These guidelines outline the general principles that the Inspectorate considers to be acceptable elements
validation studies are conducted in accordance with pre-defined protocols. Written reports
summarizing recorded results and conclusions are prepared, evaluated, approved and
changes to production processes, operating parameters, equipment or materials that may
affect product quality and/or the reproducibility of the process are also to be validated prior
These guidelines are not intended to specify how validation is to be conducted, but are indicators of what
is expected to be covered by fabricators, packagers/labellers.
The elements of validation presented in these guidelines are not intended to be all-encompassing. The
particular requirements of validation may vary according to factors such as the nature of drug products eg.
sterile, non-sterile, biologicals, and the complexity of the process. The concepts provided in these
guidelines have general applicability and provide an acceptable framework for establishing a
comprehensive approach to validation.
CHANGE CONTROL (contrôle des changements): A written procedure that describes the action to be
taken if a change is proposed (a) to facilities, materials, equipment, and/or processes used in the
fabrication, packaging, and testing of drugs, or (b) that may affect the operation of the quality or support
CLEANING VALIDATION (validation des procédés de nettoyage): The documented act of
demonstrating that cleaning procedures for the equipment used in fabricating/packaging will reduce to an
acceptable level all residues (products/cleaning agents) and to demonstrate that routine cleaning and
storage of equipment does not allow microbial proliferation.
CONCURRENT VALIDATION (validation concomitante): Aprocess where current production batches
are used to monitor processing parameters. It gives assurance of the present batch being studied, and offers
limited assurance regarding consistency of quality from batch to batch.
CRITICAL PROCESS PARAMETER (paramètre critique du procédé): A parameter which if not
controlled will contribute to the variability of the end product.
EQUIPMENT QUALIFICATION (qualification de l’équipement): Studies which establish with
confidence that the process equipment and ancillary systems are capable of consistently operating within
established limits and tolerances. The studies must include equipment specifications, installation
qualification, and operational qualification of all major equipment to be used in the manufacture of
commercial scale batches. Equipment Qualification should simulate actual production conditions,
including "worst case"/ stressed conditions.
INSTALLATION QUALIFICATION (qualification d'installation): The documented act of
demonstrating that process equipment and ancillary systems are appropriately selected and correctly
Health Canada / Health Products and Food Branch Inspectorate
Validation Guidelines For Pharmaceutical Dosage Forms / August 200
MAJOR EQUIPMENT (équipement principal): A piece of equipment which performs significant
processing steps in the sequence of operations required for fabrication/packaging of drug products. Some
examples of major equipment include tablet compression machines, mills, blenders, fluid bed dryers,
heaters, drying ovens, tablet coaters, encapsulators, fermentors, centrifuges, etc.
MASTER PRODUCTION DOCUMENT (document-type de production): A document that includes
specifications for raw material, for packaging material and for packaged dosage form, master formula,
sampling procedures, and critical processing related SOPs, whether or not these SOPs are specifically
referenced in the master formula.
MEASURING DEVICES (instruments de mesure): A device used in monitoring or measuring process
OPERATIONAL QUALIFICATION (qualification opérationelle): The documented action of
demonstrating that process equipment and ancillary systems work correctly and operate consistently in
accordance with established specifications.
PROCESS CAPABILITY (capacité du procédé): Studies conducted to identify the critical process
parameters that yield a resultant quality, and their acceptable specification ranges, based on the established
+/- 3 sigma deviations of the process, under stressed conditions but when free of any assignable causes.
PROCESS QUALIFICATION(qualification du procédé): The phase of validation dealing with sampling
and testing at various stages of the manufacturing process to ensure that product specifications are met.
PROCESS RE-VALIDATION (revalidation du procédé): Required when there is a change in any of the
critical process parameters, formulation, primary packaging components, raw material fabricators, major
equipment or premises. Failure to meet product and process specifications in sequential batches would
also require process re-validation.
