process validation nishit

8/4/2019 Process Validation Nishit

1/76

Nishitkumar S. Patel

Assistant Professor

Dharmaj Degree Pharmacy College,Dharmaj.


2/76

1. VALIDATIONValidation is a key element of the quality assurance system in apharmaceutical company

` For a long time, our understanding of pharmaceutical quality wassuch that one relied solely on the control of raw materials and final

products. The intermediate process was guaranteed by establishedexperience and the professional honesty of longtime employees.Today, our understanding is almost the reverse.

` Well-tested raw materials from qualified suppliers are used in aprocess that must be so well controlled that, theoretically, absolutely

nothing can result other than a product that conforms to thespecifications. In contrast, the place of manufacture and staffcarrying out production are interchangeable, as long as they arequalified.


3/76

` The new approach is conclusive, reasonable,sensible, since if a serious defect is identified at the

final product quality control, irreparable damage hasalready occurred. For drug products, reprocessing isprohibited in most cases or is only possible with agreat deal of additional expenditure.

` Since modern drug substances and innovativepreparations are also becoming ever more expensive,it is, therefore, necessary to avoid the final productbeing rejected using preventive measures, such asvalidation. Therefore, to guarantee a reproduciblequality, processes must be validated.


4/76

` The establishing of documented evidence which provides a high degree

of assurance that a planned process will consistently perform according to

the intended specified outcomes. (WHO guide to GMP requirements ,

part-2 ,validation, Geneva 1997)

` " Action of proving, in accordance with the principles of Good

Manufacturing Practice, that any procedure, process, equipment, material,

activity or system actually leads to the expected results. (EU GMP

Guideline)

` 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.(U. S.

Food and Drug Administration)


5/76

` Validation is an essential part of good manufacturing practices (GMP). It is,

therefore, an element of the quality assurance program associated with a

particular product or process. The basic principles of quality assurance

have as their goal the production of products that are fit for their intended

use. These principles are as follows: -

` a) Quality, safety and efficacy must be designed and built into the product.

` b) Quality cannot be inspected or tested into the product.

` c) Each critical step of the manufacturing process must be validated. Other

steps in the process must be under control to maximize the probability that

the finished product consistently and predictably meets all quality anddesign specifications.


6/76

` Validation of processes and systems is fundamental to

achieving these goals. It is by design and validation that a

manufacturer can establish confidence that the manufactured

products will consistently meet their product specifications.

Documentation associated with validation includes:-

` a) Standard operating procedures (SOPs)

` b) Specifications

` c) Validation master plan (VMP)

` d) Qualification protocols and reports

` e) Validation protocols and reports.


7/76

` The implementation of validation work requires considerable

resources such as:

` a) Time: generally validation work is subject to rigorous time

schedules.

` b) Financial: validation often requires the time of specialized

personnel and expensive technology.

` c) Human: validation requires the collaboration of experts from

various disciplines (a multidisciplinary team, comprising

quality assurance, engineering, manufacturing and otherdisciplines, depending on the product and process to be

validated).


8/76

` Validation studies verify the system under test under the extremes

expected during the process to prove that the system remains in

control. Once the system or process has been validated, it isexpected that it remains in control, provided no changes are made.

` In the event that modifications are made, or problems occur, or

equipment is replaced or relocated, revalidation is performed.

` Critical equipment and processes are routinely revalidated at

appropriate intervals to demonstrate that the process remains in

control. The validity of systems / equipment / tests/ processes can

be established by prospective, concurrent or retrospective studies.


9/76

Scope of Validation.

` Principles may be useful:

in production and control of active harmaceutical

ingredients (APIs) and finished pharmaceutical

products

` Validation of specific processes and products (e.g. sterileproduct manufacture) requires much more consideration

and a detailed approach beyond the scope of the

guideline


10/76

` Many factors affecting the different types of validation

`

Manufacturers should plan validation to ensure

regulatory compliance and

product quality, safety and consistency

` The general text in the guideline (part 1 of presentation) may be

applied to validation and qualification of:

premises, equipment, utilities and systems

processes and procedures


11/76

Advantages of Validation

` Increased throughput

` Reduction in rejections and reworks

` Reduction in utility costs

` Avoidance of capital expenditures

` Fewer complaints about process related failures

` Reduced testingin process and finished goods

` More rapid and accurate investigations into process deviations

` More rapid and reliable startup of new equipment

` Easier scale-up from development work

` Easier maintenance of the equipment

` Improved employee awareness of processes

` More rapid automation


12/76

` DEPARTMENT INTERACTIONS

` Once department missions have been formalized and the validationoperation organized, the challenge is to implement the plan. Thatimplementation requires the validation organization to interact withmany peer groups. Within the company, those other departmentsinclude the following:

` 1. R&D: involved with new product development and new processimprovement.

