Guidelines for Validation of Dosage Forms

Disclaimer

This document does not form part of the Food and Drugs Act (the Act) or its associated Regulations and in the event of any inconsistency or inconsistency between the Act or the Regulations and this document, the Act or the Regulations will have precedence. This document is an administrative document intended to facilitate the compliance of regulated parties with the Act, Regulations and applicable administrative policies. This document is not intended to provide legal advice with respect to the interpretation of the Act or the Regulations. If a regulated party has questions about their legal obligations or liabilities under the Act or the Regulations, they should seek the advice of a legal advisor.

1.0 Scope

This guidance document has been prepared to provide the pharmaceutical industry with guidance on the validation of sterile and non-sterile dosage forms, biologics and radiopharmaceuticals. It should be noted that additional guidance for sterile products not included in this document should also be considered.

Importers and distributors of pharmaceuticals should be able to prove, with supporting documentation, that their suppliers meet the validation requirements.

2.0 Introduction

This document provides guidance on issues and issues related to systems, equipment qualification, product and process validation for sterile and non-sterile dosage forms. These issues pertain to a pharmaceutical, biologics and radiopharmaceutical manufacturing sector that both the Inspectorate and the pharmaceutical industry consider important. These guidelines have been written for inspectors, evaluators and the industry, who must address issues related to validation. With this information, it should be easier to comply with Title 2 of Part C of the Food and Drug Regulations .

The recommendations made in these guidelines do not intend to become requirements in all circumstances. The information provided in the Interpretation section, with respect to the limitations that apply in particular circumstances, as well as the number of lots to be used for validation studies, is only indicative.Inspectors, evaluators and industry may consider other measures if they are supported by sound science.

3.0 Object

These guidelines describe the general principles that the Inspectorate considers acceptable validation elements for pharmaceutical manufacturers, packagers or labellers. The Good Manufacturing Practices ( GMP ) Guidelines, Part 2, Part C of the Food and Drug Regulations provide that:

• all critical manufacturing processes must be validated;
• Validation studies must be performed according to pre-established protocols. Written reports summarizing findings and conclusions should be prepared, evaluated, approved and maintained;
• changes to manufacturing processes, operating parameters of the equipment or materials that may affect the quality of the product or the reproducibility of the process must also be validated before being implemented.

These guidelines are not intended to define how validation is to be done; rather, they are indications of what should be covered by manufacturers and packagers / labellers.

The validation elements presented in these guidelines are not meant to be exhaustive. Specific validation requirements may vary depending on various factors, such as the nature of the drug product (eg, sterile or non-sterile product, biologic or radiopharmaceutical) and the complexity of the process. The concepts presented in these guidelines are generally applicable and provide an acceptable framework for a comprehensive approach to validation.

4.0 Definitions

Process capability: Studies to determine critical process parameters for stable quality, as well as their acceptable specification limits, based on established sigma +/- 3 deviations of the process under extreme conditions, but without being able to assign causes.

Worst Case Condition: The highest and lowest value of a given parameter that is evaluated during the validation exercise.

Change Control: A written procedure describing the action to be taken in the event of a change to (a) the facilities, materials, equipment and / or processes used in the manufacturing, packaging and drug analysis or (b) any change that may affect the quality or functioning of the ancillary systems.

Production Standard Document : Documents including specifications for raw materials, packaging material and packaged dosage form, standard formula, sampling procedures and standard operating procedures ( SOPs ) for critical processes whether or not these PONs are referred to in the standard formula.

Validation Team : A multidisciplinary team composed of employees primarily responsible for conducting or supervising validation studies. These studies may be conducted by one or more qualified persons because of their training or experience in a relevant discipline.

Main Equipment: A piece of equipment that performs critical processing steps in the sequence of operations required to manufacture or package pharmaceuticals. Examples include tablet presses, mills, mixers, fluid bed dryers, heaters, drying ovens, tablet wrappers, encapsulants, fermenters, centrifuges, and the like.

Measuring instruments: Apparatus used to monitor or measure the parameters of a process.

Critical process parameter : A parameter that will contribute to the variability of the final product if it is not controlled.

Master Validation Plan : An approved written plan that outlines the objectives and actions, and establishes when and how a company will comply with the GMP requirements , with respect to validation.

Validation Protocol: Written action plan detailing how process validation will be performed; this plan establishes who will perform the various tasks and defines the test parameters, sampling plans, methods of analysis and specifications, product characteristics and equipment to be used. It must also specify the minimum number of lots to be used in validation studies; it must finally define the acceptance criteria and specify who will sign / approve / disapprove the conclusions drawn from such a scientific study.

