Types of validation & validation of specific dosage.pptx

TYPES OF VALIDATION & VALIDATION OF
SPECIFIC DOSAGE FORM
MODERN PHARMACEUTICS
BY :- MISS. ANKITA SANDEEP NAKASHE
(F. Y. M. PHARMACY PHARMACEUTICS)
GUIDED BY :- MRS. PRANALI JOSHI
(ASST. PROFESSOR DEPT. OF PHARMACEUTICS)

CONTENT
1. DEFINITION
2. TYPES OF VALIDATION
3. VALIDATION OF VARIOUS DOSAGE FORMS
4. VALIDATION OF SPECIFIC DOSAGE FORM (SOLID DOSAGE FORM e. g. TABLET)
5. CONCLUSION
6. REFERENCE

DEFINITION OF VALIDATION & TYPES OF VALIDATION
 DEFINITION :
Validation is the confirmation by examination & the provision of objective evidence that
the requirements for specific intended use are fulfilled.
 TYPES OF VALIDATION :
I. Process Validation
II. Cleaning Validation
III. Equipment Validation (Qualification)
IV. Validation of Analytical Method

PROCESS VALIDATION
 DEFINITION :
As per FDA Nov. 2008, ‘the collection of data from the process design state throughout production, which
establishes scientific evidence that a process is capable of consistently delivering quality products.
 TYPES OF PROCESS VALIDATION :
a. Prospective Validation
b. Retrospective Validation
c. Concurrent Validation
d. Revalidation

a. PROSPECTIVE VALIDATION :
• Conducted prior to the distribution of either a new product or a product made under a modified
production process, where the modifications are significant and may affect the products characteristics.
• It is a preplanned scientific approach and includes the initial stages of formulation development, process
development, setting of process specifications, developing in-process tests sampling plans, designing of
batch records, defining raw material specifications, completion of pilot runs, transfer of technology from
scale-up batches to commercial size batches, listing major process is executed and environmental
controls.
• In Prospective Validation, the validation protocol is executed before the process is put into commercial
use. It is generally considered acceptable that three consecutive batches/runs within the finally agreed
parameters, giving product of the desired quality would constitute a proper validation of the process. It is
a confirmation on the commercial three batches before marketing.
b. RETROSPECTIVE VALIDATION :
• Conducted for a product already being marketed and is based on extensive data accumulated over several
lots and over time.
• Retrospective Validation may be used for older products which were not validated by the fabricator at the
time that they were first marketed, and which are now to be validated to confirm to the requirements of
division 2, Part C of the Regulation to be Food and Drugs Act.

• Retrospective Validation is only acceptable for well established detailed processes and will be
Inappropriate where there have recent changes in the formulation of the products, operating procedures,
equipment and facility.
• Some of the essential elements for Retrospective Validation are:
 Batches manufactured for a defined period (minimum of 10 last consecutive batches).
 Number of lots released per year.
 Batch size/strength/manufacturer/year/period.
 Master manufacturing/packaging documents.
 List of process deviations, corrective actions and changes to manufacturing documents.
 Data for stability testing for several batches.
 Trend analysis including those for quality related complaints.
c. CONCURRENT VALIDATION :
• A process where current production batches are used to monitor processing parameters. It gives of the
present batch being studied and offers limited assurance regarding consistency of quality from batch to
batch.
• Concurrent Validation may be the practical approach under certain circumstances. Examples of these may
be when:

 A previous validated process is being transferred to a third-party contract manufacturer or to another site.
 The product is a different strength of a previously validated product with the same ratio of active/inactive
ingredients. The number of lots evaluated under the Retrospective Validation were not sufficient to obtain
a high degree of assurance demonstrating that the process is fully under control.
 The numbers of batches produced are limited.
 Process with low production volume per batch and market demand.
 Process of manufacturing urgently needed drug due to shortage or absence of supply.
 In all above cases concurrent validation is valid, provided following conditions are appropriately.
 Pre-approved protocol for concurrent validation with rational.
 A deviation shall be raised with justification and shall be approved by plant head /head process
owner/Head-QMS. Product behavior and history shall be reviewed based on developmental/scale up /test
batches.
 A detailed procedure shall be planned for handling of the marketed product if any adverse reactions
observed in concurrent validation process.
 Concurrent validation batches shall be compiled in report and shall be approved all key disciplines.

