GUIDELINES FOR VALIADATION

1.0 Scope

This Guidance document has been prepared to provide guidance to the pharmaceutical industry in dealing with validation issues for sterile and non-sterile dosage forms, biologicals, and radiopharmaceuticals. It should be noted that additional guidance related to sterile products and not contained in this document should also be considered. These requirements may be found in supplemental process validation guidelines available on the Compliance and Enforcement website.
It is expected that importers and distributors of drug products have documented evidence that their vendors meet validation requirements.

2.0 Introduction

This document provides guidance on issues and topics related to systems, equipment qualification, product and process validation for sterile and non-sterile dosage forms. These topics reflect an area in pharmaceutical, biological, and, radiopharmaceuticals manufacture that is noted as being important by both the Inspectorate and the pharmaceutical industry. These guidelines have been prepared to provide guidance to inspectors, evaluators and the industry in dealing with issues related to validation. Utilization of this information should facilitate compliance with Division 2, Part C of the Regulations to the Food and Drugs Act.
It is not intended that the recommendations made in these guidelines become requirements under all circumstances. Information provided in the Interpretation section for limits to be applied in defined circumstances, as well as the number of batches to be utilized for validation studies are for guidance purposes only. Inspectors, evaluators and the industry may consider other alternate means if proposed and documented with appropriate scientific justification.

3.0 Purpose

These guidelines outline the general principles that the Inspectorate considers to be acceptable elements of validation which may be used by fabricators, packagers/labellers for drug products. The Guidelines on Good Manufacturing Practices (GMP), Division 2, Part C of the Food and Drug Regulations require that:

• all critical production processes be validated
• validation studies are conducted in accordance with pre-defined protocols. Written reports summarizing recorded results and conclusions are prepared, evaluated, approved and maintained
• 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 to implementation.

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 e.g. 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.

4.0 Definitions

Change Control: 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 system.
Cleaning Validation: 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: A process 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: A parameter which if not controlled will contribute to the variability of the end product.
Equipment Qualification: 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 (IQ), and operational qualification (OQ) 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: The documented act of demonstrating that process equipment and ancillary systems are appropriately selected and correctly installed.
Major Equipment: 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: A document that includes specifications for raw material, for packaging material and for packaged dosage form, master formula, sampling procedures, and critical processing related standard operating procedures (SOPs), whether or not these SOPs are specifically referenced in the master formula.
Measuring Devices: A device used in monitoring or measuring process parameters.
Operational Qualification: The documented action of demonstrating that process equipment and ancillary systems work correctly and operate consistently in accordance with established specifications.
Process Capability: 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: 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: 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: 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 the form of prospective, concurrent or retrospective validation and process qualification or re-validation.
Prospective Validation: 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: 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 Division 2, Part C of the Regulations to the Food and Drugs Act.
Validation: The documented act of demonstrating that any procedure, process, and activity will consistently lead to the expected results. Includes the qualification of systems and equipment.
Validation Master Plan: An approved written plan of objectives and actions stating how and when a company will achieve compliance with the GMP requirements regarding validation.
Validation Protocol: 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: 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: The highest and /or lowest value of a given parameter actually evaluated in the validation exercise.

5.0 Phases of Validation

The activities relating to validation studies may be classified into three phases:
Phase 1: 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.
Phase 2: Process validation phase (process qualification phase) designed to verify that all established limits of the critical process parameters are valid and that satisfactory products can be produced even under the "worst case" conditions.
Phase 3: 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 team also assures that there have been no changes/ deviations that should have resulted in requalification and revalidation.

6.0 Interpretation

General Concepts:

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 specifications.

Validation protocol:

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 specify how the data, once assembled, will be treated for relevance. The date of approval 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 following information:

• 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 where possible 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 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, summarised in a matrix format, validation approach
• re-validation activities, actual status and future planning
• key acceptance criteria
• documentation format
• 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 and 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 limits.
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" conditions
• 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, e.g. 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):

IQ 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 IQ stage, thus leading to a reduction in the scope of the IQ 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 conducted.
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 IQ stage the company should document preventive maintenance requirements for installed equipment. The preventive maintenance schedule should be incorporated into the routine maintenance schedule.
Note:
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 (OQ) 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 OQ stage. The plans for the OQ 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 OQ 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 IQ and OQ 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.