Equipment Qualification: Studies to determine with confidence that ancillary equipment and processing systems can operate consistently within established limits and tolerances. These studies must address the technical characteristics of the equipment, as well as the validation of the installation and operation of all major pieces of equipment that are used to manufacture batches on a commercial scale. The qualification of the equipment should simulate real production conditions, including those of the "worst case" and the operation under stress.

Process Qualification: The validation phase for sampling and analysis at various stages of the manufacturing process to ensure compliance with product specifications.

Installation Qualification ( IQ ): Demonstration, supporting documentation, that the equipment used for processing and ancillary systems has been well chosen and installed.

Operational Qualification ( OQ ): Demonstration, supporting documentation, that equipment used for processing and ancillary systems is working well and in accordance with established specifications.

Process Revalidation: Required when changing any of the critical process parameters, formulation, primary packaging components, raw material manufacturers, major equipment or premises. Failure to comply with process and product specifications in sequential batches would also require process revalidation.

Validation: An operation intended to demonstrate, with supporting documents, that a procedure, a process or an activity actually leads to the expected results. It includes qualification of systems and equipment.

Concurrent Validation: Process where common production batches are used to control treatment parameters. This process provides a guarantee for the lot under study, but can only give a limited guarantee of consistency of quality from batch to batch.

Validation of cleaning processes: Documented demonstration that the cleaning methods of equipment used in manufacturing and packaging reduce to an acceptable level all residues (products and cleaning agents) and that cleaning and storage equipment do not give rise to microbial growth.

Process Validation: Establish, with a high level of assurance, documented evidence that a particular process will consistently produce a product that meets its specifications and predetermined quality characteristics. The validation of a process may take the form of a prospective, concomitant or retrospective validation, or a certification or revalidation of the process.

Prospective validation: Validation carried out before the distribution of a new product or a product manufactured according to a modified manufacturing process, where the modifications are important and may have repercussions on the characteristics of the product. It is a scientific approach, planned in advance, that encompasses the initial stages of formulation development, process and process specifications, development of in-process analysis methods, and development plans. Sampling, the creation of manufacturing batch records, the definition of raw material specifications, the start-up of pre-production batches, the transfer of batch-scale technology to batches scale and enumeration of controls applicable to major equipment and the environment.

Retrospective Validation: Validation performed for a product already on the market and based on a multitude of data collected over several batches over time.Retrospective validation may be used for older products that the manufacturer has not validated when they were placed on the market, but which must now be validated to comply with the requirements of Part C, Title 2 of the food and drugs.

5.0 Phases of Validation

Activities related to validation studies can be grouped into three phases:

Phase 1 The pre-validation or qualification phase, which covers all activities related to product research and development, formulation, studies of developing pilot batches, scaling studies, transfer of technology for commercial scale batches, establishment of stability conditions, storage and handling of finished and in-process dosage forms, qualification of equipment, qualification of the installation, standard production documents, operational qualification and process capacity.

Phase 2 The process validation phase (process qualification phase) is designed to verify that all established limits of critical process parameters are valid and that satisfactory products can be produced even under the most unfavorable conditions.

Phase 3 The maintenance of validation phase requires frequent review of all process related documents, including validation audit audition reports that ensure that there has been no change, no variance , failure or modification of the production process and that all SOPs have been complied with, including change control procedures.

At this stage, the validation team also ensures that there has been no change or gap that would have led to requalification and revalidation.

6.0 Interpretation

General concepts

Quality, safety and efficacy must be an integral part of the product. To this end, special attention must be given to a number of factors, such as the selection of good quality materials and components, product and process design, process control, in-process control and the analysis of the finished product.

Due to the complexity of pharmaceuticals, routine testing of the finished product is not sufficient for several reasons. In addition, quality can not be analyzed from the finished drug product because it is an integral part of the manufacturing processes, and these processes must be controlled to ensure that the finished product meets all quality specifications. The rigorous design and validation of process systems and controls provides a high degree of confidence that all batches produced will meet specified specifications.

Validation protocol

A written plan indicating how the validation will be performed, including test parameters, product characteristics, production and packaging equipment, and decision points that are acceptable test results. This document should include details of the critical steps in the manufacturing process that need to be measured, the acceptable limits of variability, and how the system should be tested.

The validation protocol is a summary of what you want to achieve. The protocol should list the process parameters and control parameters retained, indicate the number of lots to be included in the study, and explain how the data, once aggregated, will be processed to verify their relevance. The date of approval by the validation team should also be recorded.

In the event that a protocol is altered or modified after its approval, the rationale for the change must be documented.