` 2. Engineering: involved with new or modified equipment or facilities.` 3. Production: concerned with processes that require validation.` 4. Maintenance: concerned change control, calibration, and

preventative maintenance.` 5. Quality Control: involved with the testing laboratories.

` 6. Quality Assurance: concerned with GMP compliance.

` Additionally, for those companies that outsource the manufacturing orpackaging of their products, these interactions occur with thecontracting firms Validation department. This poses an additional set ofdynamics.


13/76


14/76

PURPOSE

` To describe the functions and responsibilities of the

validation team to meet the cGMP complianceRESPONSIBILITY

` It is the responsibility of all concerned departmentsto follow the procedure. The QA manager isresponsible for SOP compliance.

PROCEDURE

1. Validation Coordinator

` All validation activities through the different progresssteps should be coordinated by one person,preferably the quality assurance manager.


15/76

2. Validation Task Force/Certification Team

` The team should consist of managers of the departmentsinvolved in the validation and outside vendors (ifapplicable); for example:

` Quality assurance manager

` Production manager

` Technical services manager

` Product development manager` Calibration manager

` Quality control manager

` Approved vendors (outside)

2.1 Responsibilities` Scope of validation

` Validation priorities

` Acceptance criteria


16/76

3. Validation Working Groups

` The executive part of the validation work should be

delegated to dedicated personnel:` A member of the validation task force

` Representatives from relevant departments

` A representative from quality assurance

` A representative from technical services

` A representative from product development

laboratory

`

A representative from quality control` A representative from the vendor (outside)


17/76

` WHAT IS A VALIDATION MASTER PLAN?

` A Validation Master Plan (VMP) is a comprehensive documentdescribing the applicable validation requirements for the

facility, and providing a plan for meeting those requirements.SCOPE OF A VALIDATION MASTER PLAN

` The Validation Master Plan (VMP) includes all relevantaspects relating to the production of pharmaceuticals in theproduction facility at ABC Pharmaceutical.

` The principles of validation, the organization of qualificationand validation, and the design and nomenclature of thedocumentation and equipment are also described. The VMPcovers all facilities used in the production of tablets, liquids,ointments, creams, suppositories, and sterile products; the

facilities for storing raw materials, interim and finishedproducts, storage, services, and the rooms for staff.


18/76

` This Validation Master Plan (VMP) specifies and coordinates all

qualification/ validation activities to ensure the production of

pharmaceutical products according to accepted international standards. Italso specifies the responsibilities for validation procedures and helps to

plan the necessary activities.

` A validation master plan is a document that summaries the companys

overall philosophy, intentions and approaches to be used for establishing

performance adequacy. The Validation Master Plan should be agreed upon

by management. Validation in general requires meticulous preparation and

careful planning of the various steps in the process.


19/76

` In addition, all work should be carried out in a structured way

according to formally authorized standard operating

procedures. All observations must be documented and wherepossible must be recorded as actual numerical results.

` The validation master plan should provide an overview of the

entire validation operation, its organizational structure, its

content and planning. The main elements of it being the

list/inventory of the items to be validated and the planning

schedule. All validation activities relating to critical technical

operations, relevant to product and process controls within a

firm should be included in the validation master plan. It should

comprise all prospective, concurrent and retrospectivevalidations as well as re validation.


20/76

` The Validation Master Plan should be a summary document and should

therefore be brief, concise and clear. It should not repeat information

documented elsewhere but should refer to existing documents such as

policy documents, SOPs and validation protocols and reports

The format and content should include:

` Introduction: validation policy, scope, location and schedule

` Organizational structure: personnel responsibilities

` Plant /process/product description: rational for inclusions or exclusions

and extent of validation

` Specific process considerations that are critical and those requiring extraattention

` List of products/ processes/ systems to be validated, summarized in a

matrix format, validation approach

` Re-validation activities, actual status and future planning

` Key acceptance criteria` Documentation format

` Reference to the required SOPs

` Time plans of each validation project and sub-project.


21/76

Validation Life-Cycle

` Validation is a continuing and evolving process. The

validation process extends from the very basicspecifics (how each item works and interacts withanother item) to a very broad theological andmethodical investigation of how the system andprocesses perform.