d. REVALIDATION :
• Required when there is a change in any of the critical process parameters, formulation, primary
packaging components, raw material fabricator, major equipment or premises.
• Failure to meet product and process specifications in batches would also require process re-validation.
• Re-Validation becomes necessary in certain situations. The following are examples some of the planned
or unplanned changes that may require re-validation:
 Changes in raw materials (physical properties such as density, viscosity, particle size distribution, and
moisture, etc., that may affect the process or product).
 Changes in the source of active raw material manufacturer.
 Changes in packaging material (primary container/closure system).
 Changes in the process (e.g., mixing time, drying temperatures and batch size).
 Changes in the equipment (e.g. addition of automatic detection system).
 Changes of equipment which involve the replacement of equipment on a “like for like” basis would not
normally require a revalidation except that this new equipment.
 Must be qualified.
 Changes in the plant/facility.
 Variations revealed by trend analysis (e.g., process drifts).

CLEANING VALIDATION
• Cleaning validation ensures that there is no cross contamination in a multi-product manufacturing plant
and prevents microbial contamination.
• Once a product is manufactured, the equipment is cleaned using appropriate cleaning SOP’S established
during IQ of the equipment.
• Types of Contamination to be considered in Cleaning Validation are :
 Cross contamination
 Microbial contamination
 Contamination by cleaning or sanitizing agent
 Contamination by other agents

EQUIPMENT VALIDATION
• Equipment validation is to provide a high level of documented evidence that the equipment and the
process is confirmed to a standard.
• Types of Equipment Validation :
 INSTALLATION QUALIFICATION (IQ)
 OPERATIONAL QUALIFICATION (OQ)
 DESIGN QUALIFICATION (DQ)
 PERFORMANCE QUALIFICATION (PQ)

VALIDATION OF ANALYTICAL METHOD
• Method validation must prove that the analytical method used for a specific test is suitable for which it
is to be carried out.
• Methods should be validated when:-
 When they are to be established for routine use.
 When the method is to be changed due to change in conditions.
 Whenever the equivalence between new method and the standard are demonstrated.
• Types of procedures to be validated are :
ACCURACY:- Accuracy of an analytical method may be defined as, "Closeness of test results obtained
by the method to true value". i.e. measure the exactness of analytical method.

• It is expressed as percent recovery by the assay of known amount of analyte in the linearity range.
• Determination methods :-
1. Application of analytical method to an analyte of known concentration.
2. Spiked-Placebo Recovery Method.
3. Standard Addition Method.
• Recommended Data :- ICH document recommend that accuracy should be measured using a
minimum of 09 determinations per 03 concentration level.
• Acceptance Criteria :- The mean value should be within 15% of the supposed value except at LLOQ,
where it should not deviate by more than 20%. The deviation of the mean from the nominal value
serves as the measure of accuracy.
PRECISION:- The precision of an analytical method may be defined as, "Closeness of agreement
between a series of measurements obtained from multiple sampling of the same standardized sample under
the prescribed conditions."
• Should be investigated using homogeneous, authentic samples.
• Expressed as SD/RSD Standard Deviation, 100 % RSD = Mean.

Precision is considered at 3 levels :
Repeatability:- It expresses the precision under the same operating conditions over a short interval of time
i.e. analysis of replicates by the analyst using the same equipment and method.
Intermediate precision:- It expresses the precision within laboratories variations. i.e. different days,
different analyst, and different equipment's etc. It is not necessary to study effects individually.
Reproducibility precision:- It expresses the precision between laboratories (two-way studies, usually
applied to standardization of method) for addition of procedures in pharmacopoeias. i.e. Validation of tests
for assay and for determination impurities includes an investigation of precision.
Recommended Data:- The standard deviation, relative standard deviation and confidence interval should
be reported for each type of precision investigates.
Acceptance criteria:- The precision determined at each concentration level should not exceed 15% of the
coefficient of variation (CV) except for the LLOQ, where it should not exceed 20% of the CV.
SPECIFICITY:- ICH defines specificity of an assay is the ability to measure accurately and specifically
the analyte in the presence of other components that may be expected to present in the sample medium.
The term specific generally refers to a method that produces a response for a single analyte only.

SELECTIVITY :- Selectivity of method to detect the analyte in the presence of components that may be
expected to be present in the sample matrix. Simply it is the ability of a separate method to resolve different
compounds. It is the measure of the relative method location of two peaks. It is the method that provides
responses for a number of chemical entities that may or may not be separated from each other. It is
determined by comparing the test results obtained on the analyte with and without addition of potentially
interfering material.
DETECTION LIMIT :- The limit of detection of an analytical procedure is the lowest amount of an
analyte in a sample that can be detected, but not necessarily quantify under stated experimental conditions.
Simply it indicates that the sample is below or above certain level. The LOD will not only depend on the
procedure of analysis but also on type of instrument.
Measurement is based on :
• Visual evaluation:- Non instrumental method uses visual assessment more than that instrumental
method. The level is set at which ingredient can be detected dependently. The samples with the known
concentration control the limit of detection.

