European Journal of Biomedical and Pharmaceutical ISSN Sciences

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1 ejbps, 2015, Volume 2, Issue 4, Review Article SJIF Impact Factor Himanshu et al. European Journal of Biomedical AND Pharmaceutical sciences European Journal of Biomedical and Pharmaceutical ISSN Sciences Volume: 2 Issue: Year: 2015 PROCESS VALIDATION A REVIEW Himanshu Paliwal*, Suresh Kumar Purohit and Kamal Singh Rathore Bhupal Nobles Institute of Pharmaceutical Sciences, Udaipur, (Raj.) Article Received on 15/05/2015 Article Revised on 10/06/2015 Article Accepted on 04/07/2015 ABSTRACT *Correspondence for Validation is a preeminent constituent of quality assurance scheme of a Author particular process. Validation is regarded as the requisite component of Himanshu Paliwal Bhupal Nobles Institute of Good Manufacturing Practices (cgmp).when such a technique is Pharmaceutical Sciences, employed in examining each step of manufacturing process; it is Udaipur, (Raj.) referred to as Process Validation. It allows us to ensure that a given pharmaceutical process will produce quality products that meet its predetermined specifications. Process Validation focuses on process design elements and maintaining control over process during commercialization and communicate that process validation is an ongoing program and align process validation activities with product lifecycle. Process Validation also accentuates understanding, identifying and control of variability. Here this article aims to explore the importance of pharmaceutical process validation. The objective is to confer a review and describe objective and principle of process validation, types of validation operations, regulatory basis, validation protocol and master plan and other relevant considerations. KEYWORDS: Process Validation, cgmp, Qualification, Quality Assurance, Protocol. INTRODUCTION Pharmaceutical Process Validation is the most important and recognized parameters of cgmps. The requirements of process validation appear of the quality system (QS) regulation. The goal of a quality system is to consistently produce products that are fit for their intended use. Process validation is a key element in assuring that these principles and goals are met. The process validation is standardization of the validation documents that must be submitted with the submission file for marketing authorization. The process validation is intended to assist manufacturers in understanding quality management system (QMS) requirements 172

2 concerning process validation and has general applicability to manufacturing process. According to FDA, assurance of product quality is derived from careful and systemic attention to a number of important factors, including: selection of quality process through inprocess and end-product testing. Validation is a concept that has evolved inunite states in 1978.The concept of validation has expanded through the years to embrace a wide range of activities from analytical methods used for the quality control of drug substances and drug products to computerized systems for clinical trials, labelling or process control. Validation is founded on, but not prescribed by regulatory requirements and is best viewed as an important and integral part of cgmp. The word validation simply means assessment of validity or action of proving effectiveness. Validation is a team effort where it involves people from various disciplines of the plant. [1] In January 2011, FDA announced the availability of a final guidance for industry entitled Process Validation: General Principles and Practices (the 2011 Guidance). The 2011 Guidance revises and replaces FDA s Guidance for industry entitled Guideline on General Principles of Process Validation, issued in May 1987 (the 1987 Guideline). The 2011 Guidance defines process validation as the collection and evaluation of data, from the process design stage through commercial production which establishes scientific evidence that a process is capable of consistently delivering quality product. The 2011 Guidance promotes a lifecycle approach to process validation that includes scientifically sound design practices, robust qualification, and process verification. [2] OBJECTIVES OF PROCESS VALIDATION The manufacturing process, in addition to the individual equipment, must be validated. The goal is to create a robust manufacturing process that consistently produces a drug product with minimal variation that adheres to quality criteria of purity, identity, and potency. A validation plan for the manufacturing process should be drafted and executed by engineers in order to satisfy guidelines. The validation plan usually involves just a PQ section. Just as equipment validation, major changes after the initial validation will result in the need for subsequent revalidation. In the end, process validation will ensure a robust product that is highly reproducible over time. [3] 173