` Its scope encompasses documentation, revisioncontrol, training, and maintenance of thesystem andprocess. Evidence of validation should be seen atthe corporate level, and be reflected in the

management structure. Validation is not just a set ofprocedures and rules to satisfy FDA, validation is amethod for building and maintaining QUALITY.


22/76


23/76

TYPES OF PROCESS VALIDATION

` Prospective process validation

` Concurrent process validation

` Retrospective process validation

` Revalidation


24/76

Pre-requisites for Process Validation

` Before process validation can be started, manufacturing

equipment and control instruments as well as the formulationmust be qualified. The information on a pharmaceutical

product should be studied in detail and qualified at the

development stage, i.e., before an application for marketing

authorization is submitted. This involves studies on the

compatibility of active ingredients and recipients, and of final

drug product and packaging materials, stability studies, etc.

` Other aspects of manufacture must be validated including

critical services (water, air nitrogen, power supply, etc.) and

supporting operations such as equipment cleaning andsanitation of premises. Proper training and motivation of

personnel are pre- requisites to successful validation.


25/76

Stages of Process Validation

` The activities relating to validation studies may be classified into

three stages:

Stage 1: Process Design

` This is the step where building and capturing of the process

knowledge and understanding took place. Early design of processes

and experiments should be performed during this stage.

` It covers all activities relating to product research and development,

formulation, pilot batch studies, scale-up studies, transfer of

technology to commercial scale batches, establishing stability

conditions, storage and handling of in-process and finished dosage

forms, equipment qualification, installation qualification, master

production documents, operational qualification, process capability.

Also this is the stage in which the establishment of a strategy forprocess control is taking place using accumulation knowledge and

understanding of the process.


26/76

Stage 2: Process Qualification

` This stage is confirmation that the process design is

capable of reproducing the manufacturing process. Itconfirms that all established limits of the Critical

Process parameters are valid and that satisfactory

products can be produced even under worst case

conditions.` GMP compliant procedures must be followed in this

stage and successful completion of this stage is

necessary before commercial distribution of a

product.


27/76

Stage 3: Continued Process Verification

` The Validation Maintenance Stage requires frequentreview of all process related documents, including

validation audit reports to assure that there have been nochanges, deviations, failures, modifications to theproduction process, and that all SOPs have beenfollowed, including change control procedures.

`

Before any batch is distributed for marketing, themanufacturer must have full assurance of itsperformance. A successful validation program dependson the knowledge and understanding and the approachto control manufacturing processes. These include the

source of variation, the limitation of the detection of thevariation, and the attributes susceptible of the variation.


28/76

Prospective Validation` Defination : Establishment of documentary evidence, prior to

process implementation, that a process does what it purports

to do based on validation master plan.

` Prospective validation is conducted prior to the distributionof either a new product or a product made under a modifiedproduction process, where the modifications are significantand may affect the products characteristics.

` It is a pre-planned scientific approach and includes the initialstages of formulation development, process development,setting of process specifications, developing in-process tests,sampling plans, designing of batch records, defining rawmaterial specifications, completion of pilot runs, transfer oftechnology from scale-up batches to commercial size batches,

listing major process equipment and environmental controls.


29/76

Organization

` Prospective validation requires a planned program

and organization to carry it to successful completion.The organization must have clearly defined areas of

responsibility and authority for each of the groups

involved in the program so that the objective of

validating the process can be met.` The important point is that a defined structure exists,

is accepted, and is in operation. An effective project

management structure will have to be established in

order to plan, execute, and control the program.


30/76

Master Documentation

` An effective prospective validation program must besupported by documentation extending from product initiation

to full-scale production. The complete documentation packagecan be referred to as the master documentation file. It willaccumulate as a product concept progresses to the point ofbeing placed in full-scale production, providing as complete aproduct history as possible.

` The final package will be the work of many individual groupswithin the organization. It will consist of reports, procedures,protocols, specifications, analytical methods, and any othercritical documents pertaining to the formulation, process, andanalytical method development. The ideal documentation

package will contain a complete history of the final productthat is being manufactured.


31/76

Product Development

` Product development usually begins when an activechemical entity has been shown to possess the necessary

attributes for a commercial product. The product

development activities for the active chemical entity,

formulation, and process form the foundation upon whichthe subsequent validation data are built.

` Generally, product development activities can be

subdivided into formulation and process development,along with scale-up development.