The validation protocol must be numbered, signed and dated, and must contain at least the following information:

• the objectives, purpose and content of the validation study
• members of the validation team, their qualifications and responsibilities
• type of validation: prospective, concurrent, retrospective, re-validation
• the number and selection of lots that must be in the validation study
• a list of all equipment to be used, their operating parameters under normal conditions of use and worst case
• QI results, QO for critical equipment
• calibration requirements for measuring devices
• critical process parameters and their respective tolerances
• description of the manufacturing steps: a copy of the master product production document
• points, levels, methods and sampling plans
• statistical tools to use in data analysis
• the training requirements of the personnel involved in manufacturing
• validated analytical methods that will be used in the analysis of in-process and finished products
• specifications for raw materials, packaging materials and methods of analysis
• forms, tables and graphs that will be used for recording results
• format for the presentation of results, documentation of conclusions, and approval of the results of the study.

Validation Master Plan

A Master Validation Plan is a document that summarizes the company's overall philosophy and intentions, as well as the approaches it intends to use to establish the adequacy of the performance. The Master Validation Plan must be approved by the management of the company.

Validation in general requires meticulous preparation and careful planning of the various process steps. In addition, all work must be done in a structured manner in accordance with the officially approved standard operating procedures. All observations should be documented and, as far as possible, recorded as actual numerical results.

The master validation plan should provide an overview of the entire validation exercise, its organizational structure, content and planning. The main elements of this plan are the list or inventory of points to be validated and the planning schedule. All validation activities related to critical technical operations, with respect to product and process controls within a company, should be included in the Master Validation Plan. This plan should include all prospective, concomitant and retrospective validations as well as revalidations.

The Master Validation Plan should be a summary document and should therefore be brief, concise, and clear. It should not repeat the information documented elsewhere but rather should refer to existing documents as policy documents, SOPs, validation protocols and validation reports.

The format and content should include:

• an introduction: validation policy, scope, location and timing
• organizational structure: staff responsibilities
• the description of the plant / process / product: the reason for inclusion or exclusion and extent of validation
• a special consideration for processes that are critical and those that require extra attention
• a list of products / processes / systems to be validated, summarized in a matrix format, the validation approach
• revalidation activities, current status and plan for the future
• the main criterion of acceptability
• the format for the documentation
• the reference to the required SOPs
• the schedule for each validation project and sub-project.

Qualification of the facility and operational qualification

The level of detail and scope of the qualification exercise are, in many respects, related to the complexity of the equipment involved and the critical nature of the equipment in relation to the quality of the finished product.

The purpose of the facility qualification and operational qualification exercises is to ensure, through appropriate performance testing and related documentation, that the equipment, systems and ancillary subsystems have been properly commissioned. The final results are that all future operations will be reliable and meet the prescribed operating limits.

The basic principles are:

• The equipment is well installed in accordance with an installation plan
• Calibration, maintenance and cleaning requirements are covered in approved SOPs
• Tests are done to make sure the equipment is working properly under normal or worst-case conditions
• The requirements for training operators of new equipment are met and documented.

At the various stages of the validation exercise, protocols, documentation, procedures, equipment, specifications, and acceptance criteria for test results are required. All these aspects must be examined, verified and authorized. Representatives of appropriate professional disciplines (eg, engineering, research and development, manufacturing, quality control, and quality assurance) should be actively involved in these activities, and final approval should be given by a validation team or the quality assurance representative.

Qualification of the installation ( IQ )

IQ is a method of confidently establishing that all major process equipment, packaging and all ancillary systems are in compliance with the installation specifications, equipment manuals, drawings and engineering drawings. This validation step includes a review of the requirements for the design, calibration, maintenance and adjustment of the equipment.

In the case of complex equipment or large pieces of equipment, a pharmaceutical manufacturer may decide to proceed to a verification of the equipment performed at the supplier's assembly facilities prior to delivery. This check before delivery does not replace the qualification of the installation. It is recognized, however, that the audits performed and documented at this stage may duplicate a number of IQ checks, which helps to reduce the scope of IQ checks.

All equipment, gauges and services should be well identified with a serial number or other reference number. This number should be included in the records for validation studies performed on the equipment.

The qualification of the installation requires an official and systematic verification of all equipment installed 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 several times to ensure the reliability and significance of the results.

At the IQ stage, the company should document the preventative maintenance requirements for the equipment in place. The preventive maintenance schedule should be integrated with routine preventative maintenance.

