Validation and Process of Validation

Validation

Validation is Establish documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes.” This approach will be applied to individual pieces of equipment. Manufacturing process as a whole. Importance of Validation Increased throughput Reduction in rejections and reworking Reduction in utility costs Avoidance of capital expenditures Fewer complaints about process-related failures Reduced testing in-process and in finished goods More rapid and reliable start-up of new equipment Easier scale-up from development work Easier maintenance of equipment Improved employee awareness of processes.

Type of Validation -: 

There are four types of validation

• Process validation
• Cleaning validation
•  Analytical validation
• Computer validation

Phases of process Validation - : 

Phases of process Validation - Validation is broken down into four phases: Design Qualification (DQ). Installation Qualification (IQ). Operational Qualification (OQ). Performance Qualification (PQ). These four protocols are used to define tests that will demonstrate that the process consistently and repeatedly produces the desired product.

Design Qualification (DQ) : 

It contains - 1) Descriptions of equipment. 2) References:- a) specifications. b) Quotation. c) Order number. 3) Machine specifications. 4) Approvals. 5) Manuals. 6) Certification

Installation Qualification (IQ) -: 

Installation Qualification (IQ) - This protocol insures that the system/equipment and its components are installed correctly and to the original manufacturer’s specifications. Calibration of major equipment, accessory equipment, and/or utilities should be performed in this step as well.

Operational Qualification (OQ) - : 

Operational Qualification (OQ ) - This step proceeds after the IQ has been performed. In the OQ, tests are performed on the critical parameters of the system/process. These are usually the independent and manipulated variables associated with the system/equipment. All tests’ data and measurements must be documented in order to set a baseline for the system/equipment.

Performance Qualification (PQ)- : 

Performance Qualification (PQ )- This is the final phase of validation. This phase tests the ability of the process to perform over long periods of time within tolerance deemed acceptable. PQ is performed on the manufacturing process as a whole. Individual components of the system are not tested individually.

Type of process Validation: 

• Prospective Validation
• Retrospective Validation
•  Concurrent Validation
•  Revalidation

Prospective Validation: 

It is a experimental plan also called as validation protocol. Validation conducted prior to distribution either of a new product. A product made under a revised manufacturing process. Validation is completed and the results are approved prior to any product release.

Retrospective Validation: 

Validation of a process for a product already in distribution, based on ; accumulated production , testing, and control data's. Summary of existing historical data

Concurrent Validation: 

·         Study of concurrent validation under protocol during the course of normal production. A combination of retrospective and prospective validation. Performed against an approved protocol but product is released on a lot-by-lot basis. Usually used on an existing product not previously validated or insufficiently validated

Revalidation: 

To validate change in equipment, packaging, formulation operating procedure . process that could impact product safety, efficacy or potency. It is important to establish a revalidation program for critical equipment to maintain validity.

Process Validation: 

1. Requalification or revalidation. 2. Calibration, verification, and maintenance of process equipment. 3. Establishing specifications and performance characteristics. 4. Selection of methods, process, and equipment to ensure the product meets specifications. 5. Qualification or validation of process and equipment. 6. Testing the final product, using validated analytical methods, in order to meet specifications. 7. Challenging, auditing, monitoring, or sampling the recognized critical and key steps of the process

Case study: Steam Sterilization Validation

STEAM STERILIZATION: 

Various types of steam sterilizers are commercially available :- • Saturated Steam • Water Immersion • Air-Steam Mixtures • Gravity Air Displacement (unpacked materials sterilization ) • Vaccum air Displacement (Packed materials)

Microbiological aspects of Steam Sterilization and Dry Heat Sterilization are basically the same . D- Value is determined in the same way Z- Value :- the z- value is the number of degrees of temperature Change to required to produce a 10-fold change in D- value this is relates to the heat of a microorganism to changes in temperature Lethality (F0 ) can be calculated in the same way.

 1 . Design Qualification : Facility layout. • Utility requirements and specifications. • Required capacity of the sterilizer. • Type of materials to be sterilized ( Liquids, wrapped ,hollow or porous materials ) • Requirement for Gravity and Prevacuum cycles.