32/76

Product development:

A. Formulation Development

` Formulation development provides the basic information onthe active chemical, the formula, and the impact of raw

materials or excipients on the product. Typical supportive data

generated during these activities may include the following:

` 1. Preformulation profile or characterization of the components

of the formula, which includes all the basic physical orchemical information about the active pharmaceutical

ingredients (API, or the chemical entity) and excipients.

` 2. Formulation profile, which consists of physical and chemical

characteristics required for the products, drug-excipient

compatibility studies, and the effect of formulation on in vitro

dissolution.


33/76

` 3. Effect of formulation variables on the bioavailability of the

product

` 4. Specific test methods` 5. Key product attributes and/or specifications

` 6. Optimum formulation

` 7. Development of cleaning procedures and test methods

` Formulation development should not be consideredcomplete until all those factors that could significantly alter

the formulation have been studied. Subsequent minor

changes to the formulation, however, may be acceptable,

provided they are thoroughly tested and are shown to have

no adverse effect on product.


34/76

` B. Process Development` The process development activities typically begin after the

formulation has been developed,dthey may also occur

simultaneously. The majority of the process developmentactivities occurdeither in the pilot plant or in the proposedmanufacturing plant. The process developmentdprogramshould meet the following objectives:

` 1. Develop a suitable process to produce a product that meetsall:

a. Product specificationsb. Economic constraintsc. Current good manufacturing practices (CGMPs)` 2. Identify the key process parameters that affect the product

attributes

` 3. Identify in-process specifications and test methods` 4. Identify generic and/or specific equipment that may be

required


35/76

` Stages of Process development

` 1. Design

` 2. Challenging of critical process parameters

` 3. Verification of the developed process


36/76

Development of Manufacturing Capability

` There must be a suitable production facility for every manufacturing

process that is developed. This facility includes buildings,

equipment, staff, and supporting functions. As developmentactivities progress and the process become more clearly defined,

there must be a parallel assessment of the capability to manufacture

the product. The scope and timing of the development of

manufacturing capability will be dependent on the process and the

need to utilize or modify existing facilities or establish new ones.

Full-Scale Process Development

` The development of the final full-scale production process proceeds

through the following steps:

` 1. Process scale-up studies

` 2. Qualification trials

` 3. Process validation runs


37/76

Process Scale-up Studies

` The transition from a successful pilot-scale process orresearch scale to a full scale process requires carefulplanning and implementation. Although a large amount ofinformation has been gathered during the developmentof the process (i.e., process characterization and processverification studies), it does not necessarily follow thatthe full-scale process can be completely predicted. Manyscale-up parameters are nonlinear.

` In fact, scale-up factors can be quite complex anddifficult to predict, based only on experience with smaller-scale equipment. For some processes, the transition

from pilot scale or research scale to full scale is relativelyeasy and orderly. For others the transition is lesspredictable.


38/76

Qualification trials

` Once the scale-up studies have been completed, it may be

necessary to manufacture one or more batches at full scaleto confirm that the entire manufacturing process,

comprising several different unit operations, can be carried

out smoothly. This may occur prior to or after the regulatory

submission, depending on the strategy used in filing.


39/76

Process validation runs

` After the qualification trials have been completed, the

protocol for the full-scale process validation runs can bewritten. Current industry standard for the validation batches

is to attempt to manufacture them at target values for both

process parameters and specifications. The validation

protocol is usually the joint effort of the following groups:

` Research and development

` Pharmaceutical technology or technical services

` Quality control (quality assurance)

` Manufacturing

` Engineering


40/76

`Concurrent process validation:Definition: Establishment of documentary evidence of

what a system does or purports to do based on informationgenerated during implementation of system.

` A process where current production batches are used tomonitor processing parameters. It gives assurance of thepresent batch being studied, and offers limited assuranceregarding consistency of quality from batch to batch.Concurrent validation is carried out during normalproduction. This method is effective only if thedevelopment stage has resulted in a properunderstanding of the fundamentals of the process.


41/76

` The first three production-scale batches must be monitored

as comprehensively as possible. (This careful monitoring of

the first three production batches is sometimes regarded as

prospective validation.)` The nature and specifications of subsequent in-process and

final tests are based on the evaluation of the results of such

monitoring. Concurrent validation together with a trend

analysis including stability should be carried out to an

appropriate extent throughout the life of the product.Concurrent validation may be the practical approach under

certain circumstances.

` Examples of these may be when:

A previously validated process is being transferred to a third

party contract manufacturer or to another manufacturing site.


42/76

.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 number of batches produced is limited (e.g. orphan drugs).

