accuracy, precision, and deviation of the
measurements produced by all the instruments
To establish the reliability of the instrument being used
and whether it can be trusted to deliver repeatable results
each time.
 To make sure that the readings of equipment/instrument
are consistent and correct every single time
1.3 Frequency Of Calibration
 Calibration frequency is the time interval between recalibrating an instrument or device. It’s also
known as a calibration interval or due date
 Calibration interval may be based on calendar.
 The frequency of calibration depends on following factors
a) What is level of accuracy desired?
b) What is the recommendation of manufacturer?

The interval between calibration varies as:

I) Weakly
II) Monthly or bi-monthly
III) Annually or semi-annually
IV) After every heavy usage of equipment or instrument.
1.4 Importance of calibration
Calibration is responsible for defining the accuracy of any
measurement and its quality that is recorded by any
instrument.
It helps in improving accuracy of the instrument.
 Calibration helps in quantifying and controlling errors
 Finally in a single word, it allows pharmaceutical
companies to have confidence in their results.
1.5 Difference Between Calibration and Validation
1.6 Calibration of weight and
measures.
 Although analytical weights are made
to a high degree of precision, their
weight may alter with time.
 Therefore weights must be checked or
calibrated from time to time.
 It should be noted that as a rule the
relative rather than the absolute
precision of the weights is important.
https://m.indiamart.com/proddetail/standard-calibration-weights-sets-22235249897.htm
 2. VALIDATION

ISO definition: Validation is the confirmation by examination and the

provision of objective evidence that the particular requirements for a specific
intended use are fulfilled.

2.1 Scope of validation

Validation requires an appropriate and sufficient infrastructure
including:
• organization, documentation, personnel and finances
• Personnel with appropriate qualifications and experience
• Extensive preparation and planning before validation is performed
• A specific programme for validation activities in place
2.3 Organization:
The organization must have clearly defined areas of responsibility
and authority.
The structure must be tailored to meet the requirements in the
specific organization, and these will vary from company to
company.
 A defined structure exists, is accepted, and is in operation.
2.4 Validation Master Plan (VMP)
• VMP is a general document that
summarizes validation policy and all the
intended validation qualification
activities, together with a description of
the facility and organizational structure.
The present EANM guidance covers the
qualification and validation aspects
intertwined with the preparation of small-
scale radiopharmaceuticals. It concerns
the preparation of radiopharmaceuticals https://pharmaanalytica.com/regulatoryaffairs.html

which are not intended for commercial

purposes or distribution.
To this regard, the overall validation activities should be described in a
general document, usually known as Validation Master Plan (VMP). VMP
should include:
i) A general validation policy, with a description of the intended working
methodology, and factors that may affect the quality of the intended
radiopharmaceutical(s);
ii) A description of the facility, with a detailed description of the critical
points.
iii) A description of the radiopharmaceutical preparation process (es);
iv) The general policy related to process validation.
v) A list of the quality control equipment to be qualified, including the
extent of qualification required.
vi) Cleaning validation of premises and equipment.
2.5 Types of Validation
Validations are of different types which are given below:
1) Process Validation
2) Analytical Method Validation
3) Cleaning Validation
4) Computerized System Validation

