PRODUCT VALIDATION

VALIDATION

 DEFINATION
Process Validation is “Establishing documented evidence which provides a
high degree of assurance that a specific process will consistently produce a
product meeting its pre-determined specifications and quality attributes.
Process validation involves a series of activities taking place over the
lifecycle of the product and process.
Type of Validation
 Retrospective Validation
 Prospective Validation
 Concurrent Validation
 Revalidation
 Retrospective Validation Validation of a process for a product already in distribution,
based on accumulated production, testing, and control dates. Summary of existing historical
data.
 Prospective Validation Validation conducted prior to distribution either of a new product,
or a product made under a revised manufacturing process. Validation is completed and the
results are approved prior to any product release.
 Concurrent Validation A combination of retrospective and prospective validation.
Performed against an approved protocol but product is released on a lot-by-lot basis. Usually
used on an existing product not previously validated or insufficiently validated.
 Revalidation To validate change in equipment, packaging, formulation operating
procedure, or process that could impact product safety, efficacy, or potency. It is important to
establish a revalidation program for critical equipment to maintain validity.
Importance of Validation

 Increased throughput.
 Reduction in rejections and reworking.
 Reduction in utility costs.
 Avoidance of capital expenditures.
 Fewer complaints about process-related failures.
 Reduced testing in-process and in finished goods.
 More rapid and reliable start-up of new equipment.
 Easier scale-up from development work.
 Easier maintenance of equipment.
 Improved employee awareness of processes.
 More rapid automation.
The major reasons for validation are:

 Quality assurance: Validation checks the accuracy and reliability

of a system or a process to meet the predetermined criteria. A
successful validation provides high degree of assurance that a
consistent level of quality is maintained in each unit of the finished
product from one batch to another batch.

 Economics: Due to successful validation, there is a decrease in

sampling and testing procedures and there are less number of
product rejections and retesting. This leads to cost-saving benefits.
 compliance: For compliance to current good
manufacturing practices, validation is essential. 
 Validation involves :
1)Choosing the desired attributes of the product.
2)Determining specifications for those attributes.
3)Selecting appropriate processes and equipment.
4)Monitoring and testing processes, equipment and
personnel while in operation.
5)Examining test procedures themselves to ensure their
accuracy and reliability.
 PRODUCT VALIDATION
 Product validation is associated with validation of the full-scale
manufacture of numerous earlier aspects of product development
that are critical to the subsequent phases of the process.
 Product validation involves following steps:
 validation of raw materials.
 validation of excipients.
 validation of analytical methods.
 validation of finished product.
 VALIDATION OF RAW MATERIALS

 Validation of raw materials is one of the major causes of product

variation or deviation from specification. The API may represent the
most uncontrollable component in the complete product.
 The validation process of dosage form begins with the validation of
raw materials, both API and excipients.
 Preformulation is one of the critical step to be validated in product
validation.
 Physical characters such as drug and particle size can affect
material flow and blend uniformity.
 Chemical characters like impurities can affect stability of drug. The
hygroscopic nature is important in both handling and reproducibility
of the manufacturing process
 VALIDATION OF EXCIPIENTS
Excipients can represent less then 1% of a tablet formula.

 Factors to be aware of are

 The grade and source of the excipients.
 Particle size and shape characteristics and
 Lot-to-lot variability Example : Microcrystalline cellulose(MCC)
used as diluents shows significant changes in the chemical
composition, crystallinity, particle size between different lots.
 Differences in particle size of MCC can affect wet granulation/blend
uniformity of tablet formulation.
 In direct compression formulations differences in particle size
distribution between lots can result in
 Non uniformity in initial mix
 Materials segregate during compression.
VALIDATION OF ANALYTICAL
METHODS
 Accuracy of method:
• Ability of a method to measure the true value of a sample.
 Specificity:
Ability to accurately measure the analyte in the presence of other components.
 Repeatability:( in day /out of day variation )
Does the precision and accuracy of the method change when conducted numerous times on
the same day and repeated on a subsequent day.
 Reproducibility: ( between operator variation )
• Repeat the precision and accuracy studies within the same lab
using the same instrument but different analysts to challenge the
reproducibility of the method.
 Precision: (between instrument variation )
• How will different instruments within the same lab run by the
same analyst affect the accuracy and precision of the method.
 Ruggedness: ( between laboratory variation)
• Will the precision and accuracy of the method be same between
the development and quality control lab.
 Validation of finished product consists of :
 Organoleptic characteristic
 Physical characteristic
 Chemical characteristic
 Biological characteristic
 Microbiological characteristic
 Stability testing
 Storage condition
Validation of tablets

 TABLET COMPRESSION

 The following in-process tests should be examined during the

compression stage-
 Appearance
 Hardness- 4 -8 kg/cm
 Tablet weight-90-110%
 Friability-0.5-1%
 Disintegration-15-30 min
 Weight uniformity
DEFECT OF TABLET COATING
 TEST FOR TABLET COATING
 cracking or peeling of the tablet.
 color uniformity .
 coating efficiency should be determined for the coating operation.
FINISHED PRODUCT
 Validation of capsules

 TEST
 Disintegration test
 Weight variation
 Dissolution test Assay
 Content uniformity
 Stability testing
ORAL LIQUID DOSAGE FORMS
 Appearance
 pH
 Viscosity
 Specific gravity
 Microbial count
 Leakage test for filled bottle (By plastic vacuum dessicator)
 Check the cap sealing
 Fill volume determination
 Particulate matter testing
 Water vapour permeability test
 Stress test
 PRODUCT FAULT DETECTION
 INTRODUCTION