Process with low production volume per batch ( e.g.

radiopharmaceuticals, anti-cancer)

Process of manufacturing urgently needed drugs due to shortage(or absence) of supply.


43/76

` It is important in these cases however, that thesystems and equipment to be used have been fullyvalidated previously. The justification for conductingconcurrent validation must be documented and theprotocol must be approved by the Validation Team.

` A report should be prepared and approved prior tothe sale of each batch and a final report should be

prepared and approved after the completion of allconcurrent batches.

` It is generally considered acceptable that a minimumof three consecutive batches within the finally agreed

parameters, giving the product the desired qualitywould constitute a proper validation of the process.


44/76

` Retrospective process validation

` Definition: Establishment of documentary evidence of what asystem does or purports to do based on review and analysis of

existing information.

` It is validation of a process for a product already in distribution

based upon accumulated production, testing and control data.Retrospective validation is used when historical data is available for

existing manufacturing processes. Types of useful data include

design drawings and specifications, operating procedures and work

instructions, manufacturing instructions, inspection reports,

production logs, production test data, material review reports,service records, customer complaints, and audit reports.

Retrospective validation may not be feasible if accumulated data is

incomplete or inadequate.


45/76

` 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 thenevaluated. Recorded difficulties and failure in production are

analyzed to determine the limits of process parameters.

` A trend analysis may be conducted to determine the extent to

which process parameters are within the permissible range.


46/76

` Retrospective validation is obviously not a quality assurance

measure in itself, and should never be applied to new processes or

products. It may be considered in special circumstances only, e.g.

when validation requirements are first introduced in a company.` Retrospective validation may then be useful in establishing the

priorities for the validation program. If the results of a retrospective

validation are positive, this indicates that the process is not in need

of immediate attention and may be individual accordance with the

normal schedule.` For tablets, which have been compressed under individual pressure

sensitive cells, and with qualified equipment, retrospective validation

is the most comprehensive test of the overall manufacturing process

of this dosage form. On the other hand, it should not be applied in

the manufacture of sterile products.


47/76

` For the purpose of retrospective validation studies, it is considered

acceptable that data from a minimum of ten consecutive batches produced

be utilized. When less than ten batches are available, it is considered that

the data are not sufficient to demonstrate retrospectively that the process isfully under control. In such cases the study should be supplemented with

data generated with concurrent or prospective validation. 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.

` Current specifications for active materials/finished products.

` List of process deviations, corrective actions and changes to manufacturing

documents.` Data for stability testing for several batches.

` Trend analyses including those for quality related complaints.


48/76

`Revalidation` Revalidation is needed to ensure that changes in the process and/or

in the process environment, whether intentional or unintentional, donot adversely affect process characteristics and product quality.` Revalidation may be divided into two broad categories:` Revalidation after any change having a bearing on product quality.` Periodic revalidation carried out at scheduled intervals.

` Revalidation after changes. Revalidation must be performed onintroduction of any changes affecting a manufacturing and/orstandard procedure having a bearing on the established productperformance characteristics. Such changes may include those instarting material, packaging material, manufacturing processes,equipment, in-process controls, manufacturing areas, or supportsystems (water, steam, etc.). Every such change requested shouldbe reviewed by a qualified validation group, which will decidewhether it is significant enough to justify revalidation and, if so, itsextent.


49/76

` Revalidation after changes may be based on the performanceof the same tests and activities as those used during theoriginal validation, including tests on sub processes and onthe equipment concerned. Some typical changes whichrequire revalidation include the following:

` Changes in the starting material(s). Changes in the physicalproperties, such as density, viscosity, particle size distribution,and crystal type and modification, of the active ingredients orexcipients may affect the mechanical properties of the

material; as a consequence, they may adversely affect theprocess or the product.` Changes in the packaging material, e.g. replacing plastics by

glass, may require changes in the packaging procedure andtherefore affect product stability.

` Changes in the process, e.g. changes in mixing time, drying

temperature and cooling regime, may affect subsequentprocess steps and product quality.


50/76

` Changes in equipment, including measuring instruments, may

affect both the process and the product; repair and maintenance

work, such as the replacement of major equipment components,

may affect the process.

` Changes in the production area and support system, e.g. the

rearrangement of manufacturing areas and/or support systems,

may result in changes in the process. The repair and

maintenance of support systems, such as ventilation, may

change the environmental conditions and, as a consequence,

revalidation/requalification may be necessary, mainly in the

manufacture of sterile products.