PROCESS VALIDATION (validation du procédé): Establishing documented evidence with a high degree
of assurance, that a specific process will consistently produce a product meeting its predetermined
specifications and quality characteristics. Process validation may take theformofProspective,Concurrent
or Retrospective Validation and Process Qualification or Re-validation.
PROSPECTIVE VALIDATION (validation prospective): Conducted prior to the distribution of either
a new product or a product made under a modified production process, where the modifications are
significant and may affect the product’s characteristics. It is a pre-planned scientific approach and includes
the initial stages of formulation development, process development, setting of process specifications,
developing in-process tests, sampling plans, designing of batch records, defining raw material
specifications, completion of pilot runs, transfer of technology from scale-up batches to commercial size
batches, listing major process equipment and environmental controls.
RETROSPECTIVE VALIDATION (validation rétrospective): Conducted for a product already being
marketed, and is based on extensive data accumulated over several lots and over time. Retrospective
Validation may be used for older products which were not validated by the fabricator at the time that they
were first marketed, and which are now to be validated to conform to the requirements of VALIDATION (validation): The documented act of demonstrating that any procedure, process, and
activity will consistently lead to the expected results. Includes the qualification ofsystems and equipment.
VALIDATION MASTER PLAN (plan maître de validation): An approved written plan ofobjectives and
actions stating how and when a company will achieve compliance with the GMP requirements regarding
VALIDATION PROTOCOL (protocole de validation): A written plan of actions stating how process
validation will be conducted; it will specify who will conduct the various tasks and define testing
parameters; sampling plans, testing methods and specifications; will specify product characteristics, and
equipment to be used. It must specify the minimum number of batches to be used for validation studies;
it must specify the acceptance criteria and who will sign/approve/ disapprove the conclusions derived from
such a scientific study.
VALIDATION TEAM (équipe de validation): A multi-disciplinary team of personnel primarily
responsible for conducting and/or supervising validation studies. Such studies may be conducted by
person(s) qualified by training and experience in a relevant discipline.
WORST CASE CONDITION (condition de la pire éventualité): The highest and /or lowest value of a
given parameter actually evaluated in the validation exercise.
Phases of Validation
The activities relating to validation studies may be classified into three phases:
Pre-Validation Phase or the Qualification Phase, which 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.
Process Validation Phase (Process Qualification phase) designed to verify that all established limits ofthe
Critical Process Parameters are valid and that satisfactory products can be produced even under the “worst
Validation Maintenance Phase requiring frequent review of all process related documents, including
validation audit reports to assure that there have been no changes, deviations, failures, modifications to
the production process, and that all SOPs have been followed, including Change Control procedures.
At this stage the Validation Teamalso assures that there have been no changes/ deviations that should have
resulted in Requalification and Revalidation.
Quality, safety and effectiveness must be built into the product. This requires careful attention to a number
of factors such as the selection of quality materials/components, product and process design, control of
processes, in-process control, and end-product testing.
Due to the complexity of the drug products, routine end-product testing alone is not sufficient due to
several reasons. Furthermore, quality cannot be tested into the finished drug product but rather be built
in the manufacturing processes and these processes should be controlled in order that the finished product
meets all quality specifications. A careful design and validation of systems and process controls can
establish a high degree of confidence that all lots or batches produced will meet their intended
A written plan stating how validation will be conducted, including test parameters, product characteristics,
production and packaging equipment, and decision points on what constitutes acceptable test results. This
document should give details of critical steps of the manufacturing process that should be measured, the
allowable range of variability and the manner in which the system will be tested.
The validation protocol provides a synopsis of what is hoped to be accomplished. The protocol should list
the selected process and control parameters, state the number of batches to be included in the study, and
specifyhow the data, once assembled, will be treated for relevance. The date ofapproval by the validation
team should also be noted.
In the case where a protocol is altered or modified after its approval, appropriate reasoning for such a
change must be documented.