The handling and examination of non-conformances and

deviations is becoming more and more important to the
pharmaceutical industry, primarily for two reasons.
The ongoing modernization of pharmaceutical quality
management systems.
The regulatory requirements and expectations of government
agencies worldwide have continued to increase in recent years
1)Modernization of pharmaceutical quality
management systems (QMS)
 Modernization of pharmaceutical QMS has made the industry
recognise the value and benefit of "failure" detection and CAPA
(Corrective and Preventive Action).
 Continuous process improvement tools have a long and successful
history, especially in the automotive industry, and these are now
being adopted and implemented in the pharmaceutical industry.
Applied properly, non-conformances can be prevented and
processes can be continuously improved.
2. Increased regulatory requirements and
expectations of government agencies
 November 2009; MHRA published a "Deficiency Data Review"1 for the period
April 2008 to March 2009, in which it cited "anomalies" as their most frequent
observation of regulatory deviations.
 Non-conformances and deviations in conjunction with CAPA being the third most
common observation.
 European Compliance Academy (ECA) published FDA Warning Letters Report
suggesting deficiencies in the "Production Record Review" (21 CFR 211.192)
among the most frequently reported GMP deviations
 In most cases, objections were applied to the poor handling of deviations and
incorrect CAPAs, the companies did actually detect the deviations themselves, but
did not properly examine them and did not define appropriate corrective and
preventive actions
Where industries fail ?

 It seems that one of the biggest challenges for companies is to

complete investigations and actions in a timely manner.
 In many cases, incorrect assumptions are made that everything is an
isolated incident. In other instances, problems are not corrected and
everything is blamed on a single employee or a simple laboratory
error.
 Sometimes the system fails to ensure that a problem does not extend
to other lots, and the incident recurs.
 The ultimate criterion for adequate correction is to ensure that it
doesn't happen again!
Introduction of CAPA

 CAPA was adopted as a new quality management tool following the

introduction of the ICH Q10 guideline. According to the ICH Q10
document, which was adopted by the FDA in April 2009 as an
industry guideline, a pharmaceutical Quality Management System
(QMS) consists of four central elements:
 process performance and product quality monitoring
 corrective action and preventive actions
 change management
 management review of process performance and product quality.
 The guideline states that a pharmaceutical company should have a
system in place to detect and evaluate non-conformances to take
respective corrective and preventive actions.
 Among other things, the information regarding non-conformances
can result from complaints, deviations, recalls, observations at
audits and inspections, or from monitoring findings.
 The examinations within the system must have the objective of
determining the actual root cause.

 As a result, the process and product should be better understood

so that improvements can be derived from it.
Quality Risk Management (fault detection)

 In earlier days risk in the product quality and process had been assessed in the following
informal ways.
 Trends review
 Check lists
 Flow charts
 Observations compilation (from complaints, deviations etc.)
 Changes review

 Now the risk management approach initiated by regulatory agencies with recognized
management tools along with support of statistical tools in combination, which make easy
for application of quality risk management principles across the industry.
 The risk management program consists of four major components:
 Risk assessment
 Risk control
 Risk review
 Risk communication

 All four components are essential.

 All the above methods should address the mentioned four basic components.
 Team selection and method selection are also plays a vital role in the risk
management process, so care should be taken while selection of risk management
team and method
Risk management methods
 To make risk-based decisions, a systematic approach is essential. The ICH Q9
guideline, Quality Risk Management, provides a structure to initiate and follow a risk
management process.
 The following methods widely used in the industry for risk management.
1. Basic risk management facilitation methods (flowcharts, check sheets, etc.)
2. Failure Mode Effects Analysis (FMEA)
3. Failure Mode, Effects, and Criticality Analysis (FMECA)
4. Fault Tree Analysis (FTA)
5. Hazard Analysis and Critical Control Points (HACCP)
6. Hazard Operability Analysis (HAZOP)
7. Preliminary Hazard Analysis (PHA)
8. Risk ranking and filtering
9. Supporting statistical tools
HOW TO DETECT THE PRODUCT
FAULT ?
 Fault should not be regarded as a flaw, but rather as an opportunity
because otherwise, there is a risk that employees may try to cover
up or play down it.
 It is crucial to understand that all faults must be addressed and
completely documented if a CAPA system is to be successful.
 In order to derive the correct — and therefore the effective —
actions from non-conformances, the root cause must be determined.
Overall, the following steps must be taken to identify the root
cause of a failure:

 Possible associated or related facts must be considered

 Annual reports and trends should be evaluated
 All equipment involved in the process should be part of the
investigation (equipment maintenance records, qualification of
equipment and the validation of process if applicable)
 Knowledge gained during process development should be
documented
 Precision and accuracy of analysis must be verified.
 POTENTIAL AREAS WHERE FAULT CAN
OCCUR
The following areas are identified as potential in the pharmaceutical industry
for quality risk management application.
 Documentation [SOPs, Batch records etc.]
 Training [Schedules and effectiveness]
 Quality defects [Complaints, deviations, OOS etc.]
 Audits [Compliance]
 Periodic reviews [Revalidation assessment]
 Change controls [Impact assessment]
 Development reports [Process and controls verification]
 Facilities, Equipment and Utilities [Components, maintenance etc.]
 Material management [Receipt, storage and distribution]
 Packaging and labeling [Container closure system and labeling]