validation, tablet validation

04/07/2023 1

Validation

• Presented by:MANISH KUMAR SHARMA

Mahashiri Arvind Institution of Pharmacy

04/07/2023 Mahashiri Arvind Institution of Pharmacy 2

Validation is• "Establishing documented evidence that provides a high degree of

assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality attributes.“

• The field of validation is divided into a number of subsections– Equipment validation– Facilities validation– HVAC system validation– Cleaning validation– Analytical method validation– Computer system validation– Process validation


Types of process validation

Prospective

Concurrent

Retrospective

Revalidation


Prospective validation is carried out during the development stage by means of a risk analysis of the production process, which is broken down into individual steps: these are then evaluated on the basis of past experience to determine whether they might lead to critical situations.

Concurrent validation is carried out during normal production. This method is effective only if the development stage has resulted in a proper understanding of the fundamentals of the process.

Retrospective validation involves the examination of past experience of production on the assumption that composition, procedures, and equipment remain unchanged; such experience and the results of in-process and final control tests are then evaluated.

Revalidation is needed to ensure that changes in the process and/or in the process environment, whether intentional or unintentional, do not adversely affect process characteristics and product quality.


Revalidation Revalidation after any change having a

bearing on product quality.

Periodic revalidation carried out at scheduled intervals.


In-Process Tests

Moisture content of “dried granulation”

• Loss on drying (LOD) used to determine whether or not the granulation solvent has been removed to a sufficient level during the drying operation.

Granulation particle size distribution

• An extremely important parameter that affect tablet compressibility, hardness, thickness, disintegration, dissolution, weight variation, and content uniformity.

Blend uniformity

• Samples of the blend are taken and analyzed to ensure that the drug is uniformly dispersed throughout the tablet/capsule blend. The proper blend time must be established so that the blend is not under- or over mixed.


Individual tablet/capsule weight

• The weight of individual tablets or capsules is determined throughout compression /encapsulation to ensure that the material is flowing properly and the equipment is working consistently.

• The particle size distribution of the drug may determine what grade of an excipient (e.g., microcrystalline cellulose) to use.

Morphology• If the drug is amorphous or has different

polymorphs, certain excipients may be used to prevent conversion of the drug to other physical forms.


Material flow & compressibility •A free flowing, highly compressible material such as microcrystalline cellulose may be used for drugs with poor flow or compressibility properties.

Hygro-scopicity •Special environmental working conditions may be required to ensure that moisture is not picked up during material storage or handling and during the manufacture of the tablet dosage form.

Melting point •If the drug has a low melting point, a direct compression formulation may need to be developed instead of a wet granulation formulation to avoid drying the material and potentially melting or degrading the drug.

True & bulk density •An excipient (e.g., diluents) that has a similar bulk density as the drug may be selected to minimize segregation, especially with a direct compression formulation .


Finished Product Tests

Appearance •The tablets should be examined for such problems as tablet mottling, picking of the monogram, tablet filming, and capping of the tablets. If the tablets are colored, the color quality needs to be examined.

Content uniformity •Samples are taken across the batch profile (beginning, middle, and end) and analyzed to ensure that the dosage forms comply with compendial standards (±15% of the labeled amount) or more stringent internal limits.

Tablet hardness •A critical parameter for dosage form handling and performance.


Tablet friability• Friability is an important characteristic on

the tablets’ ability to withstand chipping, cracking, or “dusting” during the packaging operations and shipping.

Dissolution• Dissolution is important to ensure proper

drug release characteristics (in vitro availability) and batch-to-batch uniformity.

Assay• This test will determine whether or not the

product contains the labeled amount of drug.


Types of analytical procedures to be validated

Identification tests

Quantitative tests for

impurities content

Limit tests for control of impurities

Quantitative tests of the

active ingredient in the sample

Pyrogen Sterility

Limulus Amebocyte Lysate Test


Identification tests

• Identification tests are intended to ensure the identity of an active ingredient in the sample.

