m.pharm (pharmaceutics) modern pharmaceutics- unit 2 validation- part 2 Validation of specific dosage form, Types of validation. Government regulation, Manufacturing Process Model, URS, DQ, IQ, OQ & P.Q. of facilities.

1. VALIDATION
MEHAK AGGARWAL
M.PHARM (PHARMACEUTICS)

2. CONTENT
Validation of specific dosage form
Types of validation
URS
DQ
IQ
OQ
PQ
Government Regulation
References
4/6/2022
MEHAK AGGARWAL 2

3. VALIDATION OF SPECIFIC DOSAGE FORM
PROCESS VALIDATION OF TABLETS
PROCESS STEP CONTROL VARIABLE (MONITOR) MEASURED RESPONSE (TEST)
Pre-Blending Blending time, RPM, Load size, order of addition Blending uniformity
Granulation Mixing speed, amount of granulation fluid, feed rate,
granulation time, load
Drug distribution, water solvent content, appearance,
particle size distribution, densities, loss on drying
Drying Initial temp., outlet temp., drying temp. Particle size distribution, densities, loss on drying
Milling Screen size, milling speed, feed rate Particle size, distribution shape
Lubrication Blending time, blender speed, load size Particle size distribution, loose/tapped densities, flow
properties
Compression Compression rate, granule feed rate,
Precompression force
Appearance, wt. variation, hardness, friability, thickness,
moisture content, disintegration, dissolution, dose
uniformity
Coating Pan load, pan speed, inlet/exhaust temp. and humidity % wt. gain, thickness, dissolution, assay, degradation level
4/6/2022
MEHAK AGGARWAL 3

4. PROCESS VALIDATION OF CAPSULE
PROCESS STEP CONTROL VARIABLE (MONITOR) MEASURED RESPONSE (TEST)
Mixing Load size, RPM, mixing time Mixing uniformity
Blending Load size, RPM, blending time Blend uniformity, flow characteristics
Capsulating Capsulation speed, powder feed
rate
Weight variation, disintegration time,
locking
4/6/2022
MEHAK AGGARWAL 4

5. TYPES OF VALIDATION
Major types of validation are:
1. Process Validation
2. Cleaning Validation
3. Equipment Validation
4. Validation of analytical methods
4/6/2022
MEHAK AGGARWAL 5

6. PROCESS VALIDATION
As per FDA, ‘The collection of data from the process design stage throughout production, which
establishes scientific evidence that a process is capable of consistently delivering quality products’.
PROCESS VALIDATION LIFE CYCLE
Stage 1: Process Design
Stage 2: Process Qualification
Stage 3: Continued process verification
4/6/2022
MEHAK AGGARWAL 6

7. PROCESS VALIDATION FLOW CHART
Planning
Installation
qualification
Operational
qualification
Process
qualification
Process
qualification
Revalidate
4/6/2022
MEHAK AGGARWAL 7

8. TYPES OF PROCESS VALIDATION
1. Prospective Validation
2. Retrospective Validation
3. Concurrent Validation
4. Revalidation
4/6/2022
MEHAK AGGARWAL 8

9. 1. PROSPECTIVE VALIDATION
• It is establishing documented evidence prior to process implementation that a system does what it
proposed to do based on pre-planned protocols.
•An experimental plan called the validation protocol is executed before the process is put into
commercial use.
•It is normally undertaken for a new drug product or new facilities are introduced into a routine
pharmaceutical production.
OBJECTIVES
•To prove that the process will work in accordance with a validation protocol.
•During Product development stage, Production process broken down into individual steps
•Each steps evaluated on the basis of experience or theoretical considerations
•Critical factors that may affect the quality of the finished product are determined.
4/6/2022
MEHAK AGGARWAL 9

10. 2. RETROSPECTIVE VALIDATION
•It is an establishing documented evidence that a process does what it is supposed to do based on
review and analysis of historic data.
•Validation of these processes - historical data to provide the necessary documentary evidence that the
the process is doing what it is supposed to do. Steps require for validation are:
Protocol preparation
Validation reports
Data analysis
Conclusion
Recommendations
4/6/2022
MEHAK AGGARWAL 10

11. 3. CONCURRENT VALIDATION
•Concurrent Validation means establishing documented evidence a process does what it is supposed to
to do based on data generated during actual implementation of the process.
•It is done during routine production Validation involves –
In-process monitoring
End product testing
•Personnel required are the authorized staff.
•Documentation is done as per Prospective Validation.
4/6/2022
MEHAK AGGARWAL 11

