Nishitkumar S. Patel Assistant Professor Dharmaj Degree Pharmacy College, Dharmaj.

1. VALIDATION
Validation is a key element of the quality assurance system in a pharmaceutical company
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For a long time, our understanding of pharmaceutical quality was such that one relied solely on the control of raw materials and final products. The intermediate process was guaranteed by established experience and the professional honesty of longtime employees. Today, our understanding is almost the reverse. Well-tested raw materials from qualified suppliers are used in a process that must be so well controlled that, theoretically, absolutely nothing can result other than a product that conforms to the specifications. In contrast, the place of manufacture and staff carrying out production are interchangeable, as long as they are qualified.

The new approach is conclusive, reasonable, sensible, since if a serious defect is identified at the final product quality control, irreparable damage has already occurred. For drug products, reprocessing is prohibited in most cases or is only possible with a great deal of additional expenditure. Since modern drug substances and innovative preparations are also becoming ever more expensive, it is, therefore, necessary to avoid the final product being rejected using preventive measures, such as validation. Therefore, to guarantee a reproducible quality, processes must be validated.

The establishing of documented evidence which provides a high degree of assurance that a planned process will consistently perform according to the intended specified outcomes. (WHO guide to GMP requirements , part-2 ,validation, Geneva 1997)

"Action of proving, in accordance with the principles of Good Manufacturing Practice, that any procedure, process, equipment, material, activity or system actually leads to the expected results. (EU GMP Guideline)

Establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality attributes.(U. S. Food and Drug Administration)

Validation is an essential part of good manufacturing practices (GMP). It is, therefore, an element of the quality assurance program associated with a particular product or process. The basic principles of quality assurance have as their goal the production of products that are fit for their intended use. These principles are as follows: -

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a) Quality, safety and efficacy must be designed and built into the product. b) Quality cannot be inspected or tested into the product. c) Each critical step of the manufacturing process must be validated. Other steps in the process must be under control to maximize the probability that the finished product consistently and predictably meets all quality and design specifications.

Validation of processes and systems is fundamental to achieving these goals. It is by design and validation that a manufacturer can establish confidence that the manufactured products will consistently meet their product specifications. Documentation associated with validation includes:-

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a) Standard operating procedures (SOPs) b) Specifications c) Validation master plan (VMP) d) Qualification protocols and reports e) Validation protocols and reports.

The implementation of validation work requires considerable resources such as:

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

b) Financial: validation often requires the time of specialized personnel and expensive technology. c) Human: validation requires the collaboration of experts from various disciplines (a multidisciplinary team, comprising quality assurance, engineering, manufacturing and other disciplines, depending on the product and process to be validated).

Validation studies verify the system under test under the extremes expected during the process to prove that the system remains in control. Once the system or process has been validated, it is expected that it remains in control, provided no changes are made. In the event that modifications are made, or problems occur, or equipment is replaced or relocated, revalidation is performed. Critical equipment and processes are routinely revalidated at appropriate intervals to demonstrate that the process remains in control. The validity of systems / equipment / tests/ processes can be established by prospective, concurrent or retrospective studies.

Scope of Validation.
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Principles may be useful:

in production and control of active harmaceutical ingredients (APIs) and finished pharmaceutical products

Validation of specific processes and products (e.g. sterile product manufacture) requires much more consideration and a detailed approach beyond the scope of the guideline

Many factors affecting the different types of validation Manufacturers should plan validation to ensure regulatory compliance and product quality, safety and consistency

The general text in the guideline (part 1 of presentation) may be applied to validation and qualification of: premises, equipment, utilities and systems processes and procedures

Advantages of Validation
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Increased throughput Reduction in rejections and reworks Reduction in utility costs Avoidance of capital expenditures Fewer complaints about process related failures Reduced testingin process and finished goods More rapid and accurate investigations into process deviations More rapid and reliable startup of new equipment Easier scale-up from development work Easier maintenance of the equipment Improved employee awareness of processes More rapid automation

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DEPARTMENT INTERACTIONS Once department missions have been formalized and the validation operation organized, the challenge is to implement the plan. That implementation requires the validation organization to interact with many peer groups. Within the company, those other departments include the following: 1. R&D: involved with new product development and new process improvement. 2. Engineering: involved with new or modified equipment or facilities. 3. Production: concerned with processes that require validation. 4. Maintenance: concerned change control, calibration, and preventative maintenance. 5. Quality Control: involved with the testing laboratories. 6. Quality Assurance: concerned with GMP compliance. Additionally, for those companies that outsource the manufacturing or packaging of their products, these interactions occur with the contracting firms Validation department. This poses an additional set of dynamics.