Re-Qualification:

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 documentation system of the preventative maintenance program.

Process Validation:

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 some time without any significant changes may also be validated according to an approved protocol (retrospective validation).

a) Prospective Validation:

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 been determined.
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 some considerable time to accumulate these data.
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 same process 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. However, discrete manufacturing steps such as compression, and coating that involve different tools, equipment, and process conditions for the different dosage strengths can not be generally validated using the matrix approach. It should be recognized that the matrix approach has limitations when there are concerns with respect to physical characteristics such as flow properties, particle size distribution, homogeneity.
The "family" approach means a plan to conduct process validation on different products manufactured with the same processes using the same equipment.
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.

b) Concurrent Validation:

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 characteristics.
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
• 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 the process.

c) Retrospective Validation:

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, annual product quality review reports, 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 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

Process Re-Validation:

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.

Change Control:

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.

7.0 References

1. Guidelines on General Principles of Process Validation, CDER, US-FDA 1987
2. Pharmaceutical Process Validation; 2^nd edition, Editors: I. R. Berry and R.A. Nash, 1993
3. Recommendations on Validation Master Plan, Installation and Operational Qualification, Non-Sterile Process Validation, Cleaning Validation, PIC/S September, 2007.

Cleaning Validation Procedures

·        General concept

Ø      Three consecutive validations will be performed to prove that the method is validated.

Ø      Whenever a new product is introduced, equipment usage and nature of potential contaminant will be studied to assess whether it poses a challenging study for cleaning validation.

Ø      If the new product represents worst case, study/ identify/develop method of cleaning to be employed. Simultaneously develop Analytical method for cleaning and validate the same.

Ø      Revalidation Policy.

·        Level of cleaning:

Ø      Levels of cleaning during processing depends on:

o       Equipment usage (e.g. dedicated or not)

o       Stages of manufacturing

o       Nature of contaminant (e.g. solubility, toxicity, color etc.)

Ø      Our policy is to carry out cleaning after the end of each process, so that the equipment is clean and ready for the next use.

·        Elements of cleaning validation:

·        Cleaning validation study includes:

Ø      Cleaning Procedure

o       Identification of equipment

o       Characterization of products

o       Determination of cleaning agents

Ø      Analytical method and its validation

Ø      Sampling procedure

Ø      Establishment of acceptance criteria

Ø      Validation protocol

Ø      Validation Reports

·        Cleaning Procedure:

Ø      Prior to developing cleaning validation study, evaluate the following:

o       Identification of Equipments:

ü Identify equipments to be cleaned.

ü Identify difficult to clean areas

ü Check for ease of dismantling

o       Characterization of products:

ü  Study activity/toxicity, solubility of the active substance of current batch and dosage and batch size of next product to be taken on the equipment.

o       Determination of Cleaning Agents:

ü Identify cleaning agents to be used

ü Identify number of cleaning cycles

ü Identify equipments / materials to be used for cleaning.

o       Based on above, prepare detailed written cleaning procedures for each equipment.

·        Analytical Methods and its validation:

Ø      In order for the analytical testing of the cleaning validation samples to yield meaningful results, the analytical methods used should be validated.

Ø      Analytical method validation for cleaning should include limit of detection, limit of quantification, acceptance criteria and rationale for setting the specified limits.

·        Sampling Procedure:

Ø      Sampling plan for validation study should be drawn which includes:

Ø      Sampling technique: Type of Sampling methods to be used are,

o       Direct surface sampling by swab.

o       Rinse water sampling (for equipment cleaning).

o       Plate exposure (for area cleaning).

Ø      Sampling Locations:

o       Two easy to clean and two hard to clean areas should be clearly defined in Protocol.