• This is normally achieved by comparison of a property of the sample e.g. spectrum, chromatographic behavior, chemical reactivity, etc) to that of a reference standard.

Sterility testing

• Applied to products that are required to be sterile.• A satisfactory result indicates that no contaminating microorganism has been found in the sample

examined in the condition of the test. • For sterility testing it is imperative that the testing procedure adopted by the manufacturers include all

aspects of validation of the testing method including the precautions against microbial contamination.


Quantitative tests for impurities content

• Testing for impurities can be either a quantitative test or a limit test for the impurity in the sample.

• Either tests is intended to accurately reflect the purity characteristics of the sample.

Pyrogen Test & Limulus Amebocyte Lysate Test

• includes product independent data such as equipment validation, • validation of temperature system,• lysate sensitivity• product dependent validation data such as inhibition / enhancement studies• validation for routine LAL tests according to the type of LAL test method

employed eg. Gel Clot method, quantitative end point method or quantitative kinetic method.


GIPPROCESS VALIDATION

General view of process validation


Design Qualification (DQ)

Documented review of the design, at an appropriate stage in a project, for conformance to operational and regulatory expectations.

Impact Assessment

The process of evaluating the impact of the operating, controlling, alarming and failure conditions of a system on the quality of a product

04/07/2023 Mahashiri Arvind Institution of Pharmacy

Installation Qualification (Definition)

• Documented verification that all aspects of a facility, utility or equipment that can affect the product quality adhere to approved specifications and are correctly installed.

• The process of checking/verifying the installation to ensure that the critical components meet the approved specifications and that they are installed correctly in accordance with design documentation.

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Installation Qualification (PURPOSE)

• To establish that the critical components are installed correctly and in accordance with design documentation requirements (i.e. PO’s, Contracts etc.), that supporting documentation is in place and of suitable quality.

• To record the checks and verifications for critical components in Direct Impact Systems.

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Operational Qualification (Definition)

• Documented verification that all aspects of a facility, utility or equipment that can affect product quality operate as intended throughout all anticipated ranges. It is the process of testing to ensure that individual components and systems operate as specified, and how that information is recorded.


Operational Qualification (PURPOSE)

• To establish through documented testing, that all critical components and direct impact systems are capable of operating within established limits and tolerances.

• To test parameters that regulate the process or product quality. To verify the proper operation of controllers, indicators, recorders, alarms and interlocks, is performed and documented during the operational qualification testing.


Performance Qualification (Definition)

• Documented verification that all aspects of a facility, utility or equipment that can affect the product quality perform as intended in meeting the predetermined acceptance criteria.


Performance Qualification (Purpose)

• To integrate procedures, personnel, systems and materials to verify that the utility / environment / equipment / support systems produces the required output. This output may be a product contact utility, sterilization condition or environment.


Validation Master Plan

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Introduction Qualification Personnel Schedule Preventive Maintenance

Installation

Operation

Process

Responsibilities

Training

Change Control

ProceduresDocumentsAppendices


Typical validation characteristics which should be considered are listed below: • Accuracy • Precision

Repeatability Intermediate Precision • Specificity • Detection Limit • Quantization Limit • Linearity • Range


1. 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.

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. 3.1. Repeatability Repeatability expresses the precision under the same operating conditions over a short interval of time. Repeatability is also termed intra-assay precision . 3.2. Intermediate precision Intermediate precision expresses within-laboratories variations: different days, different analysts, different equipment, etc. 3.3. Reproducibility Reproducibility expresses the precision between laboratories (collaborative studies, usually applied to standardization of methodology).


3. SPECIFICITY Specificity is the ability to assess unequivocally the analyte in the presence of components which may be expected to be present. Typically these might include impurities, degradants, matrix, etc. Lack of specificity of an individual analytical procedure may be compensated by other supporting analytical procedure(s).4. DETECTION LIMIT 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.5. QUANTITATION LIMIT 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. The quantitation limit is a parameter of quantitative assays for low levels of compounds in sample matrices, and is used particularly for the determination of impurities and/or degradation products.


6. 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.

7. 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.

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