PURPOSE ` To describe the functions and responsibilities of the validation team to meet the cGMP compliance RESPONSIBILITY ` It is the responsibility of all concerned departments to follow the procedure. The QA manager is responsible for SOP compliance. PROCEDURE 1. Validation Coordinator ` All validation activities through the different progress steps should be coordinated by one person, preferably the quality assurance manager.

2. Validation Task Force/Certification Team ` The team should consist of managers of the departments involved in the validation and outside vendors (if applicable); for example: ` Quality assurance manager ` Production manager ` Technical services manager ` Product development manager ` Calibration manager ` Quality control manager ` Approved vendors (outside) 2.1 Responsibilities ` Scope of validation ` Validation priorities ` Acceptance criteria

3. Validation Working Groups ` The executive part of the validation work should be delegated to dedicated personnel: ` A member of the validation task force ` Representatives from relevant departments ` A representative from quality assurance ` A representative from technical services ` A representative from product development laboratory ` A representative from quality control ` A representative from the vendor (outside)

WHAT IS A VALIDATION MASTER PLAN? ` A Validation Master Plan (VMP) is a comprehensive document describing the applicable validation requirements for the facility, and providing a plan for meeting those requirements. SCOPE OF A VALIDATION MASTER PLAN ` The Validation Master Plan (VMP) includes all relevant aspects relating to the production of pharmaceuticals in the production facility at ABC Pharmaceutical. ` The principles of validation, the organization of qualification and validation, and the design and nomenclature of the documentation and equipment are also described. The VMP covers all facilities used in the production of tablets, liquids, ointments, creams, suppositories, and sterile products; the facilities for storing raw materials, interim and finished products, storage, services, and the rooms for staff.
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This Validation Master Plan (VMP) specifies and coordinates all qualification/ validation activities to ensure the production of pharmaceutical products according to accepted international standards. It also specifies the responsibilities for validation procedures and helps to plan the necessary activities.

A validation master plan is a document that summaries the companys overall philosophy, intentions and approaches to be used for establishing performance adequacy. The Validation Master Plan should be agreed upon by management. Validation in general requires meticulous preparation and careful planning of the various steps in the process.

In addition, all work should be carried out in a structured way according to formally authorized standard operating procedures. All observations must be documented and 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, SOPs and validation protocols and reports The format and content should include: ` Introduction: validation policy, scope, location and schedule ` Organizational structure: personnel responsibilities ` Plant /process/product description: rational for inclusions or exclusions and extent of validation ` Specific process considerations that are critical and those requiring extra attention ` List of products/ processes/ systems to be validated, summarized in a matrix format, validation approach ` Re-validation activities, actual status and future planning ` Key acceptance criteria ` Documentation format ` Reference to the required SOPs ` Time plans of each validation project and sub-project.
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Validation Life-Cycle ` Validation is a continuing and evolving process. The validation process extends from the very basic specifics (how each item works and interacts with another item) to a very broad theological and methodical investigation of how the system and processes perform. ` Its scope encompasses documentation, revision control, training, and maintenance of thesystem and process. Evidence of validation should be seen at the corporate level, and be reflected in the management structure. Validation is not just a set of procedures and rules to satisfy FDA, validation is a method for building and maintaining QUALITY.

TYPES OF PROCESS VALIDATION

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Prospective process validation Concurrent process validation Retrospective process validation Revalidation

Pre-requisites for Process Validation ` Before process validation can be started, manufacturing equipment and control instruments as well as the formulation must be qualified. The information on a pharmaceutical product should be studied in detail and qualified at the development stage, i.e., before an application for marketing authorization is submitted. This involves studies on the compatibility of active ingredients and recipients, and of final drug product and packaging materials, stability studies, etc. ` Other aspects of manufacture must be validated including critical services (water, air nitrogen, power supply, etc.) and supporting operations such as equipment cleaning and sanitation of premises. Proper training and motivation of personnel are pre- requisites to successful validation.

Stages of Process Validation ` The activities relating to validation studies may be classified into three stages: Stage 1: Process Design ` This is the step where building and capturing of the process knowledge and understanding took place. Early design of processes and experiments should be performed during this stage. ` It covers all activities relating to product research and development, formulation, pilot batch studies, scale-up studies, transfer of technology to commercial scale batches, establishing stability conditions, storage and handling of in-process and finished dosage forms, equipment qualification, installation qualification, master production documents, operational qualification, process capability. Also this is the stage in which the establishment of a strategy for process control is taking place using accumulation knowledge and understanding of the process.

