Types of validation used in pharmaceutical industry. it will help people to understand and develop understanding regarding validations used in industry.

1. Types ofValidation
&
Its Aspects
SABA ASIF

2. VALIDATION
This term comes from the word “valid or validity” which means “legally
defined”
“The validation process is the documented evidence which provides a high
degree of assurance that a process consistently produces a result or
product meeting its predetermined specifications”.

3. Types ofValidation
There are four types ofValidation:
• Analytical MethodValidation
• ProcessValidation
• CleaningValidation
• EquipmentValidation

4. Type 1: Analytical MethodValidation
“Analytical method validation is the process of demonstrating that an
analytical procedure is suitable for its intended purpose”.
“The analytical procedure refers to the way of performing the analysis. It
should describe in detail the steps necessary to perform each analytical
test”

5. Types of Analytical Procedures to be
Validated
• The validation of analytical procedures is directed to the four most
common types of analytical procedures:
• - Identification tests
• - Quantitative tests for impurities content
• - Limit tests for the control of impurities
• - Quantitative tests (Assay) of the active moiety in samples of drug
substance or drug product or other selected component(s) in the drug
product

6. VALIDATION CHARACTERISTICS
• Typical validation characteristics which should be considered are listed below:
• Specificity
• Precision
• Repeatability
• Intermediate Precision
• Reproducibility
• Accuracy
• Linearity
• Range
• Detection Limit
• Quantitation Limit
• Robustness

7. 1. Specificity:
“It is the ability to assess clearly the analyte in the presence of
components which may be expected to be present. Typically these
might include impurities, degradants, matrix, etc.”
2. Precision:
“The precision of an analytical procedure expresses the closeness
of agreement (degree of scatter) between a series of
measurements obtained from multiple sampling of the same
homogeneous sample under the prescribed conditions”.
Precision may be considered at three levels: repeatability,
intermediate precision and reproducibility”.

8. 3. Accuracy:
“The accuracy of an analytical procedure expresses the closeness of
agreement between the value which is accepted either as a conventional true
value or an accepted reference value and the value found“
This is sometimes termed trueness.
4.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”.

10. 5. Range:
The range of an analytical procedure is the interval between the upper and
lower concentration (amounts) of analyte in the sample (including these
concentrations) for which it has been demonstrated that the analytical
procedure has a suitable level of precision, accuracy and linearity”.
The specified range is normally derived from linearity studies and depends on
the intended application of the procedure.
6. Limit of Detection (LOD):
“The detection limit of an individual analytical procedure is the lowest amount
of analyte in a sample which can be detected but not necessarily quantitated
as an exact value.”

11. 7. Limit of Quantification (LOQ):
“The quantitation limit of an individual analytical procedure is the lowest
amount of analyte in a sample which can be quantitatively determined with
suitable precision and accuracy.”
8. Robustness:
“The robustness of an analytical procedure is 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.”

12. Type 2: ProcessValidation
• “It is a documented evidence which provide a high degree of
assurance that a specific process will consistently produce a product
meeting its predetermined specifications and quality attributes”.
or
• Validation of the individual steps of the process is called process
validation.

13. When Process Validation is required
• Before introduction of a new manufacturing method or new product
into routine use.
• Whenever the conditions change for which a method has been
validated, e.g. instruments with different characteristics.
• Whenever the Source of API or Excipient changed.

14. Significance of ProcessValidation
• Effective process validation contributes significantly to assuring drug
quality.
• The basic principle of quality assurance is that a drug should be
produced that is fit for intended use. This principle incorporates the
understanding that the following conditions exist:
• Quality, safety, and efficacy are designed or built into the product.
• It reduce the risk of regulatory non compliance.
• It may reduce the time to market the new drug product.
• Reduce the defect cost.
• Make the process better understood and assuring smooth running of
process.

15. Types of ProcessValidation
Process validation
Analysis of
Historical data
Experimental
Approach
Revalidation
Prospective
Validation
Concurrent
Validation
Retrospective
Validation
Periodic
Revalidation
Revalidation
on after
change

16. 1.Prospective validation
It is done during the product development stage.
When develop a new manufacturing process each step in new
process is required to be established that it will give us desired
result.
During this step the parameters are selected and clearly specified
2.Retrospective validation
“In this type, Validation of the facilities, processes, and process controls is
done using historical data to provide the necessary documentary
evidence that the process is doing what it is believed to do”.