2. Installation Qualification- CALIBRATIONS :- The following pieces of equipment should be calibrated by removing . • Pressure Gauges. Timing Devices. Temperature Recording Devices. Verification of safety Systems and Devices.

3. Operational Qualification :- The actual operational performance of the Electro/mechanical components and utilities. It Should be verified and documented. Clean Steam Generator. Air Filtration Systems and compressed air Power Source Heat Exchanger, Cooling Water

4. Performance Qualification : Temperature Distribution :- External monitoring and recording instruments Shall be calibrated before and after the OQ/PQ Studies (3 point calibration, ± 0.5 0C tolerance). Uniformity of the temperature distribution in Case of Min & Max . loading should be verified by using Thermocouples with 3 replicates

At least one T/C shall be placed located in the steam exhaust line or adjacent to the equipment temperature controller. Min . 10-12 T/C ‘s shall be used . They should not be inserted in the load . Data should be recorded during the whole cycle at 1 min intervals. Location of the “cold spot” should be determined and documented

Performance Qualification : Heat Penetration- Acceptance Criteria: Thermocouples should be inserted into the load. At least three biological indicators and T/C’s shall be placed around the cold spot. External T/C readings should comply with manufacturer’s specifications (with Max ± 1 0C difference ) Biological indicator (bacillus stearothermophilus ) results should ensure the 6-log reduction and Lethality calculation should verify the Equivalent F0 (15 min. at 121 0C) value for defined cycle and

Bowie-Dick or DART Test :- : 

The Bowie-Dick test verifies the performance of a dynamic air-removal steam sterilizer. The test only verifies the ability of the sterilizer to remove air and replace it with steam . Origins and history:- The first Bowie-Dick Test was created by Dr. J. Bowie and Mr. J. Dick and was first published in the ‘Lancet’ journal in 1963. The Bowie-Dick Test is a Class 2 Chemical Indicator and purpose of evaluating the efficacy of dynamic air removal sterilizer systems. The Bowie-Dick Test is not to be considered a biological performance test. If the air is not effectively removed, air pockets will occur in the chamber and sterilization conditions will not be attained . Bowie-Dick or DART Test pack, the uniformity of the color change on the indicator sheet should be checked. (3.5 min. at 134 0C )

LEAK RATE TEST:-: 

The presence of air prevents proper penetration of of the load by steam and thus inhibits sterilization. Air leaking from outside into the chamber at the end of sterilization cycle will contaminate the load. A leak rate equivalent to a rate of change in pressure of 1 mm Hg/min. over a period of 10 min . after stabilization is the maximum permitted rate.

CHANGE CONTROL AND REVALIDATION: 

Any changes to the sterilization equipment and/or related utilities should be evaluated by a Change Control Procedure. Typical Changes Requiring Revalidation • Any changes in operating cycle ( i.e:temperature , time , belt speed, chamber pressure) • Change in load configuration. • Change in sterilized materials. • Major maintenance work on critical instruments/elements or utilities

Validation - The Essential Quality Assurance Tool for Pharma Industries

Validation is an essential part of good manufacturing practices (GMP). It is an element of the quality assurance programmed associated with a particular product or process. Establishing documented evidence. Provide a high degree of assurance. Quality is always an imperative prerequisite when we consider any product. It becomes prime when it relates to life saving products like pharmaceuticals. Although it is mandatory from the government and regulatory bodies but it is also a fact that quality of a pharmaceutical product cannot be adequately controlled solely by pharmacopoeial analysis of the final product. Today quality has to be built in to the product right from its inception and rigorous international environmental, safety and regulatory standards need to be followed. Validation had proven to be an important tool for quality management of pharmaceuticals. According to ISO 9000:2000.

Validation is defined as "Confirmation, through the provision of objective evidence, that the requirements for a specific intended use or application have been fulfilled". In contrast with Verification, Validation rather focuses on the question whether a system can perform its desired functions. This review is an attempt to prove the it as essential tool for quality management in pharmaceutical industry.