Note 
The installation of the equipment may not have been initially qualified and the technical and manual drawings of the equipment may no longer be available at the manufacturer's plant. However, the equipment in place has a long history of trouble-free operation or design changes since initial installation. In these particular circumstances, the Inspectorate considers that it may be appropriate to verify a limited number of the most critical parameters demonstrating that the equipment has been properly installed. The company can then move directly to the Operational Qualification ( OQ ) stage if there is sufficient documented evidence to conclude that these elements have always been well maintained and calibrated according to a pre-established schedule.

Operational Qualification ( OQ )

An operational qualification exercise must be performed according to an authorized protocol. Critical parameters for the operation of equipment and systems should be defined at the operational qualification stage. Operational qualification plans should specify the studies to be undertaken on the critical variables, the sequence of these studies and the measurement instruments to be used and the acceptance criteria to be met.

Studies of critical variables should include a condition or series of conditions that encompass the upper and lower limits of treatment and function, referred to as the "extreme case". At the end of a successful operational qualification exercise, it should be possible to finalize the final version of the documentation on the operation of the equipment and instructions for operators. This documentation must be used for the purposes of operator training.

At the end of a properly completed facility qualification and operational qualification exercise, it should be possible to issue a formal authorization for the equipment to be submitted to the next stage of the validation exercise. process, provided that the requirements for calibration, cleaning, preventive maintenance and operator training are met and that the results of this exercise are documented.

Re-qualification

Modifications to, or relocation to, equipment should be made after a satisfactory review and prior authorization of the change request by following a change control procedure. This formal review should include considerations for the re-qualification of equipment. Minor changes or changes that have no direct impact on the quality of the final product or the product being manufactured should be made through a documentation system of a preventive maintenance program.

Validation of the process

In principle, the process validation step must be completed before the distribution of a finished product for sale (prospective validation), otherwise it may be necessary to validate the processes during the process. normal production (concomitant validation). Processes that have been used for some time and have not undergone any significant changes could also be validated according to an approved protocol (retrospective validation).

a) Prospective validation

In the case of a prospective validation, the validation protocol is applied before the process is used for commercial purposes. In the product development stage, the manufacturing process must be broken down into stages. Each step must then be evaluated in the light of previous observations or theoretical considerations, the object being to determine what are the critical parameters that may affect the quality of the finished product. A series of experiments should be designed to establish the critical importance of these factors. Each experiment should be planned and fully described in an approved protocol.

All equipment, the production environment and the methods of analysis that are intended to be used must have been validated. The batch documents can be prepared once the critical process parameters have been defined and the machine settings, component specifications and environmental conditions have been determined.

A series of lots should be manufactured using this process. In principle, the number of manufacturing batches made and observations made should be large enough so that normal variations and trends can occur so that sufficient data can be obtained for evaluation. In general, it is considered that the manufacture of three batches or the production of three consecutive production cycles according to the approved parameters, indicating that the products have the required quality, would constitute an appropriate validation of the process. In practice, the collection of these data may require considerable time.

Certain factors must be considered when selecting the process validation strategy, in particular, the use of different batches of active raw materials and excipients important, lots manufactured in different shifts, the use of equipment and various installations for commercial manufacture, critical processes operating range and a thorough analysis of data relating to process, if requalification and revalidation.

When processing the validation batches, it would take many samples of the product and submit them in various stages of testing, and record observations made during this exercise. The packaged finished product should also be subject to further analysis.

After the evaluation should make recommendations concerning the importance of surveillance and control measures in the normal manufacturing process. These recommendations should be integrated into the production file and packing lots or to appropriate SOPs. Clarify the limits, frequencies and actions to be taken in case of exceeding set limits.

Approach by the matrix method or "class" of products in this prospective validation of the method:

It would be possible and acceptable, in particular circumstances, for a manufacturer that uses the same process for several related products, develop a validation plan scientifically proven for this process rather than different plans for each product manufactured by this process.

The approach by the matrix method generally means a plane to perform the validation process on different strengths of the same product. However, the discrete manufacturing steps such as compression, coating that involve various tools, equipment and process conditions for different dosages, can be validated according to the matrix method. It must be recognized that the matrix approach has its limitations in respect to physical properties, such as the flow, the distribution of particle size and uniformity.

The approach by "category" of products means a plan for executing the process validation on different products manufactured with the same process using the same equipment.

Process validation using these approaches should include lots of different dosages or products that should be chosen to represent the conditions or worst case scenarios to demonstrate that the process is uniform for all assays or products involved.

b) concomitant Validation

L`Inspectorat not advocating unconditional use of this approach, which should not be considered the "norm".