• Signal to noise ratio:- Exhibition baseline noise is necessary for this type of analysis. The sample gives
the signals. That signal is compared with the analyte containing the least sample concentration. The
blank sample is also analysed. Identification of the minimal concentration which can be identified can be
found out. The commonly satisfactory signal-to-noise ratio is 3 or 2:1.
• The standard deviation of the response and the slope:- the equation for the analysis is 3.3 (sigma)/S.
Sigma = the standard deviation of the response, S = Slope of the calibration curve of the analyte from
regression line.
QUANTITATION LIMIT :- The LOQ is the lowest amount of analyte in a sample which can
quantitatively determine that may be measured with an acceptable level of accuracy and precision under the
stated operational conditions of the method. LOQ can vary with the type of method employed and the nature
of the sample. It is generally used for the determination of impurities or degradation products.
Measurement is based on
• Visual evaluation:- LOQ is determined by the analysis of samples with known concentration of analyte
and by establish the minimum level at which the analyte can be detected. It can be used for instrumental
and non-instrumental procedure.

• Signal to noise ratio:- This approach can only be applied to analytical procedure which shows baseline
noise. It is performed by comparing measured signals from samples with known low concentration of
analyte with those of blank samples and establishes the minimum concentration at which the analyte can
be detected. Signal to noise ratio 10:1 is generally accepted.
• The standard deviation of the response and the slope:- LOD =10(sigma)/S
Sigma= Standard deviation of the response.
S= Slope of the calibration curve of the analyte from regression line.
LINEARITY :- Linearity is the ability of the method to obtained test results that are directly proportional to
the analyte concentration within a given range. A linear relationship should be evaluated across the range of
the analytical procedure. It may be established directly on the drug substance by dilution of a standard stock
solution. Linearity should be evaluated by visual inspection of a plot a graph of concentration (on x – axis)
Vs mean response (on Y – axis). Calculate the regression equation, Y- intercept and correlation co efficient.
Data from the regression line itself may be helpful to provide mathematical estimates of the degree of
linearity. For the determination of linearity, a minimum of 5 concentrations is recommended.
ROBUSTNESS :- It is the measure of the capacity of the analytical method to remain unaffected by small
but deliberate changes in procedure to provide an indication about variability of the method during normal
laboratory conditions.

Examples of typical variations are:
• Stability of analytical solutions
• Extraction time.
In the case of liquid chromatography, examples of typical variations are:
• Influence of variations of pH in a mobile phase
• Influence of variations in mobile phase composition
• Different columns
• Temperature
• Flow rate
In the case of gas-chromatography, examples of typical variations are:
• Different columns
• Temperature
• Flow rate.

RANGE :- Range of analytical procedure is the interval between the upper and lower concentration of
analyte in the sample for which it has been demonstrated that the analytical procedure has a suitable level of
precision, accuracy, and linearity. Normally derived from linearity studies and specific range is dependent
upon proposed application of the procedure.
The following minimum specified ranges should be considered:
• Assay of a drug substance or a finished (drug) product: 80 to 120 % of the test concentration.
• Content uniformity: 70 to 130 % of the test concentration.
• Dissolution testing: +/-20 % over the specified range.

VALIDATION OF VARIOUS DOSAGE FORMS
• Validation of various dosage forms include :
 Solid Dosage Form (Tablets, Capsules etc.)
 Liquid Dosage Form (Suspension, Emulsion, Solutions, Elixirs, Syrup, Liquid Drops etc.)
 Semi-Solid Dosage Form(Ointment, Cream etc.)

VALIDATION OF SOLID DOSAGE FORM (TABLETS)
 A tablet is a most known solid pharmaceutical dosages form and comprises of a mixture of active
substances and suitable excipients. Binders, glidants, lubricants etc. are some the popularly used
excipients in the tablets.
 The excipients are used for different purposes in the tableting; like disintegrants used to enhance the
breakdown, glidants used to increase the flow of the powder, flavoring agents to impart different flavors in
the tablets.
 The knowledge of stepwise manufacturing process of any dosages form is a must for validating any
process. It helps in determining the critical areas which need special consideration in terms of causing
problems during the process.