12. 4. REVALIDATION
• Re-validation provides the evidence that changes in a process and/or the process environment,
introduced either intentionally or unintentionally, do not adversely affect process characteristics and
product quality.
•There are two basic categories of Re-validation:
Re-validation in cases of known change (including transfer of processes from one company to another
another or from one site to another).
Periodic Re-validation carried out at scheduled intervals.
4/6/2022
MEHAK AGGARWAL 12

13. •Revalidation is done when there is:
Changes of raw materials
Change of starting material
Changes of packaging material
Changes in the process (e.g. mixing times, drying temperatures)
Changes in the equipment (e.g. addition of automatic detection systems)
Changes of equipment
Production area and support system changes (e.g. rearrangement of areas, new water treatment
method)
Transfer of processes to another site
4/6/2022
MEHAK AGGARWAL 13

14. CLEANING VALIDATION
•A process of attaining and document in 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 are:
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.
4/6/2022
MEHAK AGGARWAL 14

15. •Factors Influencing Cleaning validation :
Product.
Equipment.
Facilities.
Cleaning methods.
Cleaning agents.
Sampling.
Testing, Limits, and acceptance criteria.
4/6/2022
MEHAK AGGARWAL 15

16. EQUIPMENT VALIDATION
•Action of proving that any equipment works correctly and leads to the expected result is equipment
qualification.
•It is not a single step activity but instead result from many discrete activities.
•Steps involved are:
User requirement specification
Design qualification
Installation qualifications
Operational qualifications
Performance qualification
4/6/2022
MEHAK AGGARWAL 16

17. PROCESS FLOW CHART
DQ
•Before purchasing a new instrument
IQ
•At documented installation of new or existing instruments
OQ
•After installation
•After major changes e.g., repair, updates
•At regular intervals (risk based)
PQ
•Whenever the instrument is used e.g., daily
4/6/2022
MEHAK AGGARWAL 17

18. VALIDATION OF ANALYTICAL
METHODS
•“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 closeness of test results obtained by that method to the true value. This accuracy
should be established across its range.”
•Precision: “The degree of agreement among individual test results when the method is applied
repeatedly to multiple sampling of a homogenous sample.”
•Specificity : “The ability to assess unequivocally the analyte in the presence of components that may
expected to be present, such as impurities degradation products and matrix components.”
4/6/2022
MEHAK AGGARWAL 18

19. •Limit of Quantitation : “A characteristic of quantitative assays for low levels of compounds in sample
matrices such as impurities in bulk substances and degradation products in finished pharmaceuticals. It
It is the lowest amount of analyte in a sample that can be determined with acceptable precision and
accuracy under the stated experimental conditions.”
•Range : “Interval between the upper and lower of analyte (including these levels) that have been
demonstrated to be determined with a suitable level of precision , accuracy and linearity using the
method as written. The range is normally expressed in the same units as test results. ( e.g. Percentage ,
, parts per million, etc.) obtained by the analytical method.”
•Ruggedness: The degree of reproducibility of test results obtained by the analysis of the same sample
under a variety of conditions such as different laboratories, different analysts, different instruments ,
different lots of reagents, different elapsed assay times, different assay temperatures, different days,
etc.”
4/6/2022
MEHAK AGGARWAL 19

20. •Robustness: "A measure of its capacity to remain unaffected by small but deliberate variations in
method parameters and provides an indication of its reliability during normal usage.”
•Linearity : “Its ability to elicit tests that are directly or by a well defined mathematical transformations
proportional to the concentration of analyte in samples within a given range.”
•Limit of Detection : The lowest amount of analyte in a sample that can be detected but not necessarily
quantitated, under the stated experimental conditions.”
4/6/2022
MEHAK AGGARWAL 20

21. USER REQUIREMENTS SPECIFICATION
(URS)
• User Requirements Specification (URS), is the most critical of documents and yet, the most often
bungled. Whether the system is purely mechanical, or a mix of electro-mechanical, or solely a
software program, the successful compilation and execution of the Installation Qualification (IQ) (for
installation), Operational Qualification (OQ) (for functionality) and the Performance / Product
Qualification (PQ) (for operability), is dependent on an User Requirements Specification (URS)
containing clear, concise and testable requirements.
•The URS can contain a large number of requirements and should therefore be structured in a way that
will permit easy access to information.
•The requirement specification must be formally reviewed and approved by the pharmaceutical
manufacturer.
4/6/2022
MEHAK AGGARWAL 21

22. •The following guidelines should be followed during the production of the URS :
1. Each requirement statement to be uniquely referenced, and no longer than 250 words.
2. Requirement statements should not be duplicated nor contradicted.
3. The URS should express requirements and not design solutions.
4. Each requirement should be testable.
5. The URS must be understood by both user and supplier; ambiguity and jargon should be avoided.
6. The use of diagrams is often useful.
7. The scope for readers to make assumptions or misinterpret should be minimized.
8. Wherever possible, the URS should distinguish between mandatory/regulatory requirements and
desirable features.
4/6/2022
MEHAK AGGARWAL 22