When using this approach, we still may have to modify the process parameters or specifications during a given period. This often raises questions concerning measures against lots whose sale has already been approved and for which we later found quality problems.

It might be convenient to opt for a concurrent validation in certain circumstances, for example:

• when a previously validated method is transferred to a subcontractor or another manufacturing site;
• when the product is not the same concentration that a product already validated with the same respect inactive-active ingredients;
• when the number of batches evaluated using the retrospective validation method was not sufficiently high so that we can establish, with high certainty, that the process is well under control;
• when the number of batches produced is limited (eg. orphan drugs).

However, in such cases, it is important that the systems and equipment that is to be used have been properly validated. The reasons justifying the use of concurrent validation must be documented and the protocol must be approved by the validation team. A report must be drafted and approved before each product lot is on sale, and a final report should be prepared and approved including the manufacture of all items having served concurrent validation. In general, it is considered that the manufacture of three consecutive batches in accordance with approved parameters, indicating that the products have the desired quality, would be an appropriate process validation.

c) Retrospective Validation

In many institutions, the processes that are stable and which are used regularly have not been subject to a validation process rigorously documented. Historical data can be used as necessary documentary evidence confirming process validation.

This type of validation still has several steps, including the preparation of a protocol and communicating the results of the data review, leading to a conclusion and a recommendation.

Retrospective validation is only acceptable for established and detailed methods that include limits for each critical process step. It will not be appropriate where recent changes have been made to the product formulation, procedure, equipment and installation.

Data sources for the retrospective validation should include, among others, documents about lots graphics on process control, annual review reports on the quality of the product, the maintenance control registers, records of personnel changes, studies on process capability, analysis results of the finished product, including trend analysis, and the results of stability tests.

For retrospective validation studies, it would be acceptable to use the data collected on a minimum of ten consecutive batches. When no data on at least ten lots, considering that there are insufficient data to retrospectively demonstrate that the process is fully under control. In such cases, the study should be completed by the data produced during a concurrent or prospective validation.

A retrospective validation includes essential elements, among others, the following:

• batches manufactured during a given period (at least the last ten consecutive batches)
• number of batches released annually
• lot size / concentration / manufacturer / year / period
• Form of manufacturing / packing
• Common specifications for active and finished products raw materials
• list of deviations from the process, corrective actions and changes to manufacturing documents
• Data for stability testing for several lots
• analysis of trends, including trends on complaints related to quality.

Revalidation of the method

Revalidation provides evidence that changes to a process or environment of a process does not harm the characteristics of the process or the product quality. The documentation requirements are the same as for the initial process validation.

Periodic review and trend analysis should be conducted at regular intervals. Revalidation is needed in certain situations. The list below gives some examples of modifications or changes planned or not planned or unplanned planned that may require revalidation:

• Change in the raw materials (physical properties such as density, viscosity, particle size, particle size distribution and moisture, etc. which can affect the process or product)
• Changing manufacturer of active raw materials
• Changes to the packaging material (primary container / closure system)
• the process changes (eg. ex., mixing time, drying temperature and batch size)
• Changes to the equipment (p. Ex., Adding an automatic detection system). The changes to the equipment, including the replacement of equipment with an identical, normally not require revalidation except that this new equipment will be qualified
• Changes to the plant or facility
• Variations identified during the trend analysis (eg drift in the process)

The decision not to conduct revalidation studies must be fully justified and documented.

Change control

Written procedures must be in place to describe the steps to be taken when a change is proposed in the composition of a product, equipment, environment, site, method of production or analysis, or any what other changes could affect the quality of a product, or the operations of the backup system.

All changes must be the subject of a formal request and must be documented and accepted by the validation team. It will be necessary to assess the potential impact of the change on the product or the risk that may be associated with it, and to determine the need for revalidation and, if so, the extent of revalidation.

To ensure ongoing validation of the affected systems, it is critical that the company commits to control all changes to the premises, back-up services, systems, raw materials, equipment, and manufacturing processes. and packaging pharmaceutical forms.

The change control system should ensure that all reported or requested changes are satisfactorily reviewed, documented and authorized. Products manufactured under the modified processes should not be released for sale without the validation team being fully informed of the change and having reviewed it. The team must decide on the need for revalidation before the proposed change is made.

7.0 References

1. Guidelines on General Principles of Process Validation, CEDR , US - FDA , 1987
2. Pharmaceutical Process Validation; 2 nd edition, Editors: The IR Berry and RA Nash , 1993
3. Recommendations on Validation Master Plan, Installation and Operational Qualification, Non-Sterile Validation Process, Cleaning Validation, PIC / S , August 2001