Stage 2: Process Qualification ` This stage is confirmation that the process design is capable of reproducing the manufacturing process. It confirms that all established limits of the Critical Process parameters are valid and that satisfactory products can be produced even under worst case conditions. ` GMP compliant procedures must be followed in this stage and successful completion of this stage is necessary before commercial distribution of a product.

Stage 3: Continued Process Verification ` The Validation Maintenance Stage requires 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. ` Before any batch is distributed for marketing, the manufacturer must have full assurance of its performance. A successful validation program depends on the knowledge and understanding and the approach to control manufacturing processes. These include the source of variation, the limitation of the detection of the variation, and the attributes susceptible of the variation.

Prospective Validation Defination : Establishment of documentary evidence, prior to process implementation, that a process does what it purports to do based on validation master plan. Prospective validation is conducted prior to the distribution of either a new product or a product made under a modified production process, where the modifications are significant and may affect the products 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.

Organization ` Prospective validation requires a planned program and organization to carry it to successful completion. The organization must have clearly defined areas of responsibility and authority for each of the groups involved in the program so that the objective of validating the process can be met. ` The important point is that a defined structure exists, is accepted, and is in operation. An effective project management structure will have to be established in order to plan, execute, and control the program.

Master Documentation ` An effective prospective validation program must be supported by documentation extending from product initiation to full-scale production. The complete documentation package can be referred to as the master documentation file. It will accumulate as a product concept progresses to the point of being placed in full-scale production, providing as complete a product history as possible. ` The final package will be the work of many individual groups within the organization. It will consist of reports, procedures, protocols, specifications, analytical methods, and any other critical documents pertaining to the formulation, process, and analytical method development. The ideal documentation package will contain a complete history of the final product that is being manufactured.

Product Development
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Product development usually begins when an active chemical entity has been shown to possess the necessary attributes for a commercial product. The product development activities for the active chemical entity, formulation, and process form the foundation upon which the subsequent validation data are built. Generally, product development activities can be subdivided into formulation and process development, along with scale-up development.

Product development: A. Formulation Development ` Formulation development provides the basic information on the active chemical, the formula, and the impact of raw materials or excipients on the product. Typical supportive data generated during these activities may include the following: ` 1. Preformulation profile or characterization of the components of the formula, which includes all the basic physical or chemical information about the active pharmaceutical ingredients (API, or the chemical entity) and excipients. ` 2. Formulation profile, which consists of physical and chemical characteristics required for the products, drug-excipient compatibility studies, and the effect of formulation on in vitro dissolution.

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3. Effect of formulation variables on the bioavailability of the product 4. Specific test methods 5. Key product attributes and/or specifications 6. Optimum formulation 7. Development of cleaning procedures and test methods Formulation development should not be considered complete until all those factors that could significantly alter the formulation have been studied. Subsequent minor changes to the formulation, however, may be acceptable, provided they are thoroughly tested and are shown to have no adverse effect on product.

B. Process Development ` The process development activities typically begin after the formulation has been developed,dthey may also occur simultaneously. The majority of the process development activities occurdeither in the pilot plant or in the proposed manufacturing plant. The process developmentdprogram should meet the following objectives: ` 1. Develop a suitable process to produce a product that meets all: a. Product specifications b. Economic constraints c. Current good manufacturing practices (CGMPs) ` 2. Identify the key process parameters that affect the product attributes ` 3. Identify in-process specifications and test methods ` 4. Identify generic and/or specific equipment that may be required
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Stages of Process development 1. Design 2. Challenging of critical process parameters 3. Verification of the developed process

Development of Manufacturing Capability ` There must be a suitable production facility for every manufacturing process that is developed. This facility includes buildings, equipment, staff, and supporting functions. As development activities progress and the process become more clearly defined, there must be a parallel assessment of the capability to manufacture the product. The scope and timing of the development of manufacturing capability will be dependent on the process and the need to utilize or modify existing facilities or establish new ones. Full-Scale Process Development ` The development of the final full-scale production process proceeds through the following steps: ` 1. Process scale-up studies ` 2. Qualification trials ` 3. Process validation runs

Process Scale-up Studies ` The transition from a successful pilot-scale process or research scale to a full scale process requires careful planning and implementation. Although a large amount of information has been gathered during the development of the process (i.e., process characterization and process verification studies), it does not necessarily follow that the full-scale process can be completely predicted. Many scale-up parameters are nonlinear. ` In fact, scale-up factors can be quite complex and difficult to predict, based only on experience with smallerscale equipment. For some processes, the transition from pilot scale or research scale to full scale is relatively easy and orderly. For others the transition is less predictable.