17. 3.Concurrent Validation
“Concurrent validation is used for establishing documented evidence that a
facility and processes do what they purpose to do, based on information
generated during actual imputation of the process”.
This approach involves monitoring of critical processing steps and end product
testing of current production, to show that the manufacturing process is in a
state of control.
Re-Validation
• Consider periodic re-validation when the changes occur:
• Source change of raw materials
• Batch size enhancement / reduction
• New product
• Change in formulation
Process validation includes 3 consecutive batches.

18. Why do we take 3 batches for process validation?
• If we select 2 batches for validation then we can not compare the data of
two batches because comparison between two points always gives a linear
line so to show a difference we need three points. So generally we take 3 or
more than 3 batches for validation.

19. Approach to ProcessValidation

20. Approach to ProcessValidation
• Process validation involves a series of activities taking place over the
lifecycle of the product and process that includes;

21. Type 3: CleaningValidation
“The process of providing documented evidence with a high degree of
assurance that the cleaning methods employed consistently control potential
carryover of product, cleaning agents and extraneous material into
subsequent product to the predetermined and acceptable limits”.

22. Objective:
The cleaning validation demonstrates
• The effectiveness of cleaning procedures
• The cleaning procedure consistently removes residues of the substance
previously manufactured down to levels that are acceptable
• Ensure no risks are associated with cross-contamination of previous
products, residues of cleaning agents as well as control of potential
microbial contaminants
Scope:
• Three consecutive applications of the cleaning procedure should be performed
after manufacturing & filling of Marker compound and before commencing the
manufacturing & filling of the next products in order to prove that the
procedure is validated.
• This procedure is applicable to all product contact parts of non-dedicated
equipment.

23. Potential Residues
• 1. Precursors to the Active Pharmaceutical Ingredient
• 2. By products & / or degradation products of the API
• 3. The previous product
• 4. Solvents and other materials employed during manufacturing process
• 5. Micro-organisms
• 6. Cleaning agents

24. Bracketing &Worst Case Rating
• Validation effort could be huge. In order to minimize the amount of
validation required, a worst case approach for the validation can be used.
• Step 1; By means of a bracketing procedure the substances are grouped.
• Step 2; A worst case rating procedure is used to select the worst case in each group.
• The worst case rating priority will then support a conclusion that the
cleaning procedures are effective for all drug substances and other
chemicals within the bracket, including those not individually tested.

25. Worst Case Rating (WCR)
• A worst case rating study will prioritize existing drug substances, in a cleaning
validation program, based on information on applicable criteria chosen by the
company.
• Company chose the following criteria which are relevant to the molecule
preparation in their facility (companies should evaluate individual situations):
a. Hardest to clean
b. Solubility in used solvent
c. Lowest Acceptable Daily Exposure or Permitted Daily Exposure ( IfADE / PDE data are not
available, other data such as pharmacological dose, OEL or toxicity data ( LD50 ) may be
used.
d. Lowest therapeutic dose

26. Re-Rating
• Change control should be applied to the WCR. If the conditions for the
rating are changed, then a re-rating procedure should be carried out.The
following listing gives examples where a formal re-rating procedure may be
required:
• Changed cleaning method / process
• Changed / additional new product
• Changed / new equipment

27. Sampling Method
• A combination of the two methods is generally the most desirable. For all
methods the sampling points should be fixed in a manner such that the true
contamination of the equipment will be reflected.
• Swab sampling (direct surface sampling)
• Rinse or wash solvent sampling

28. Establishment of Acceptance Limit
The following should be calculated:
• MaximumAllowable Carryover (MACO)
• TargetValue for Swab
• Target value for Rinse
• Recovery of the methods

29. Recovery
• This can be achieved, for example, by spiking a surface equivalent to the
equipment surface (e.g. material, polish grade) with different known
amounts of the impurity.
• The impurity can then be recovered and analyzed using the same sampling
and analytical methods that will be used for the cleaning validation study.
The overall results from this procedure are then compared to criteria for
detection or quantitation limits as defined in ICH Q2 (R1).

