Validation

Guided by presented byMrs vandana gupta Nagendra sharma

1.Introduction 2. Components of validation 3.Scope of validation 4. Importance of validation 5.limitation of validation 6.Phases of validation 7. Approaches to validation process 8. Analytical method validation 9. Process validation ; steps in tablet

manufacturing 10. Conclusion

Content-

Let us take an example ,we want to manufacture one sterile batch of diazepam injection and we want to test the reliability of of end product testing ,we must design an efficient sampling plan. Suppose 100 samples are required and I contaminate a vial that means 1% batch is contaminated . So that chances of detection of contamination is 1% .this means over sterility test may fail to detect contamination in batch . We cant rely solely on end product testing so quality cant be tested in finished product ,but rather be built in the manufacturing process and these process should be controlled in order to ensure that the finished product meets all quality specification.

why validation necessary?

1.Regulatory reuirement- validation is regulatory requirement all over globe eg usfda ; cGMP for finished products

21 CFR parts 210 and 211 21 CFR parts 820 ; GMP for medical device 2.Assurance of quality compliance3.Efficient production operation 4.Optimisation of resources ,-to make as

effective as perfect as useful as possible at lowest cost.

5 Reduced no of samples ,inspecion and test are required.

According to who- validation is the establishment of documented evidence that a system does what it is supposed to do

pharmaceutical dosage form canada; the documented act of demonstrating that any procedure ,process ,equipment, material, activity or system will consistently lead to expected results.

South african GMP guidelines-validation means to provide documented evidence that an item of equipment ,process ,system or method is in state of control

Validation defined under guidelines-

Definition

“ Validation is a documented program which provide a high

degree of assurance that a specific process will consistently

produce a products to meeting it’s Pre-determined Specification

and quality attributes”

This document presents a discussion of the characteristics for

Consideration during the validation of the analytical procedures

Included as part of registration applications submitted.

This document does not necessarily seek to cover the testing that may be required for registration in, or expert to, other areas of the world.

Furthermore, this text presentation serves as a collection of terms and their definition and is not intended to provide direction on how to accomplish validation.

These terms and definitions are required to bridge the differences that often exist between various commending and regulators.

Regulatory AuthoritiesCountry: Name of authority:

INDIA

UNITED KINGDOM

SOUTH AFRICA

CANADA

AUSTRALIA

Indian FDA.

MHRA-Medicine Health & Regulatory Agency.

MCC-Medicinal Control Council.

HPB-Health Protection Branch.

TGA-Therapeutic Goods Administration.

Netherland

Uganda.

World-wide

Brazil-

IDA-International Dispensary Association.

NDA-National Drug Authority.

WHO & ICH.

ANVISA-National Agency for Vigilance Sanitare.

Scope of validation Pharmaceutical validation is vast area of work and it practically

cover every aspect of pharmaceutical process activities. Following area or operation will point out for pharmaceutical validation, Analytical test method.

Instrument calibration.

Raw material.

Packaging material.

Equipment validation.

Facilities.

Manufacturing operation

Product design.

Cleaning validation.

Operator.

Process utility services.

Validation involves careful determination of critical variables of the process such as moisture of granules,drying temperature, acceptable range and tolerance limit for the same.

Designing of all variables parameters of dosage form.

Product design based on the expected expected performance

Validation of related system ,facility and equipment.

Personnel training.

1.Raw material specification 2.Product development and design 3.Process validation 4.Manufacturing stages 5.facilities 6.Critical support system 7.Equipments 8.Instrument calibration 9.Analytical test methods 10. Packaging materials 11.Cleaning 12. Documentation

Components of validation:

Importance of validation Every activity in any business unit is done to get some benefit

from that.

Validation activity must give the industry some advantages, some benefit & Some added value.

• Reduction of Quality cost• Process optimization• Assurance of Quality• Safety

Reduction of quality cost : Preventive cost : To prevent failure or reduce the appraisal cost 1. Quality planning. 5. Process validation 2. Training. 6. Self inspection. 3. Calibration. 7. Documentation. 4. Sanitation 8. Review of data.

Internal failure cost : Non-confirming material . 1. Reject 3. Re-inspection

2. Rework 4. Re-test

External failure cost : Non- confirming condition after the product left the company ownership.