The validation protocol should be numbered, signed and dated, and should contain as a minimum the
objectives, scope of coverage of the validation study
validation team membership, their qualifications and responsibilities
type of validation: prospective, concurrent, retrospective, re-validation
number and selection of batches to be on the validation study
a list of all equipment to be used; their normal and worst case operating parameters
outcome of IQ, OQ for critical equipment
requirements for calibration of all measuring devices
critical process parameters and their respective tolerances
description of the processing steps: copy of the master documents for the product
sampling points, stages of sampling, methods of sampling, sampling plans
statistical tools to be used in the analysis of data
training requirements for the processing operators
validated test methods to be used in in-process testing and for the finished product
specifications for raw and packaging materials and test methods
forms and charts to be used for documenting results
format for presentation of results, documenting conclusions and for approval of study results.
Validation Master Plan
A validation master plan is a document that summarises the company’s 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. In addition, all work should be carried out in a structured way according to formally authorised
standard operating procedures. All observations must be documented and wherepossiblemustberecorded
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 retrospective validations as well as re-validation.
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, SOP’s 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 extra attention
list of products/ processes/ systems to be validated, summarized in a matrix format, validation
re-validation activities, actual status and future planning
key acceptance criteria
reference to the required SOP’s
time plans of each validation project and sub-project.
Installation and Operational Qualification
The detail and scope of a qualification exercise is in many respects related to the complexity of the
equipment involved and the critical nature of that equipment with respect to the quality of the final
product. Installation and Operational Qualification exercises assure through appropriate performance tests
related documentation that equipment, ancillary systems and sub-systems have been commissioned
correctly. The end results are that all future operations will be reliable and within prescribed operating
The basic principles are:
equipment be correctly installed in accordance with an installation plan
requirements for calibration, maintenance and cleaning be covered in approved SOP’s
tests be conducted to assure that equipment is operating correctly, under normal and “worst case”
operator training requirements pertaining to new equipment be conducted and documented.
At various stages in a validation exercise there is need for protocols, documentation, procedures,
equipment, specifications and acceptance criteria for test results. All these need to be reviewed, checked
and authorised. It would be expected that representatives from the appropriate professional disciplines,
eg. Engineering , Research and Development, Manufacturing, Quality Control and Quality Assurance be
actively involved in these undertakings with the final authorisation given by a validation team or the
Quality Assurance representative.
Installation Qualification (IQ):
I.Q. is the method of establishing with confidence that all major processing, packaging equipment and
ancillary systems are in conformance with installation specifications, equipment manuals, schematics and
engineering drawings. This stage of validation includes examination of equipment design, determination
of calibration, maintenance and adjustment requirements.
For complicated or large pieces of equipment, a pharmaceutical manufacturer may elect to undertake a pre-
delivery check of the equipment at the supplier’s assembly facility. This pre-delivery check cannot
substitute for the Installation Qualification. However, it is acknowledged that the checks conducted and
documented at this stage may duplicate a number of the checks conducted at the I.Q. stage, thus leading
to a reduction in the scope of the I.Q. checks.
All equipment, gauges and services should be adequately identified and should be given a serial number
or other reference number. This number should appear in the reports for the equipment validation studies
Installation qualification requires a formal and systematic check of all installed equipment against the
equipment supplier’s specifications and additional criteria identified by the user as part of the purchase
specifications. These checks, tests and challenges should be repeated a significant number of times to
assure reliable and meaningful results.
At the I.Q. stage the company should document preventive maintenance requirements for installed
equipment. The preventive maintenance schedule should be incorporated into the routine maintenance
There will be cases where installation of the equipment had not been qualified at the time of installation,
and the engineering drawings and manuals for the equipment are no longer available at the manufacturing
site. However, the equipment in place operates for a lengthy period of time without any problem or
modifications of its design since it was first installed. In such situations, the Inspectorate considers that
it may be appropriate for those specific cases to verify a limited number of the most critical parameters
demonstrating that the equipment had been adequately installed. Thereafter, the company could pass
directly to the operational qualification (O.Q.) stage if there is sufficient documented evidence that these
units have always been well maintained and calibrated according to an adequate pre-established schedule.