` Unexpected changes and deviations may be observed during

self-inspection or audit, or during the continuous trend analysis

of process data.


51/76

` Installation qualification (IQ)

` Establishing by objective evidence that all key aspects of the process equipmentand ancillary system installation adhere to the manufacturers approved

specification and that the recommendations of the supplier of the equipment are

suitably considered.

` Simply put, IQ means is it installed correctly?

` Important IQ considerations are:

` Equipment design features (i.e. materials of construction cleanability, etc.)

` Installation conditions (wiring, utilities, functionality, etc.)

` Calibration, preventative maintenance, cleaning schedules

` Safety features

` Supplier documentation, prints, drawings and manuals

` Software documentation

` Spare parts list

` Environmental conditions (such as clean room requirements, temperature, humidity)


52/76

` Sometimes activities are conducted at the equipment suppliers

site location prior to equipment shipment. Equipment suppliers

may perform test runs at their facilities and analyze the results

to determine that the equipment is ready to be delivered.

` Copies of the suppliers qualification studies should be used as

guides, to obtain basic data, and to supplement installation

qualification.

` However, it is usually insufficient to rely solely upon the

validation results of the equipment supplier. Each medical

device manufacturer is ultimately responsible for evaluating,

challenging, and testing the equipment and deciding whether

the equipment is suitable for use in the manufacture of a specific

device(s). The evaluations may result in changes to the

equipment or process.


53/76

` Operational qualification - (OQ)

` Establishing by objective evidence process control limits and actionlevels which result in product that meets all predeterminedrequirements.

` In this phase the process parameters should be challenged toassure that they will result in a product that meets all definedrequirements under all anticipated conditions of manufacturing, i.e.,worst case testing.

` During routine production and process control, it is desirable tomeasure process parameters and/or product characteristics to allowfor the adjustment of the manufacturing process at various actionlevel(s) and maintain a state of control. These action levels shouldbe evaluated, established and documented during process

validation to determine the robustness of the process and ability toavoid approaching worst case conditions.

OQ id i i l d


54/76

OQ considerations include:`Process control limits (time, temperature, pressure, line

speed, setup conditions, etc.)`Software parameters`Raw material specifications`Process operating procedures`Material handling requirements`Process change control

`Training`Short term stability and capability of the process,(latitude studies or control charts)

`Potential failure modes, action levels and worst-caseconditions (Failure Mode and Effects Analysis, Fault

Tree Analysis)`The use of statistically valid techniques such asscreening experiments to establish key processparameters and statistically designed experiments tooptimize the process can be used during this phase.

P f lifi ti (PQ)


55/76

Performance qualification - (PQ)` Establishing by objective evidence that the process,

under anticipated conditions, consistently produces a

product which meets all predetermined requirements.

` In this phase the key objective is to demonstrate theprocess will consistently produce acceptable productunder normal operating conditions.

` Methods and tools for process validation.

` PQ considerations include:` Actual product and process parameters and procedures

established in OQ Acceptability of the product.` Assurance of process capability as est ablished in OQ

Process repeatability, long term process stability


56/76

` Challenges to the process should simulate conditionsthat will be encountered during actual manufacturing.Challenges should include the range of conditions as

defined by the various action levels allowed in writtenstandard operating procedures as established in the OQphase. The challenges should be repeated enough timesto assure that the results are meaningful and consistent.

` Process and product data should be analyzed to

determine what the normal range of variation is for theprocess output. Knowing the normal variation of theoutput is crucial in determining whether a process isoperating in a state of control and is capable ofconsistently producing the specified output. One of the

outputs of OQ and PQ is the development of attributesfor continuous monitoring and maintenance.

P d d t d t h ld l b l d t id tif


57/76

` Process and product data should also be analyzed to identifyany variation due to controllable causes. Depending on thenature of the process and its sensitivity, controllable causes ofvariation may include:

` Temperature` Humidity` Variations in electrical supply` Vibration` Environmental contaminants

` Purity of process water` Light` Human factors (training, ergonomic factors, stress, etc.)` Variability of materials` Wear and tear of equipment

` Appropriate measures should be taken to eliminatecontrollable causes of variation. Eliminating controllablecauses of variation will reduce variation in the process outputand result in a higher degree of assurance that the output willconsistently meet specifications.


58/76


59/76


60/76


61/76


62/76


63/76


64/76


65/76


66/76


67/76


68/76


69/76


70/76


71/76


72/76


73/76


74/76


75/76


76/76

process validation nishit

Documents