Ø      Sampling Procedure:

o       Should mention how many samples are to be taken

ü Swab samples should be taken separately for chemical and microbiological studies

ü For each of chemical and microbiological analysis take 2 swabs from easy to clean hard to clean locations

ü How the samples are to be taken

Ø      Sample Numbering:

o       Swab samples should be numbered numerically and sequentially like 01, 02 etc for identification.

Ø      Establishment of Acceptance Criteria:

o       Based on the data available calculate acceptance criteria for both Pharmacological dose method and limiting the level of product to 10 ppm which appear in the following product.

o       Of these two, choose the criterion with stringent limits and detectable by analytical method.                                                                                          

o       Microbiological limit is 50 CFU/100 cm^2. Per swab

·        Validation Protocol

Ø      Validation protocol defines protocol number.

Ø      Protocol defines a validation team that will be responsible for carrying out validation studies. Validation team comprises of at least one responsible person from production, QC & QA department.

Ø      Responsibilities of team member are:-

o       Production – Carrying out cleaning methods & implementing validation protocol.

o       Quality Control – Developing analytical method for cleaning, sampling, testing & recording the results.

o       Quality Assurance – Issuing & reviewing of protocol, supervision of validation activities.

Ø      Validation protocol given details location, product manufactured, profile of active ingredient, cleaning agents used, testing equipment to be used, sampling points, sampling procedures, limit of detection acceptance calculation, surface area, validation report etc.

Ø      Responsible persons from Production, QC and QA should formally approve the cleaning validation protocol.

Ø      After approval Validation protocol is issued to QC Department.

Ø      QC will perform validation studies in accordance with protocol and record results in validation report.

·        Validation Procedure:

Ø      After completion of the manufacturing process, workman will clean the equipment.

Ø      If the cleaned equipment is listed in the protocol, production person will inform QC Department to collect samples for testing and QA department for supervision.

Ø      QA/QC chemist will first check visually for cleanliness of equipment.

Ø      If it observed not clean, instruct for re-cleaning.

Ø      If it observed visually cleaned, collect samples separately for both chemical and microbial analysis (if required) from locations given in the protocol as per sampling procedure.

Ø      Samples are carried to QC, where testing of the samples will be done using validated Analytical method.

·        Validation Report:

Ø      QC will record the results of testing in the protocol.

Ø      QC will return the protocol with documented results and attachments like work sheet, graphs, chromatograms etc. to QA for review.

Ø      After completion of documented studies, QA will write conclusions regarding acceptability of the results and status of procedures considered for validation.

Ø      Any recommendations based on the documented results will be mentioned.

Ø      References to the procedures used for cleaning, sampling and testing should be mentioned in the validation report.

Ø      All the members of validation team should approve conclusion

Ø      In cases where it is unlikely that further batches of the product will be manufactured for a period of time, it is advisable to generate interim reports on batch-to-batch basis till such time the cleaning validation study is complete.

Ø      If the results of validation of any of the three studies are non-conforming to set limits of acceptance criteria, QC should inform immediately to QA.

Ø      Further manufacturing process on the equipment/in the area should be suspended.

Ø      Re-validation should be performed.

Ø      Prior to re-validation, cleaning methods/procedures, sampling methods/ procedures and analytical procedures employed should be re-checked and reviewed.

·        Re-validation Policy:

Ø      Revalidation of validated cleaning procedures will be considered –

o     Once in a year, three replicate studies will be performed.

o     In case of changes in equipment/process of product

Ø      If the new product represents worst-case challenge

1.0  The result of inadequate cleaning procedures is that any of a number of contaminants may be present in the next batch manufactured on the equipment such as:

o       Precursors to the Active Pharmaceutical Ingredient

o       By-products and/or degradation products of the Active Pharmaceutical

         Ingredient

o       The previous product

o       Solvents and other materials employed during the manufacturing process.

o       Micro-organisms

         This is particularly the case where microbial growth may be sustained   by the product.

o       Cleaning agents themselves and lubricants

2.0 Cleaning techniques to be evaluated

o       Manual cleaning

o       CIP (Clean-in place)

o       COP (clean-out-of-place)

o       Semi automatic

o       Automatic

o       Time considerations

o       Number of cleaning cycles.

type Of Validation Procedures

T

1)         PROCESS VALIDATION

Ø         prospective validation

Ø         concurrent validation

Ø         retrorospective validation

2)         cleaning validation

3)         change control

4)         Re- validation

Cleaning validation

Documented evidence to establish that cleaning procedures are removing residues to predetermined levels of acceptability, taking into consideration factors such as batch size, dosing, and toxicology and equipment size.