23. BENEFITS TO VALIDATION
1. Clarifies technical, quality, and documentation requirements to the vendor.
2. Enables the pharmaceutical manufacturer to assess the technical, regulatory, and commercial
compliance (or otherwise) of submitted bids against a formal specification.
3. Ensures the basis of a structured approach to the presentation of information.
4. Provides a basis for testing and test acceptance criteria.
5. Provide a baseline for validation and verification.
4/6/2022
MEHAK AGGARWAL 23

24. DESIGN QUALIFICATION
(DQ)
•Design qualification (DQ) is the process of completing and documenting design reviews to illustrate
that all quality aspects have been fully considered at the design stage.
•The purpose is to ensure that all the requirements for the final systems have been clearly defined at
the start.
•Design Qualification (DQ) defines the functional and operational specifications of the instrument and
details the conscious decisions made in the selection of the supplier.
•DQ should ensure that instruments have all the necessary functions and performance criteria that will
enable them to be successfully implemented for the intended application and to meet user
requirements.
4/6/2022
MEHAK AGGARWAL 24

25. The list below shows the recommended steps that should be considered for inclusion in a Design
Qualification.
Description of the analysis problem
Description of the intended use for the equipment
Description of the intended environment
Preliminary selection of the functional and performance specifications (technical, environmental,
safety)
Preliminary selection of the supplier
Final selection of the supplier and equipment
Development and documentation of final functional and operational specifications
4/6/2022
MEHAK AGGARWAL 25

26. INSTALLATION QUALIFICATION
(IQ)
•Installation qualification (IQ) is the process of checking the installation, to ensure that the
components meet the approved specification and are installed correctly, and to see how that
information is recorded.
•The purpose is to ensure that all aspects (static attributes) of the facility or equipment are installed
correctly and comply with the original design.
•All of the instrumentation components are identified and checked against the manufacturer’s
component listing.
•The working environment conditions are documented and checked to ensure that they are suitable
for the operation of the instrument.
4/6/2022
MEHAK AGGARWAL 26

27. OPERATIONAL QUALIFICATION
(OQ)
•Operational qualification (OQ) is the process of testing to ensure that the individual and combined
systems function to meet agreed performance criteria and to check how the result of testing is
recorded.
•The purpose is to ensure that all the dynamic attributes comply with the original design.
•Each of the instrument’s function are checked to ensure that they conform to the manufacturer’s
specifications.
•This includes the use of certified, traceable electrical simulators and standards to verify that the
equipment is processing input signals correctly.
4/6/2022
MEHAK AGGARWAL 27

28. PERFORMANCE QUALIFICATION
(PQ)
•Performance qualification (PQ), also called process qualification, is the process of testing to ensure
that the individual and combined systems function to meet agreed performance criteria on a
consistent basis and to check how the result of testing is recorded.
•The purpose is to ensure that the criteria specified can be achieved on a reliable basis over a period
of time.
•The performance of the equipment for its routine analytical use is checked to ensure that this
complies with its specification.
•The temperature sensor readings are compared with a certified reference thermometer.
•After calibration, the conductivity sensor readings are compared using certified, traceable control
standards.
4/6/2022
MEHAK AGGARWAL 28

29. GOVERNMENT REGULATION
•Validation is considered to be an integral part of GMPs.
•Worldwide compliance with validation requirements is necessary for obtaining approval to
manufacture and to introduce new products.
•The accuracy, sensitivity, specificity and reproducibility of test methods employed by the firm shall be
established and documented.
4/6/2022
MEHAK AGGARWAL 29

30. REFERENCES
•P. P. Sharma, “Validation in Pharmaceutical Industry- concepts, approaches & guidelines”, 1st edition, 2007
Vandana Publication House.
•B. T. Loftus & R. A. Nash, "Pharmaceutical Process Validation", Drugs and Pharm Sci. Series, Vol. 129, 3rd
Ed., Marcel Dekker Inc., N.Y.
•R. Sawant & S. Hapse, “Fundamental of quality assurance techniques”, First edition Dec 2011, Career
publications.
•M. Potdar, “Pharmaceutical Quality Assurance”, Second edition Dec 2007,Nirali Prakashan.
•N. Kumar, et.al., IJRPC 2011 ‘An overview of pharmaceutical validation: quality assurance.
•E. Jatto, A.O. Okhamafe, TJPR Review Article ‘An Overview of Pharmaceutical Validation and Process
Controls in Drug Development’.
4/6/2022
MEHAK AGGARWAL 30

31. 4/6/2022
MEHAK AGGARWAL 31