Qualification trials ` Once the scale-up studies have been completed, it may be necessary to manufacture one or more batches at full scale to confirm that the entire manufacturing process, comprising several different unit operations, can be carried out smoothly. This may occur prior to or after the regulatory submission, depending on the strategy used in filing.

Process validation runs

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After the qualification trials have been completed, the protocol for the full-scale process validation runs can be written. Current industry standard for the validation batches is to attempt to manufacture them at target values for both process parameters and specifications. The validation protocol is usually the joint effort of the following groups: Research and development Pharmaceutical technology or technical services Quality control (quality assurance) Manufacturing Engineering

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` Concurrent

process validation:

Definition: Establishment of documentary evidence of what a system does or purports to do based on information generated during implementation of system.
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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. Concurrent validation is carried out during normal production. This method is effective only if the development stage has resulted in a proper understanding of the fundamentals of the process.

The first three production-scale batches must be monitored as comprehensively as possible. (This careful monitoring of the first three production batches is sometimes regarded as prospective validation.) The nature and specifications of subsequent in-process and final tests are based on the evaluation of the results of such monitoring. Concurrent validation together with a trend analysis including stability should be carried out to an appropriate extent throughout the life of the product. Concurrent validation may be the practical approach under certain circumstances.

Examples of these may be when: A previously validated process is being transferred to a third party contract manufacturer or to another manufacturing site.
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.The product is a different strength of a previously validated product with the same ratio of active/inactive ingredients. The number of lots evaluated under the Retrospective Validation were not sufficient to obtain a high degree of assurance demonstrating that the process is fully under control The number of batches produced is limited (e.g. orphan drugs). Process with low production volume per batch ( e.g. radiopharmaceuticals, anti-cancer) Process of manufacturing urgently needed drugs due to shortage (or absence) of supply.

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.

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Retrospective process validation

Definition: Establishment of documentary evidence of what a system does or purports to do based on review and analysis of existing information. It is validation of a process for a product already in distribution based upon accumulated production, testing and control data. Retrospective validation is used when historical data is available for existing manufacturing processes. Types of useful data include design drawings and specifications, operating procedures and work instructions, manufacturing instructions, inspection reports, production logs, production test data, material review reports, service records, customer complaints, and audit reports. Retrospective validation may not be feasible if accumulated data is incomplete or inadequate.

Retrospective validation involves the examination of past experience of production on the assumption that composition, procedures, and equipment remain unchanged; such experience and the results of in-process and final control tests are then evaluated. Recorded difficulties and failure in production are analyzed to determine the limits of process parameters. A trend analysis may be conducted to determine the extent to which process parameters are within the permissible range.

Retrospective validation is obviously not a quality assurance measure in itself, and should never be applied to new processes or products. It may be considered in special circumstances only, e.g. when validation requirements are first introduced in a company. Retrospective validation may then be useful in establishing the priorities for the validation program. If the results of a retrospective validation are positive, this indicates that the process is not in need of immediate attention and may be individual accordance with the normal schedule. For tablets, which have been compressed under individual pressure sensitive cells, and with qualified equipment, retrospective validation is the most comprehensive test of the overall manufacturing process of this dosage form. On the other hand, it should not be applied in the manufacture of sterile products.

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For the purpose of retrospective validation studies, it is considered acceptable that data from a minimum of ten consecutive batches produced be utilized. When less than ten batches are available, it is considered that the data are not sufficient to demonstrate retrospectively that the process 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.

` Revalidation
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Revalidation is needed to ensure that changes in the process and/or in the process environment, whether intentional or unintentional, do not adversely affect process characteristics and product quality. Revalidation may be divided into two broad categories: Revalidation after any change having a bearing on product quality. Periodic revalidation carried out at scheduled intervals. Revalidation after changes. Revalidation must be performed on introduction of any changes affecting a manufacturing and/or standard procedure having a bearing on the established product performance characteristics. Such changes may include those in starting material, packaging material, manufacturing processes, equipment, in-process controls, manufacturing areas, or support systems (water, steam, etc.). Every such change requested should be reviewed by a qualified validation group, which will decide whether it is significant enough to justify revalidation and, if so, its extent.