1. MIXING OR BLENDING :
• Mixing is one of the most critical step and used at various stages during manufacturing of tablets.
• Materials with like physical properties can easily form a uniform mix or blend and not segregate as soon
as materials with large differences.
• Parameters to be considered are:
 Mixing Or Blending Technique: The techniques like Diffusion (tumble), convection (planetary or high
intensity), or pneumatic (fluid bed) are used to mix or blend materials. The choice of technique depends
on whether the drug and excipients are mixed for a direct compression formulation or for adding the
lubricant (e.g., magnesium stearate) to the granulation.
 Mixing or Blending Speed: Mixing the drug and excipient requires more intense mixing than adding the
lubricant to the final blend.
 Mixing or Blending Time: The mixing or blending time of the product will be dependent on the mixing
or blending technique and speed.
 Drug uniformity: The test for content uniformity is usually performed to estimate the uniformity of drug
throughout the mix or blend.

 Excipient Uniformity: Besides drug uniformity, excipients uniformity is also necessary in the granulation
or blend. Two key excipients are:
 Lubricants: Uneven distribution of the lubricant can result in picking and sticky problems during
compression. It can also lead to tablet performance problems (low dissolution due to excessive lubricant
in some tablets).
 Coloring Agents or Colorants: The colorant(s) need(s) to be evenly distributed in the mixture so that the
tablets have a uniform appearance (e.g., color, and intensity).
2. WET GRANULATION :
• Wet granulation parameters to be considered during development and validation are :
 Binder Addition: Adding the binder dry avoids the need to determine the optimal binder concentration
and a separate manufacture for the binder solution.
 Binder Concentration: The optimal binder concentration will need to be determined for the formulation.
If the binder is to be sprayed, the binder solution needs to be dilute enough so that it can be pumped
through the spray nozzle. It should also be sufficiently concentrated to form granules without over
wetting the materials.

 Amount of Binder Solution/Granulating Solvent: Too much binder or solvent solution will over wet
the materials and prolong the drying time. The amount of binder solution is related to the binder
concentration.
 Binder Solution/ Granulating Solvent Addition Rate: The rate or rate range at which the binder
solution or granulating solvent can be added to the materials should be defined properly.
 Mixing Time: Granulations that are not mixed long enough can form incomplete or weak granules.
These granules may have poor flow and compression properties. On the other hand, over mixing the
granulation can lead to harder granules and a lower dissolution rate.
3. WET MILLING :
• Sometimes wet milling of granules is needed before subjecting it for drying to efficiently dry them.
• Factors to be considered are :
 Equipment Size And Capacity: The mill should be large enough to de lump the entire batch within a
reasonable time period to minimize manufacturing time and prevent the material from drying during
this operation.
 Screen Size: The screen needs to be small enough to de lump the material, but not too small to cause
excessive heating of the mill, resulting in drying of the granulation.

 Mill Speed: The speed should be sufficient to efficiently de-lump the material without straining the
equipment.
 Feed Rate: The feed rate of the wet granulation is interrelated to screen size and mill size and speed.
4. DRYING :
• The type of drying technique (e.g., tray, fluid bed, and microwave) required for the formulation needs to
be determined and justified.
• The type of technique may be dependent on such factors as drug or formulation properties and equipment
availability.
• Changing dryer techniques could affect such tablet properties as hardness, disintegration, dissolution, and
stability.
• The optimal moisture content of the dried granulation needs to be determined.
i. High moisture content can result in
a) Tablet picking or sticking to tablet punch surfaces
b) Poor chemical stability because of hydrolysis.
ii. An over dried granulation could result in poor hardness and friability.

• Parameters to be considered are :
 Inlet/Outlet Temperature: The inlet temperature is the temperature of the incoming air to the dryer,
while the outlet temperature is the temperature leaving the unit. The inlet temperature is critical to the
drying efficiency of the granulation and should be set high enough to maximize drying without affecting
the chemical/physical stability of the granulation. The outlet temperature is an indicator of the granulation
temperature and will increase toward the inlet temperature as the moisture content of the granulation
decreases (vaporization rate).
 Airflow: There should be sufficient airflow to ensure removal of moisture laden air from the wet
granulation. Insufficient air flow could prolong drying and affect the chemical stability of the drug.
 Moisture Uniformity: The moisture content could vary within the granulation
 Equipment Capability/Capacity: The load that can be efficiently dried within the unit needs to be
known.
5. DRY MILLING:
• The milling operation will reduce the particle size of the dried granulation.
• The resultant particle size distribution will affect such material properties as flow, compressibility,
disintegration, and dissolution.
• An optimal particle size/size distribution for the formulation will need to be determined. Factors to
consider in dry milling are same as that of wet milling.