Introduction to Validation

Validation is a concept that has been evolving continuously since its first formal appearance in United States in 1978. The concept of validation has expanded through the years to encompass a wide range of activities from analytical methods used for the quality control of drug substances and products to computerized system for clinical trial, labeling or process control. Validation is the overall expression for a sequence of activities in order to demonstrate and document that a specific product can be reliably manufactured by the designed processes, usually, depending on the complexity of today’s pharmaceutical products, the manufacturer must ensure; "that products will be consistently of a quality appropriate to their intended use”.

To achieve this with confidence, only in process control and finished product testing alone are not sufficient to assure product quality; but all factors including the services which could affect product quality must be correctly designed, demonstrated to work effectively. Consistently and their performance is also regularly conformed so that consistent quality product is obtained. For example, no sampling plan for applying sterility tests to a specified proportion of discrete units selected from a sterilization load is capable of demonstrating with complete assurance that all of the untested units are infect sterile .

In recent year many manufacture houses have attempted to define their philosophy and strategy for self inspecting their plants for manufacturing ,processing and packing ,including holding of drugs .As much these manufacturers are interpreting the GMP guidelines as evaluated by Food and drug Authority and the schedule M after due modification in 1988

A philosophy of performing systematic inspection has worked and may be termed “Drug in- process inspection and validation”. The compliance to their working rules defines a validated manufacturing process as “one has been proven to do what it purport or it represented to do. The proof of validation is obtained through the collection and evaluation of data, preferably beginning from the process development phase and continuing through in to the product phase. Validation necessarily includes process qualification such as materials, equipment, system, building and personnel, but it also includes the control of the entire process for repeated batches or runs.

The word “validation” simply means assessment of validity or action of proving effectiveness. According to European community for medicinal products, validation is action of proving in accordance with the principals of good manufacturing practices, that any procedure, process, equipment, material, activity or system actually leads to expected results.

Validation is a proof that a process works and this must be done using scientific and statically principles. This is done to establish process capability and to confirm product acceptability.⁴ Validation determined process variables and the acceptable limits for these variables and accordingly sets up appropriate in process controls, which specifies alert and action levels.

Validation is defined as to establishing documented evidence that a process or system, when operated within established parameters, can perform effectively and reproducibly to produce a medicinal product meeting its pre-determined specifications and quality attributes.