Revalidation after changes may be based on the performance of the same tests and activities as those used during the original validation, including tests on sub processes and on the equipment concerned. Some typical changes which require revalidation include the following: ` Changes in the starting material(s). Changes in the physical properties, such as density, viscosity, particle size distribution, and crystal type and modification, of the active ingredients or excipients may affect the mechanical properties of the material; as a consequence, they may adversely affect the process or the product. ` Changes in the packaging material, e.g. replacing plastics by glass, may require changes in the packaging procedure and therefore affect product stability. ` Changes in the process, e.g. changes in mixing time, drying temperature and cooling regime, may affect subsequent process steps and product quality.
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` Changes in equipment, including measuring instruments, may

affect both the process and the product; repair and maintenance work, such as the replacement of major equipment components, may affect the process.

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

rearrangement of manufacturing areas and/or support systems, may result in changes in the process. The repair and maintenance of support systems, such as ventilation, may change the environmental conditions and, as a consequence, revalidation/requalification may be necessary, mainly in the manufacture of sterile products.

` Unexpected changes and deviations may be observed during

self-inspection or audit, or during the continuous trend analysis of process data.

` Installation
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qualification (IQ)

Establishing by objective evidence that all key aspects of the process equipment and ancillary system installation adhere to the manufacturers approved specification and that the recommendations of the supplier of the equipment are suitably considered. Simply put, IQ means is it installed correctly? Important IQ considerations are: Equipment design features (i.e. materials of construction cleanability, etc.) Installation conditions (wiring, utilities, functionality, etc.) Calibration, preventative maintenance, cleaning schedules Safety features Supplier documentation, prints, drawings and manuals Software documentation Spare parts list Environmental conditions (such as clean room requirements, temperature, humidity)

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Sometimes activities are conducted at the equipment suppliers site location prior to equipment shipment. Equipment suppliers may perform test runs at their facilities and analyze the results to determine that the equipment is ready to be delivered. Copies of the suppliers qualification studies should be used as guides, to obtain basic data, and to supplement installation qualification. However, it is usually insufficient to rely solely upon the validation results of the equipment supplier. Each medical device manufacturer is ultimately responsible for evaluating, challenging, and testing the equipment and deciding whether the equipment is suitable for use in the manufacture of a specific device(s). The evaluations may result in changes to the equipment or process.

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Operational qualification - (OQ) Establishing by objective evidence process control limits and action levels which result in product that meets all predetermined requirements. In this phase the process parameters should be challenged to assure that they will result in a product that meets all defined requirements under all anticipated conditions of manufacturing, i.e., worst case testing. During routine production and process control, it is desirable to measure process parameters and/or product characteristics to allow for the adjustment of the manufacturing process at various action level(s) and maintain a state of control. These action levels should be evaluated, established and documented during process validation to determine the robustness of the process and ability to avoid approaching worst case conditions.

OQ considerations include: ` Process control limits (time, temperature, pressure, line speed, setup conditions, etc.) ` Software parameters ` Raw material specifications ` Process operating procedures ` Material handling requirements ` Process change control ` Training ` Short term stability and capability of the process, (latitude studies or control charts) ` Potential failure modes, action levels and worst-case conditions (Failure Mode and Effects Analysis, Fault Tree Analysis) ` The use of statistically valid techniques such as screening experiments to establish key process parameters and statistically designed experiments to optimize the process can be used during this phase.

Performance qualification - (PQ)

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Establishing by objective evidence that the process, under anticipated conditions, consistently produces a product which meets all predetermined requirements. In this phase the key objective is to demonstrate the process will consistently produce acceptable product under normal operating conditions. Methods and tools for process validation. PQ considerations include: Actual product and process parameters and procedures established in OQ Acceptability of the product. Assurance of process capability as est ablished in OQ Process repeatability, long term process stability

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Challenges to the process should simulate conditions that will be encountered during actual manufacturing. Challenges should include the range of conditions as defined by the various action levels allowed in written standard operating procedures as established in the OQ phase. The challenges should be repeated enough times to assure that the results are meaningful and consistent. Process and product data should be analyzed to determine what the normal range of variation is for the process output. Knowing the normal variation of the output is crucial in determining whether a process is operating in a state of control and is capable of consistently producing the specified output. One of the outputs of OQ and PQ is the development of attributes for continuous monitoring and maintenance.

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Process and product data should also be analyzed to identify any variation due to controllable causes. Depending on the nature of the process and its sensitivity, controllable causes of variation may include: Temperature Humidity Variations in electrical supply Vibration Environmental contaminants Purity of process water Light Human factors (training, ergonomic factors, stress, etc.) Variability of materials Wear and tear of equipment Appropriate measures should be taken to eliminate controllable causes of variation. Eliminating controllable causes of variation will reduce variation in the process output and result in a higher degree of assurance that the output will consistently meet specifications.