1)Process Validation:
The manufacturing process should be flexible with some restrictions
during the process of manufacture of the product. The achievement
of the alluring qualities should be ensured with the prevention of
essential properties. For achieving these, process validation is
performed
Types of Process validation
2) Analytical Validation
“The process by, which it is established, by laboratory studies, that the
performance characteristics of the method meet the requirements for the
intended analytical application”.
Accuracy:
The accuracy of an analytical method is the extent to which test results
generated by the method and the true value agree. Accuracy can also be
described as the closeness of agreement between the value that is
adopted, either as a conventional, true, or accepted reference value, and
the value found.
Precision:
Precision provides an indication of random errors and can be broken
down into repeatability and intermediate precision. This procedure
should only be performed when the entire analytical method procedure is
finalized.
Specificity:
“The ability to assess unequivocally the analyte in the presence of
components that may be expected to be present, such as impurities
degradation products and matrix components.”
Linearity :
The linearity of an analytical procedure is its ability (within a given
range) to obtain test results which are directly proportional to the
concentration (amount) of analyte in the sample. It may be directly
demonstrated on the analyte, or on spiked samples using at least five
concentrations over the whole working range.
Repeatability :-
In addition to the system precision, this short-term variability includes the
contributions from the sample preparation, such as weighing, aliquoting,
dilution, extraction, homogenization, and etc. Therefore, it is essential to
apply the whole analytical procedure (as described in the control test), rather
merely to injecting the same sample solution six times. This is also the
reason for using authentic samples because only then can the analytical
procedure be performed exactly as in the routine application.
Intermediate precision.
Intermediate precision includes the influence of additional random effects
according to the intended use of the procedure in the same laboratory and can
be regarded as an (initial) estimate for the long-term variability. Relevant
factors, such as operator, instrument, and days should be varied. Intermediate
precision is obtained from several independent series of applications of the
(whole) analytical procedure to (preferably) authentic, identical samples.
Reproducibility
represents the precision obtained between different laboratories. The objective is to verify that the
method will provide the same results in different laboratories. The reproducibility of an analytical
method is determined by analyzing aliquots from homogeneous lots in different laboratories with
different analysts, and by using operational and environmental conditions that may differ from, but
they are still within, the specified parameters of the method (inter laboratory tests). Validation of
reproducibility is important whether the method is to be used in different laboratories. The main
factors affecting the reproducibility are:
 Reproducibility Differences in room temperature and humidity.
 Operators with different experience and thoroughness.
 Equipment with different characteristics, e.g., delay volume of an HPLC system.
 Variations in material and instrument conditions, e.g., HPLC, composition of mobile phase, pH,
and flow rate of mobile phase.
 Variation in experimental details not specified by the method.
 Equipment and consumables of different ages.
 Columns from different suppliers or different batches.
Robustness:-
Robustness tests examine the effect that operational parameters have on the analysis results. For
the determination of robustness, a number of method parameters are varied within a realistic
range, and the quantitative influence of the variables is determined. If the influence of the
parameter is within a previously specified tolerance, the parameter is said to be within the
robustness of the method range. Obtaining data on these effects helps to assess whether a
method needs to be revalidated, for instance, when one or more parameters are changed to
compensate the column performance over time. In the ICH document, it is recommended to
consider the evaluation of robustness of the method during the development phase, and any
results that are critical for the method should be documented. In summary, an analyst must have
a critical look at three different types of parameters when robustness and ruggedness are
investigated:
 Internal parameters (e.g., temperature, pH, and etc., in the case of HPLC).
 External parameters (e.g., different analysts, instruments, laboratories, and etc.).
 Basic parameters (e.g., stability of test solutions and etc.).
3) Cleaning Validation
“A process of documenting sufficient evidence to give reasonable assurance,
given the current state of Science and Technology, that the cleaning process
under consideration does, and / or will do, what it purpose to do.”
Objectives
To minimize cross contamination.
To determine efficiency of cleaning process.
 To do troubleshooting in case problem identified in the cleaning process and
give suggestions to improve the process.
4) Computer System Validation
Computerized system validation (CSV) is a documented process that
ensures a computer system meets its intended use and performs as
designed.
CSV is a critical process in the pharmaceutical industry to ensure
that computerized systems used for manufacturing, testing, and
quality control comply with regulatory requirements .

Ex. Empower 3 software

2.5 STREAMLINING VALIDATION OPERATIONS
Set of strategies, mostly risk and science based, to
transform or standardize validation activities and
documentation.

• Typically reduces resources such as time, personnel,

and cost.

• The practice enhances reliability, cost, and quality of

the product.
Advantages of validation:
Optimized processes.
Assured quality of products.
Reduced cost of maintaining quality.
Reduced complaints, rejections, batch failure, mix-ups, and
cross-contamination.
Faster scale-up from pilot level to the manufacturing level.
 Better compliance with regulatory requirements
Reference
1)Huber, L., 2007. Validation and qualification in analytical
laboratories. CrC Press.
2)Alexeyev, V., 2000. Quantitative analysis: a textbook.
3) CR Journals (Page 48–58) 2020. All Rights Reserved
4)World Health Organization, 2009. Forty-third report of the
WHO Expert Committee on specifications for pharmaceutical
preparations.