6. LUBRICATION :
• Lubricants are added to remove the problem of sticking and picking in the tablets.
 Selection of Lubricant: Grade of the lubricant used and compatibility with other ingredients should be
studied thoroughly and then the appropriate one must be chosen.
 Amount of Lubricant Added: How much lubricant is required? Too much lubricant will form
hydrophobic layer on the tablet resulting in dissolution problems.
 Mixing Time: The optimum mixing time must be decided on proper trial of batches because if not
mixed long enough form problems like chipping, capping, etc.
7. TABLET COMPRESSION :
• Compression is a a critical step in the production of a tablet dosage form. As for the compressibility
properties of the formulation, it should be examined on an instrumented tablet press.
• Factors to be considered during compression are as follows:
 Tooling: The shape, size, and concavity of the tooling should be examined based on the formulation
properties and commercial specifications.

 Compression Speed: The formulation should be compressed at a wide range of compression speeds to
determine the operating range of the compressor.
 Compression/Ejection Force: The compression profile for the tablet formulation will need to be
determined to establish the optimal compression force to obtain the desired tablet hardness.
• The following in-process tests should be examined during the compression stage:
I. Appearance
II. Hardness
III. Tablet weight
IV. Friability
V. Disintegration
VI. Weight uniformity
VII. Tablet Coating
8. TABLET COATING :
• Tablet Coating can occur by different techniques (e.g., sugar film, or compression). Film coating has been
the most common technique over recent years and will be the focus of this section.

• Key areas to consider for tablet coating include the following:
 Tablet Properties: Tablet properties such as hardness, shape, etc., are important to obtain a good film-
coated tablet. The tablet needs to be hard enough to withstand the coating process.
 Equipment Type: The type of coater will need to be selected. Conventional or perforated pan and fluid
bed coaters are potential options.
 Coater Load: Having too large a pan load could cause attrition of the tablets because of the overall tablet
weight in the coater. In the case of a fluid bed coater, there may not be sufficient airflow to fluidize the
tablets.
 Pan Speed: This will be interrelated to other coating parameters, such as inlet temperature, spray rate, and
flow rate.
 Spray Guns: The number and types of guns should be determined to efficiently coat the tablets.
 Application/Spray Rate: The optimal application/spray rate should be determined. Spraying too fast will
cause the tablets to become over wet, resulting in clumping of tablets and possible dissolution of the tablet
surface. Spraying too slowly will cause the coating materials to dry prior to adhesion to the tablets. This
will result in a rough tablet surface and poor coating efficiency.

 Tablet Flow: The flow or movement of the tablets in the coater should be examined to ensure proper
flow. The addition of baffles may be required to provide adequate movement of tablets for tablet coating.
 Inlet/Outlet Temperature and Airflow: These parameters are interrelated and should be set to ensure
that the atomized coating solution reaches the tablet surface and then is quickly dried.
 Coating Solution: The concentration and viscosity of the coating solution will need to be determined.
The solution will need to be sufficiently diluted to spray the material on the tablets.
 Coating Weight: A minimum and maximum coating weight should be established for the tablet.
 Residual Solvent Level: If solvents are used for tablet coating, the residual solvent level will need to be
determined.

REFERENCE
 Industrial Pharmacy, A Comprehensive Approach by D.K. Tripathi, Pg. no: 671-699
 Pharmaceutical process validation : An overview , by M. D. Shoaib Alam etal;Journal of advanced
pharmacy education & research ,oct-dec 2012,vol 2, issue 4, pg. no: 190-196 24
 Kaur Harpreet*, Singh Gurpreet, Seth Nimrata PHARMACEUTICAL PROCESS VALIDATION: A
REVIEW Journal of Drug Delivery & Therapeutics; 2013, 3(4), 189-194

CONCLUSION
 Validation is a proven assurance of the process efficiency and sturdiness, and it is the full-fledged quality
control tool for the pharmaceutical industries. It eliminates the chances of batch failures as the products
are manufactured as per pre optimization of each manufacturing steps. The conventional process of testing
at last stage created much problems in maintain uniformity of each batch but with the introduction of
concept of validation, it has been easy to maintain the batch uniformity of the product along with
imparting quality in them.

Types of validation & validation of specific dosage.pptx

Types of validation & validation of specific dosage.pptx

More Related Content

What's hot (20)

Similar to Types of validation & validation of specific dosage.pptx (20)

Recently uploaded (20)

Types of validation & validation of specific dosage.pptx