Operational Qualification (OQ):
The conduct of an Operational Qualification should follow an authorised protocol. The critical operating
parameters for the equipment and systems should be identified at the O.Q. stage. The plans for the O.Q.
should identify the studies to be undertaken on the critical variables, the sequence of those studies and the
measuring equipment to be used and the acceptance criteria to be met.
Studies on the critical variables should include a condition or a set of conditions encompassing upper and
lower processing and operating limits referred to as “worst-case” conditions. The completion of a
successful O.Q. should allow the finalisation of operating procedures and operator instructions
documentation for the equipment. This information should be used as the basis for training of operators
in the requirements for satisfactory operation of the equipment.
The completion of satisfactory I.Q. and O.Q. exercises should permit a formal “release” of the equipment
for the next stage in the process validation exercise as long as calibration, cleaning, preventive
maintenance and operator training requirements have been finalised and documented.
Modifications to, or relocation of equipment should follow satisfactory review and authorization of the
documented change proposal through the change control procedure. This formal review should include
consideration of re-qualification of the equipment. Minor changes or changes having no direct impact on
final or in-process product quality should be handled through the documentationsystemofthe preventative
It would normally be expected that process validation be completed prior to the distribution of a finished
product that is intended for sale (Prospective Validation). Where this is not possible, it may be necessary
to validate processes during routine production (Concurrent Validation). Processes which have been in
use for sometime without any significant changes may also be validated according to an approved protocol
In Prospective Validation, the validation protocol is executed before the process is put into commercial
use. During the product development phase the production process should be broken down into individual
steps. Each step should be evaluated on the basis of experience or theoretical considerations to determine
the critical parameters that may affect the quality of the finished product. A series of experiments should
be designed to determine the criticality of these factors. Each experiment should be planned and
documented fully in an authorised protocol.
All equipment, production environment and the analytical testing methods to be used should have been
fully validated. Master batch documents can be prepared only after the critical parameters of the process
have been identified and machine settings, component specifications and environmental conditions have
Using this defined process a series of batches should be produced. In theory, the number of process runs
carried out and observations made should be sufficient to allow the normal extent of variation and trends
to be established to provide sufficient data for evaluation. It is generally considered acceptable that three
consecutive batches/runs within the finally agreed parameters, giving product of the desired quality would
constitute a proper validation of the process. In practice, it may take someconsiderable time to accumulate
Some considerations should be exercised when selecting the process validation strategy. Amongst these
should be the use of different lots of active raw materials and major excipients, batches produced on
different shifts, the use of different equipment and facilities dedicated for commercial production,
operating range of the critical processes, and a thorough analysis of the process data in case of
Requalification and Revalidation.
During the processing of the validation batches, extensive sampling and testing should be performed on
the product at various stages, and should be documented comprehensively. Detailed testing should also
be done on the final product in its package.
Upon completion of the review, recommendations should be made on the extent of monitoring and the in-
process controls necessary for routine production. These should be incorporated into the Batch
manufacturing and packaging record or into appropriate standard operating procedures. Limits,
frequencies and actions to be taken in the event of the limits being exceeded should be specified.
Matrix or “Family” approaches to prospective process validation:
It may be possible and acceptable in particular circumstances for a manufacturer that uses the sameprocess
for several related products to develop a scientifically sound validation plan for that process rather than
different plans for each product manufactured by that process.
The matrix approach generally means a plan to conduct process validation on different strengths of the
same product, whereas the “family” approach means a plan to conduct process validation on different
The validation process using these approaches must include batches of different strengths or products
which should be selected to represent the worst case conditions or scenarios to demonstrate that the process
is consistent for all strengths or products involved.