Validation

Action of proving and documenting that any process, procedure or method actually and consistently leads to the expected results.

Process validation

Documented evidence which provides a high degree of assurance that a specific process will consistently result in a product that meets its predetermined specifications and quality characteristics

Concurrent validation

Validation carried out during routine production of products intended for sale.

Prospective validation

Validation carried out during the development stage on the basis of a risk analysis of the production process, which is broken down into individual steps; these are then evaluated on the basis of past experience to determine whether they may lead to critical situations.

Retrospective validation

Involves the evaluation of past experience of production on the condition that composition, procedures, and equipment remain unchanged.

- The sources of data for this validation may include batch   documents, process control chart, maintaince logbook, records of personnel change process capability studies, fp data and stability results.

Validation report (VR)

A document in which the records, results and evaluation of a completed validation programme are assembled and summarized. It may also contain proposals for the improvement of processes and/or equipment.

Process Validation Program

The number of process runs for validation should depend on the complexity of the process or the magnitude of the process change being considered. For prospective and concurrent validation, three consecutive successful production batches should be used as a guide, but there may be situations where additional process runs are warranted to prove consistency of the process

For retrospective validation, generally data from 10 to 30 consecutive batches should be examined to assess process consistency, but fewer batches can be examined if justified.

Critical process parameters should be controlled and monitored during process validation studies. Process parameters unrelated to quality, such as variables controlled to minimize energy consumption or equipment use, need not be included in the process validation.

Process validation should confirm that the impurity profile for each API is within the limits specified. The impurity profile should be comparable to, or better than, historical data and, where applicable, the profile determined during process development or for batches used for pivotal clinical and toxicological studies.

Approaches to validation

5.1.1 There are two basic approaches to validation—one based on evidence obtained through testing (prospective and concurrent validation), and one based on the analysis of accumulated (historical) data (retrospective validation). Whenever possible, prospective validation is preferred. Retrospective validation is no longer encouraged and is, in any case, not applicable to the manufacturing of sterile products.

5.1.2 Both prospective and concurrent validation, may include:

• extensive product testing, which may involve extensive sample testing (with the estimation of confidence limits for individual results) and the demonstration of intra- and inter-batch homogeneity;

• simulation process trials;

• challenge/worst case tests, which determine the robustness of the process; and

• control of process parameters being monitored during normal production runs to obtain additional information on the reliability of the process.

5.2 Scope of validation

5.2.1 There should be an appropriate and sufficient system including organizational structure and documentation infrastructure, sufficient personnel and financial resources to perform validation tasks in a timely manner. Management and persons responsible for quality assurance should be involved.

5.2.2 Personnel with appropriate qualifications and experience should be responsible for performing validation. They should represent different departments depending on the validation work to be performed.

5.2.3 There should be proper preparation and planning before validation is performed. There should be a specific programmed for validation activities.

5.2.4 Validation should be performed in a structured way according to the documented procedures and protocols.

5.2.5 Validation should be performed:

— for new premises, equipment, utilities and systems, and processes and procedures;

— at periodic intervals; and

— when major changes have been made. (Periodic revalidation or periodic requalification may be substituted, where appropriate, with periodic evaluation of data and information to establish whether requalification or revalidation is required.)

5.2.6 Validation should be performed in accordance with written protocols. A written report on the outcome of the validation should be produced.

5.2.7 Validation should be done over a period of time, e.g. at least three consecutive batches (full production scale) should be validated, to demonstrate consistency. Worst case situations should be considered.

5.2.8 There should be a clear distinction between in-process controls and validation. In-process tests are performed during the manufacture of each batch according to specifications and methods devised during the development phase. Their objective is to monitor the process continuously.