1.Recall. 2. Complaints. 3.Return due to Quality problem

Process optimization:

Make the process effective, efficient, perfect or as useful as possible at the minimum cost.

Trained qualified people are the key element in any process, thus greatest impact on improving efficiency and productivity.

In this context GMP training program cannot be separated from a total training programme that includes, how to do the job correctly, easily and repeatedly.

Assurance of quality :

Validation is a extension of quality assurance, in other words validation and process control are the heart of GMP.

Without validated and controlled process it is impossible to produce quality product consistently.

Safety

Validation can also result in increased operation safety.

e.g. gauges used in equipment that is designed to operate at certain temperature, and pressure must be reliable i.e. they must be calibrated.

Limitation of validation Validation has a practical limit and related cost, hence while

deciding the limit of validation, we need to balance between the process cost and the benefits derived from such limit.

Eg.The cost of controlling weight variation in tablet or capsule, if 1 person keep limit of 5% & other person keep at limit 0.5% using high tech.& high cost. Availability of facilities and equipment, cost, inadequate technology.People while being a companies greatest assets are also the cause of many problems with a process.A validated process require that people follow procedures ,do their jobs consciently and without errors ,do not modify the system etc.

People deficiency that affect product quality and productivity are not confined to operators ,deficiency of supervisors and management(adequate equipments, facilities,systems,and procedures) are more significant.

A 100% assurance of quality is impossible. Specifications needs to be chalanged in

this light ,as the manufacturing process is challenged .

Complete assurance of the substance of all impurities is not reliable.

Phase1-pre validation or qualification phase it covers all activities related to product research, development and formulation,stability studies, sops ,equipment qualification,etc

Phase 2-process validation phase- process validation is also known as process qualification this phase varifies all the established limits of critical process parameters are appropriate and gives assuarance that the process produce the product.

Phase 3-validation maintenance phase-this phase ensures that the process will remain in control throughout production cycle ,if standard operating procedure and conditions are strictly allowed.

Phases of validation-

APPROACHES TO VALIDATION PROCESS

Types of Process validation

Prospective Validation

Concurrent Validation

Revalidation

Retrospective validation

Prospective Validation :- Prospective validation is done during the Product development stage. - When we develop a new mfg process and formula each step will be validated to achieve desire result.-On the basis of past experience to determine whether they might lead to critical situation.-Formation of team-Preparation of validation master plan-Formulation development-Process development-Qualification of process-Qualification of equipments-qualification of product

Conti… Unsatisfactory process must be modified & improve until the validation exercise prove them to be satisfactory.

Essential in order to limit the risk of error occurring on the production scale.

Every aspect from laboratory scale to commercial scale is

documented on record of Process validation.

Concurrent Validation : Concurrent validation is carried out during production.

This time the in-process quality control parameter are also decided & monitored for use of regular production, final control & stability.

If initial batches use same type of equipment then revalidation may not be required only IPQC test are enough.

IPQC test should be carried out for every batch to see the process is moving forward in the excepted direction.

Conti

Process & procedure should undergoes periodic critical revalidation to ensure that achieving the desire result.

The verification of process parameter are evaluated for the mfg. facilities batch after batch if any changes is required.

The premises and equipment to be used have been validated previously and then decision to carry out concurrent validation.

Revalidation “Revalidation is needed to ensure that changes in the process and in process environment whether intentional or unintentional do not adversely affect process characteristics and product quality” e.g. Change in : Formula. Equipment. Procedure. Quality of raw material. Physical variation. May required revalidation process.

Types of Revalidation :

Revalidation after any changes bearing on product quality.

Periodic revalidation carried out at schedule interval.

Revalidation after any changes bearing on product quality.

Change in Starting material.

Density Viscosity. Particle size. Crystal type. Modification of active ingredients.

Change in Packaging material.

Replacing plastic by a glass.

Change in Process.

Mixing time Drying temp. Cooling regimen.

Change in Equipment.

Conventional granulator Replaced by Rapid mixer granulator or Fluid bed processor.

Periodic revalidation carried out at schedule interval. It is well known that the process changes may occur gradually even

if experienced operator works correctly, similaraly equipment may also cause gradual changes. Periodic revalidation is based on review of historical data. i.e. data generated during in process & finished product testing. Any change in master formula & method, batch size etc. Has preventive maintenance been performed in accordance with the Program & time schedule. Have the (SOPs) been properly updated. Have the (SOPs) been implemented. Have the cleaning & hygiene program been carried out.