Unconditional use of this approach is not encouraged by the Inspectorate and is not acceptable as being
the “norm”. In using this approach there is always the risk of having to modify process parameters or
specifications over a period of time. This situation often leads to questions regarding disposition of the
batches that had already been released for sale, subsequently known to have undesired quality
Concurrent validation may be the practical approach under certain circumstances. Examples of these may
when a previously validated process is being transferred to a third party contract
manufacturer or to another manufacturing site
where the product is a different strength of a previously validated product with the same
ratio of active / inactive ingredients
when 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
when the number of batches produced are limited (e.g. orphan drugs).
It is important in these cases however, that the systems and equipment to be used have been fully validated
previously. The justification for conducting concurrent validation must be documented and the protocol
must be approved by the Validation Team. A report should be prepared and approved prior to the sale of
each batch and a final report should be prepared and approved after the completion of all concurrent
batches. It is generally considered acceptable that a minimum of three consecutive batches within the
finally agreed parameters, giving the product the desired quality would constitute a proper validation of
In many establishments, processes that are stable and in routine use have not undergone a formally
documented validation process. Historical data may be utilized to provide necessary documentary
evidence that the processes are validated.
The steps involved in this type of validation still require the preparation of a protocol, the reporting of the
results of the data review, leading to a conclusion and recommendation.
Retrospective validation is only acceptable for well established detailed processes that include operational
limits for each critical step of the process and will be inappropriate where there have been recent changes
in the formulation of the product, operating procedures, equipment and facility.
The source of data for retrospective validation should include amongst others, batch documents, process
control charts, maintenance log books, process capability studies, finished product test results, including
trend analyses, and stability results.
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 is fully under control. In
such cases the study should be supplemented with data generated with concurrent or prospective
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
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
Re-validation provides the evidence that changes in a process and /or the process environment that are
introduced do not adversely affect process characteristics and product quality. Documentation
requirements will be the same as for the initial validation of the process.
Periodic review and trend analysis should be carried out at scheduled intervals. Re-validation becomes
necessary in certain situations. The following are examples of some of the planned or unplanned changes
that may require re-validation:
Changes in raw materials (physical properties such as density, viscosity, particle size
distribution, and moisture, etc., that may affect the process or product).
Changes in the source of active raw material manufacturer
Changes in packaging material (primary container/closure system).
Changes in the process (e.g., mixing time, drying temperatures and batch size)
Changes in the equipment (e.g. addition of automatic detection system). Changes of
equipment which involve the replacement of equipment on a “like for like” basis would not
normally require a re-validation except that this new equipment must be qualified.
Changes in the plant/facility.
Variations revealed by trend analysis (e.g. process drifts)
A decision not to perform re-validation studies must be fully justified and documented.
Written procedures should be in place to describe the actions to be taken if a change is proposed to a
product component, process equipment, process environment, processing site, method of production or
testing or any other change that may affect product quality or support system operations.
All changes must be formally requested, documented and accepted by the Validation Team. The likely
impact / risk of the change on the product must be assessed and the need for the extent of re-validation
should be determined.
Commitment of the company to control all changes to premises, supporting utilities, systems, materials,
equipment and processes used in the fabrication/packaging of pharmaceutical dosage forms is essential
to ensure a continued validation status of the systems concerned.
The change control system should ensure that all notified or requested changes are satisfactorily
investigated, documented and authorised. Products made by processes subjected to changes should not
be released for sale without full awareness and consideration of the change by the Validation Team. The
Team should decide if a re-validation must be conducted prior to implementing the proposed change.
Guidelines on General Principles of Process Validation, CDER, US-FDA 1987
Pharmaceutical Process Validation; 2
edition, Editors: I. R. Berry and R.A. Nash, 1993
Recommendations on Validation Master Plan, Installation and Operational Qualification, Non-
Sterile Process Validation, Cleaning Validation, PIC/S, August 2001