5.2.9 When a new manufacturing formula or method is adopted, steps should be taken to demonstrate its suitability for routine processing. The defined process, using the materials and equipment specified, should be shown to result in the consistent yield of a product of the required quality.

5.2.10 Manufacturers should identify what validation work is needed to prove that critical aspects of their operations are appropriately controlled. Significant changes to the facilities or the equipment, and processes that may affect the quality of the product should be validated. A risk assessment approach should be used to determine the scope and extent of validation required.

Analytical Method Validation

WHY VALIDATE ANALYTICAL PROCEDURES ?

There are many reasons for the need to validate analytical procedures. Among them

are regulatory requirements, good science, and quality control requirements. The

Code of Federal Regulations (CFR) 311.165c explicitly states that “ the accuracy,

sensitivity, specifi city, and reproducibility of test methods employed by the fi rm shall

be established and documented. ” Of course, as scientists, we would want to apply

good science to demonstrate that the analytical method used had demonstrated

accuracy, sensitivity, specifi city, and reproducibility. Finally management of the

quality control unit would defi nitely want to ensure that the analytical methods that

the department uses to release its products are properly validated for its intended

use so the product will be safe for human use.

CYCLE OF ANALYTICAL METHODS
The analytical method validation activity is not a one - time study. This is illustrated
and summarized in the life cycle of an analytical procedure in Figure 1 . An analytical

method will be developed and validated for use to analyze samples during the early
development of an active pharmaceutical ingredient (API) or drug product. As drug
development progresses from phase 1 to commercialization, the analytical method
will follow a similar progression. The fi nal method will be validated for its intended
use for the market image drug product and transferred to the quality control laboratory
for the launch of the drug product. However, if there are any changes in the
manufacturing process that have the potential to change the analytical profi le of the
drug substance and drug product, this validated method may need to be revalidated
to ensure that it is still suitable to analyze the API or drug product for its intended
purpose.

General Concepts

Ø      Validation is the act of demonstrating and documenting a procedure that operates effectively.

Ø      The discussion of the validation of analytical procedures is directed to the four most common types of analytical procedure:

R           Identification tests

R           Quantitative tests for impurities content

R           Limit tests for the control of impurities

R           Quantitative tests of the active moiety in samples of drug substance or drug product or other selected components in the drug product.

Ø      Typical validation characteristics which should be considered are:

R           Accuracy

R           Precision

R           Specificity

R           Quantitation Limit

R           Linearity and Range

R           Robustness

·        Method Validation Parameter for the assay of Mebendazole:

Ø      Linearity: Mebendazole to be analyzed as per proposed method. The results obtain is used to statistically evaluate for coefficient of determination (r²), standard error of estimate and y intercept.

Ø      Precision: Precision of the chemical method is ascertained by carrying out the analysis as per the procedure and as per normal weight taken for analysis. Repeat the analysis five times. Calculate the % assay, mean assay, % Deviation and % relative standard deviation and %RSD.

Ø      Accuracy: Accuracy of the method is ascertained by standard addition method at 3 levels. Standard quantity equivalent to 80%, 100% and 120% is to be added in sample.

·        Method Validation Parameter for residual solvent by GC for Mebendazole:

Ø      Specificity: Resolution of the analyte peak from the nearest peak: Solution of each of the analyte was injected separately and their retention time is noted. The standard working solution containing a mixture of the component being analyze is also injected and each of analyte peaks is check for its resolution from the nearest.

Ø      Precision:

R     Repeatability: Six replicate injections of standard solution for system precision should analyze as per the proposed method and from the chromatograms obtained the percentage % RSD is calculated.

R     Intermediate precision: The purpose of this test is to demonstrate the intermediate precision of the method when method is executed by a different analyst and on different day. Results obtained will be compared.

Ø      Linearity and Range: Solution of analyte solvent, having different concentration should make separate from L.O.Q. concentration, which is 50% to 150%. The result obtained is statistically evaluated for coefficient of determination (r²), standard error of estimate and y intercept.