Retrospective validation: Establishing documented evidence that a system does what if purpose to do based on a review and analysis of historical data and information obtained during production of marketable products.

This validation includes: Batch documents. Process control chart. Maintenance log book. Record of personnel changes. Finished product data. Storage stability result.

Analytical Method validation is the process of demonstrating that analytical procedures are suitable for their intended use and that they support the identity, strength, quality, purity and potency of the drug substances and drug products.

Analytical Method Validation

The main objective of validation of an analytical procedure is to demonstrate that the procedure is suitable for its intended purpose.

In practice, it is usually possible to design the experimental work so that appropriate validation characteristics can be considered simultaneously to provide a sound, overall knowledge of the capabilities of the analytical procedure, for instance: specificity, linearity, range, accuracy and precision.

Well-characterized reference materials, with documented purity, should be used throughout the validation study.

Validation of Analytical Procedures

Chromatographic Methods – HPLC, GC, TLC, GC etc. Bioanalytical Analysis – In support of PK/PD/Clinical

Studies. Spectrophotometric Methods – UV-VIS, IR, NIR, AA,

NMR, XRD, MS, etc. Capillary Electrophoresis Methods – Zone, Isoelectric

Focusing, Isotachophoresis, etc. Particle Sizer Analysis Methods – Laser, Microscopic,

Photozone, Sieving etc. Titration Methods. Automated Analytical Methods – Robots, Automated

Analysis.

Examples of Methods That Require Validation Documentation

Specificity (Selectivity) Linearity Range Accuracy Precision Repeatability Intermediate Precision Reproducibility

(Ruggedness)

Detection Limit Quantitation Limit Robustness System Suitability Testing

Method Characteristics to Be Considered for Validation

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.

It is not always possible to demonstrate that an analytical procedure is specific for a particular analyte (complete discrimination). In this case a combination of two or more analytical procedures is recommended to achieve the necessary level of discrimination

Specificity

-repeatability expresses the precision under the same operating conditions over a short interval of time .aslo called as intra –assay precision.

Repeatability

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.

Linearity

The range of an analytical procedure is the interval between the upper and lower concentration (amounts) of analyte in the sample for which it has been demonstrated that the analytical procedure has a suitable level of precision, accuracy and linearity.

Range

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.

Accuracy

Repeatability expresses the precision under the same operating conditions over a short interval of time. Repeatability is also termed intra-assay precision.

Intermediate Precision expresses within-laboratories variations: different days, different analysts, different equipment, etc.

Reproducibility expresses the precision between laboratories (collaborative studies, usually applied to standardization of methodology).

Precision

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.

Detection 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.

Quantitation Limit

Accuracy should be assessed on samples (substance / product) spiked with known amounts of impurities

Impurities (Quantitation)

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

Robustness

The ruggedness is defined there as the degree of reproducibility of the test results obtained under a variety of normal test conditions such as different laboratories, different analyst, different instrument ,different lots of reagents, different elapsed assay times ,different assay temperatures, differen days.

Ruggedness

System suitability testing is an integral part of many analytical procedures. The tests are based on the concept that the equipment, electronics, analytical operations and samples to be analyzed constitute an integral system that can be evaluated as such. System suitability test parameters to be established for a particular procedure depend on the type of procedure being validated.

System Suitability Testing

PROCESS VALIDATION STEPS IN TABLETMANUFACTURING :

PROCESS-VALIDATION: PROCESSING STEPS & IN-PROCESSVARIABLES (TABLETS). (Fish Bone diagram)

CONTENT UNIFORMITYDISINTEGRATIONDISSOLUTION

GRANULATION

DRYING

PRE-BLENDINGOF POWDERS

BLENDGRANULATION

SIZING GRANULES

TABLET COMPRESSION

BLENDING ADDITION OF LUBRICANT

SPEED TEMP SPEED

SPEEDSPEED

LOAD

LOAD

LOAD

TIME

TIME

ConclusionValidation starts from the product development Phase and continued through to production phase, which provides high degree of assurance that process will produce a product meeting its predetermined specification and quality attributes. May used to achieve reduction of cost, process optimization, assurance of quality and safety. Validation involves series of activity taking place over the Lifecycle of the product and process.