VALIDATION PRINCIPLES the basic principle of quality assurance is that a drug should be produced that is fit for its intended use. In order to meet this principle, a good understanding of the processes and their performance is important. Quality should be built into the manufacturing processes. Careful design and validation of system and process controls can establish a high degree of confidence that all lots or batches produced will meet their intended specifications. Validation activity is not the responsibility of any one single department in an organization. The organization must have a group of people pulled from various departments and convert It into a good homogenous team. The team member may be taken from research and development. Any one person who has a basic understanding of validation and capability and maturity of a manager should head this team. A clear communication system should be developed amongst the team member and the other members of the organization the validation activity is a highly challenging and each member of the team has to accept this challenge. The Validation Master Plan is a document that describes how the validation program will be executed in a facility. I t is the document that outlines the principles involved in the qualification of a facility, defines the areas and systems to be validated provide the format required for each particular validation document (IQ, OQ, PQ for EQ and systems; process validation, analytical assay validation) indicate what information is to be contained within each document indicate why and when revalidations will be performed who will decide what validations will be performed order in which each part of the facility is validated. Indicate how to deal with any deviations state the time interval permitted between each validation. VMP should reflect the key elements of the validation programmed. It should be concise and clear and contain at least the following A Validation policy organizational structure of validation activities. summary of facilities, systems, equipment and processes validated and to be validated documentation format (e.g. protocol and report format) planning and scheduling, change control. The VMP describes clearly and concisely the company’s philosophy, expectations and approach to be followed.. Identifies the systems and controls to be validated. The level of testing required. Covers all aspects of the project as equipment qualification. Developed in the early stages of a production. Object and allow a logical progression from plan to validation schedule. The VMP can also assist in monitoring and tracking the progress of the project by performing periodic audit reviews v/s the approved version of the VMP. Importance of the VMP: It provides the total pictures of the project. It is a management tool for tracking progress. Assignment of responsibility, which promote team work. It identifies acceptance criteria before the start of validation . Benefits of VMP: Cover page ( approvals) Scope of project (which process being validated) Objectives / backgrounds Description Installation qualification (IQ), Operational qualification (OQ), Performance qualification ( PQ) Role and responsibilities. SOP’s requirement. Process monitoring . Format for validation protocol: Acceptance criteria /test methods . Deliverables. Documentation requirement Additional information- -A flow chart of the process -Sampling methods to be used -In process samples to be collected and details of collection -Testing to be conducted on samples collected -Sample size ,type of container, and swab techniques -Tools and precautions Almost all GMP texts recommend that whenever there are significant changes in the facility, equipment or process, revalidation should be carried out . In following Conditions revalidation should be carried out: Change in a critical component Change or replacement in a critical piece of modular equipment Change in a facility and/or plant Significant increase or decrease in batch size Sequential batches that fail to meet product and process specifications . IV ) Revalidation. Clearly defined procedures are required in order to control any changes in the production processes. These procedures should control all the planned changes and ensure the presence of sufficient supporting data that show that modified process will result in a product of the desired quality. The change control system should ensure that all notified or requested changes are satisfactorily investigated, documented and authorized. Products made by processes subjected to changes should not be released for sale without full awareness and consideration of the change by the Validation.

APPROACHES TO VALIDATION There is two basic approaches to validation Prospective and concurrent validation Retrospective validation. Qualification define as Action of proving and documenting that any premises, systems and equipment are properly installed, and/or work correctly and lead to the expected results. Qualification is often a part (the initial stage) of validation, but the individual qualification steps alone do not constitute process validation . There is five type of Qualification. Defines the functional and operation specification of the instrument , program, or equipment and details the rationale for choosing the supplier DQ should ensure that instruments have all the necessary functions and performance criteria that will enable them to be successfully implemented for the intended application and to meet user requirements. Design Qualification (DQ ) D Q considerations include: Description of the analysis problem. Description of the intended use for the equipment. Description of the intended environment. Preliminary selection of the functional and performance specification (technical, environmental, safety ). Preliminary selection of the supplier. Final selection of the supplier and equipment. Development and documentation of final functional and operational specifications.

Written for critical processing EQ and systems list all the identification information, location, utility requirements, and any safety features of EQ verify that the item matches the purchase specifications II Installation qualification (IQ): Equipment design features Installation conditions Calibration, preventative maintenance, cleaning schedules Safety features Supplier documentation, prints, drawings and manuals Software documentation Spare parts list Environmental conditions Important IQ considerations are: Follow an authorized 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 . pH meter, incubator, centrifuge, freezer; IQ,OQ Operational Qualification (OQ) Process control limits Software parameters Raw material specifications Process operating procedures Material handling requirements Process change control Training Short term stability and capability of the process OQ considerations include: In this phase the key objective is to demonstrate the process will consistently produce acceptable product under normal operating conditions. PQ considerations include: Actual product and process parameters and procedures established in OQ Acceptability of the product Assurance of process capability as established in OQ Process repeatability, long term process stability Performance qualification 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 system: air (HVAC), compressed air, pure steam, raw steam, purified water, WFI, central vacuum; IQ, OQ, PQ EQ: autoclave, oven, lyophilizer, continuous flow centrifuge; IQ, OQ, PQ CQ is a relatively new term developed in 2005. This term refers to the manufacturing of auxiliary components to ensure that they are manufactured to the correct design criteria. CQ considerations include: packaging components such as folding cartons , shipping cases, labels or even phase change material . Component qualification (CQ) 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

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Posted by:Indian Biological Sciences and Research Institute, NOIDA