30. Swab recovery technique

31. Recovery
≥ 90% is considered
good
> 50% is considered
reasonable
< 50% is considered
questionable

32. Type 4: EquipmentValidation
“EquipmentValidation is a detailed process of confirming that an instrument is
installed correctly, that it is operating efficiently, and that it is performing
without error”.
The process of equipment validation is based on the principle that equipment
must be designed, constructed, maintained, and adapted to perform the
operations which are to be carried out.

33. Types of equipment validation
The process of equipment validation is not a single step activity that it has
different phases which have further subsections or steps, these are as follow:
• Design qualification
• Installation qualification
• Operational qualification
• Performance qualification

34. 1. Design Qualification (DQ)
“It is a documented verification of design of the equipment and manufacturing
facilities. The main purpose of Design qualification is to make sure that all the
requirements for the systems should clearly defined at the start. Design
qualification process will illustrate that all quality aspects are fully considered
at the design stage. It defines the functional and operational specifications of
the instrument with all requirements, as mentioned in the user requirement
specification (URS) and the applicable cGMP rules and regulations”.

35. 2. Installation Qualifications (IQ)
“Installation qualification confirms that the précised equipment has been
received and installed as per target and agreement in exact design or format in
the undamaged form with parts, spares, services gauges, and other required
compounds. It is documental verification of that the equipment has been
installed and calibrated appropriately.The purpose of IQ is to ensure that all
the aspects of the equipment are installed correctly match with the original
(URS) design. As per the manufacture’s recommendations for installation, the
working sites working environmental conditions are documented and
confirmed that they are suitable for the operation of the instrument”.

36. 3. Operational Qualifications (OQ)
“Operational qualification ensures that installed equipment/instrument will function perfectly
according to its operation specification in the mention environmental conditions. It also
checks that the equipment function perfectly to meet pre-assigned performance criteria and
ensure how the testing results are recorded.The purpose of the operational qualification is to
make sure that all the dynamic conditions well comply with original (URS) design. For
verification, it includes traceable electric stimulators and standards which verify that
equipment is processing correctly as required. Operational qualification gave high degree of
assurance that the equipment functionally verifies compliance of manufactures specifications
and user required specifications (URS).Operational qualification is also known as process
validation that it ensures the processing of the equipment from the user and manufacturer
point of view with proper documentation verification”.

37. 4. Performance Qualification (PQ)
“Performance qualification ensures that the equipment consistently performs
functions according to the mentioned specification which appropriates to its
daily/routine use. It is a documented verification process which verifies that all
aspects of facility, utility, and performance of equipment meeting pre-
assigned acceptance criteria from user requirement specification (URS) and
manufactures specifications. Performance qualification is performed under
controlled conditions that are similar to daily sample analysis and it is
performed on daily basis (at least repeated after a week) when equipment is
used or functioning performed. It is also known as system suitability testing,
its testing frequency is quite higher than that of operational qualification.The
test frequency depends not only on functioning of equipment but also on the
stability of each unit of entire system which contributes to the analysis result”.

38. Equipment Re-validation after
change/modifications
• Periodic re-validation process refers to the re-validation process which carried out
in pharmaceutical industry at periodic intervals and it is mandatory especially when
the company made any change in the formulas, procedures, manufacturing
systems, packaging, and support system such as electricity/ power supply, water
supply, and steam. A separate and well qualified team will come for the process of
re-validation in case of equipment re-validation that the analyst will come from the
manufacturer side. Minor change in the product may affect the product’s quality up
to a great extent hence to carry validation become necessary even after the minute
change. Sometimes operational and performance tests were re-performed, which
were done even during first time validation.

39. References
• ICH HARMONISEDTRIPARTITE GUIDELINE (Q2R1)
• Guidance for Industry for processValidation
• APIC Guideline of aspects of cleaning validation in active pharmaceutical
ingredient plants
• Validation – In pharmaceutical industry: Equipment validation

40. Thanks