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  • 8/4/2019 Process Validation Nishit


    Nishitkumar S. Patel

    Assistant Professor

    Dharmaj Degree Pharmacy College,Dharmaj.

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    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.

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    ` 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.

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    ` 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


    ` 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)

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    ` 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.

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    ` 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.

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    ` The implementation of validation work requires considerable

    resources such as:

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


    ` 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


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    ` 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.

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    Scope of Validation.

    ` Principles may be useful:

    in production and control of active harmaceutical

    ingredients (APIs) and finished pharmaceutical


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

    and a detailed approach beyond the scope of the


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    ` 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

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    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

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    ` 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.

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    ` 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.


    1. Validation Coordinator

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

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    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

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    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



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

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    ` 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.

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    ` 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.

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    ` 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.

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    ` 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.

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    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.

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    ` Prospective process validation

    ` Concurrent process validation

    ` Retrospective process validation

    ` Revalidation

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    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.

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    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.

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    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


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    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.

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    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.

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    ` 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.

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    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.

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    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.

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    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


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


    ` 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.

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    ` 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


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


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    ` Stages of Process development

    ` 1. Design

    ` 2. Challenging of critical process parameters

    ` 3. Verification of the developed process

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    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

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    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.

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    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.

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    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

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    `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.

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    ` 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.

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    .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.

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    ` 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.

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    ` 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.

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    ` 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.

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    ` 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.

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    ` 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.

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    `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.

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    ` 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.

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    ` 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.

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    ` 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)

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    ` 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


    ` 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.

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    ` 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

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    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)

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    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

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    ` 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

  • 8/4/2019 Process Validation Nishit


    ` 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.

  • 8/4/2019 Process Validation Nishit


  • 8/4/2019 Process Validation Nishit


  • 8/4/2019 Process Validation Nishit


  • 8/4/2019 Process Validation Nishit


  • 8/4/2019 Process Validation Nishit


  • 8/4/2019 Process Validation Nishit


  • 8/4/2019 Process Validation Nishit


  • 8/4/2019 Process Validation Nishit


  • 8/4/2019 Process Validation Nishit


  • 8/4/2019 Process Validation Nishit


  • 8/4/2019 Process Validation Nishit


  • 8/4/2019 Process Validation Nishit


  • 8/4/2019 Process Validation Nishit


  • 8/4/2019 Process Validation Nishit


  • 8/4/2019 Process Validation Nishit


  • 8/4/2019 Process Validation Nishit


  • 8/4/2019 Process Validation Nishit


  • 8/4/2019 Process Validation Nishit


  • 8/4/2019 Process Validation Nishit