Ø      LOD & LOQ:

R     The limit of Detection (L.O.D.) was calculated as per below equation:

                    

                      LOD          =              3.3     X       SD

                                                                  Slope 

R     The limit of Quantification (L.O.Q.) was calculated as per below equation:

                                   

                                                LOQ         =              10      X     SD

                                                                                         Slope

Ø      Accuracy / % Recovery (By Standard Addition Method): Accuracy of the method was ascertained by standard addition method at 3 levels.

R     Standard solution quantity equivalent to 50%, 100% and 150% are added in sample.

R     The solutions amount is analyzed by the proposed method and chromatogram obtained.

R     The amount recover by the method is compared to the amount added. Percent deviation is calculated at each levels and a grand average across all the levels are also calculated.

Methanol standard concentration ––  3000 ppm

Acetic acid standard concentration –– 5000 ppm

DMF standard concentration ––          880  ppm

Ø      Robustness:

R     The evaluation of robustness should be considered during the development phase and depends on the type of procedure under study. It should show the reliability of an analysis with respect to deliberate variations in method parameters.

R     If measurements are susceptible to variation in analytical conditions, the analytical condition should be suitably controlled or a precautionary statement should be included in the procedure.

R     One consequence of the robustness should be that a series of system suitability parameters (e.g. resolution test) is established to ensure that the validity of the analytical procedure is maintained whenever used.

PROCESS OF ANALYTICAL METHOD VALIDATION
The typical process that is followed in an analytical method validation is chronologically listed below:
1. Planning and deciding on the method validation experiments
2. Writing and approval of method validation protocol
3. Execution of the method validation protocol
4. Analysis of the method validation data
5. Reporting the analytical method validation
6. Finalizing the analytical method procedure
The method validation experiments should be well planned and laid out to ensure
effi cient use of time and resources during execution of the method validation. The best way to ensure a well - planned validation study is to write a method validation protocol that will be reviewed and signed by the appropriate person (e.g., laboratory management and quality assurance).
The validation parameters that will be evaluated will depend on the type of
method to be validated. Analytical methods that are commonly validated can be
classifi ed into three main categories: identifi cation, testing for impurities, and assay. Table 3 lists the ICH recommendations for each of these methods.
Execution of the method validation protocol should be carefully planned
to optimize the resources and time required to complete the full validation
study. For example, in the validation of an assay method, linearity and accuracy may be validated at the same time as both experiments can use the same standard solutions.
A normal validation protocol should contain the following contents at a
minimum:
(a) Objective of the protocol
(b) Validation parameters that will be evaluated
(c) Acceptance criteria for all the validation parameters evaluated
(d) Details of the experiments to be performed
(e) Draft analytical procedure
The data from the method validation data should be analyzed as the data are
obtained and processed to ensure a smooth fl ow of information. If an experimental error is detected, it should be resolved as soon as possible to reduce any impact it may have on later experiments. Analysis of the data includes visual examination of the numerical values of the data and chromatograms followed by statistical treatment of the data if required.

Upon completion of all the experiments, all the data will be compiled into a

detailed validation report that will conclude the success or failure of the validation

exercise. Depending on the company ’ s strategy a summary of the validation data may also be generated. Successful execution of the validation will lead to a final analytical procedure that can be used by the laboratory to support future analytical work for the drug substance or drug product.

METHOD REVALIDATION

There are various circumstances under which a method needs to be revalidated.

Some of the common situations are described below:

1. During the optimization of the drug substance synthetic process, signifi cant

changes were introduced into the process. To ensure that the analytical method

will still be able to analyze the potentially different profi le of the API, revalidation

may be necessary.

2. If a new impurity is found that makes the method defi cient in its specifi city,

this method will need to be modifi ed or redeveloped and revalidated to ensure

that it will be able to perform its intended function.

3. A change in the excipient composition may change the product impurity

profi le. This change may make the method defi cient in its specifi city for the

assay or impurity tests and may require redevelopment and revalidation.

4. Changes in equipment or suppliers of critical supplies of the API or fi nal drug

product will have the potential to change their degradation profi le and may

require the method to be redeveloped and revalidated.