3 BASIC PRNCIPLE FOR PROCESS VALIDATION The basic principle for validation may be stated as follows. 1. Installation Qualification (IQ): Establishing by objective evidence that all key aspects of the process equipment and ancillary system installation adhere to the manufacturer s approved specification and that the recommendation of the supplier of the equipment are suitably considered. IQ considerations are Equipment design features (i.e. material of construction cleanability, etc.) Installation conditions (wiring, utility, functionality, etc.) Calibration, preventative maintenance,cleaning schedules. Safety features. Supplier documentation, prints, drawings and manuals. Software documented. Spare parts list. Environmental conditions (such as clean room requirements, temperature, and humidity). 2. Operational Qualification (OQ): Establishing by objective evidence process control limits and action levels which result in product that all predetermined requirements. 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. The use of statistically valid techniques such as screening experiments to optimize the process can be used during this phase

4 3. Performance Qualification (PQ): Establishing by objective evidence that the process, under anticipated conditions, consistently produces a product which meets all predetermined requirements. 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. [4] Re Qualification Requalification should be done in accordance with a defined schedule. The frequency of requalification may be determined on the basis of factors such as the analysis of results relating to calibration, verification and maintenance. There should be periodic requalification, as well as requalification after changes (such as changes to utilities, systems, equipment; maintenance work; and movement). Requalification should be considered as part of the change control procedure. [5] Qualification of Established (in-use) Equipment While it is not possible to undertake the details of an Installation Qualification for established equipment nor the detailed approach for an Operational Qualification, nevertheless there should be data available that support and verify the operating parameters and limits for the critical variables of the operating equipment. Additionally, the calibration, cleaning, preventative maintenance, operating procedures and operator training procedures for the use of the equipment should be documented and in use as standard operating procedures (SOPs). [6] TYPES OF PROCESS VALIDATION Prospective Validation: During prospective validation, critical parameters that may affect the quality of the finished product are assessed. Sequence of trial should be designed to determine the criticality of these factors. All equipment, production environment and the analytical testing methods to be used should be fully validated. Preparation of Master batch documentation will be initiated after identification of critical parameters, machine settings, component specifications and environmental conditions of the process. [7] Conducted prior to the distribution of either a new product or a product made under a modified production 175

5 process, where the modifications are significant and may affect the products characteristics. It is a preplanned 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 is executed and environmental controls. [8] In Prospective Validation, the validation protocol is executed before the process is put into commercial use. It is generally considered acceptable that three consecutive batches/runs within the finally agreed parameters, giving product of the desired quality would constitute a proper validation of the process. It is a confirmation on the commercial three batches before marketing. [9] Concurrent Validation A process where current production batches are used to monitor processing parameters. It gives of the present batch being studied, and offers limited assurance regarding consistency of quality from batch to batch. [8] Concurrent Validation may be the practical approach under certain circumstances. Examples of these may be when. [9] A previous validated process is being transferred to a third party contract manufacturer or to another site. The product is a different strength of a previously validated product with the same ratio of active/inactive ingredients. The numbers 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 numbers of batches produced are limited. Process with low production volume per batch and market demand. Process of manufacturing urgently needed drug due to shortage or absence of supply. In all above cases concurrent validation is valid, provided following conditions are appropriately. Pre-approved protocol for concurrent validation with rational. A deviation shall be raised with justification and shall be approved by plant head /head process owner/head-qms. Product behaviour and history shall be reviewed based on developmental/scale up /test batches

6 A detailed procedure shall be planned for handling of the marketed product if any adverse reactions observed in concurrent validation process. Concurrent validation batches shall be compiled in report and shall be approved all key disciplines. Retrospective Validation Retrospective validation is applicable to processes that are stable and in routine use which have not undergone a formally documented validation process. Documentary evidence for the validity of the processes can be provided by utilizing the historical data. Retrospective validation requires the preparation of a protocol and reporting of the results for the data review, which leads to a conclusion and recommendation. Retrospective validation is only acceptable approach for well established detailed processes that include operational limits for each critical step of the process and will be inappropriate where there is a change in operating procedures, product formulation, equipment and facility. Data from batch documents, process control charts, annual product quality review reports, maintenance log books, process capability studies, finished product test results, including trend analyses, and stability results acts as a source for retrospective validation. [7] Conducted for a product already being marketed, and is based on extensive data accumulated over several lots and over time. Retrospective Validation may be used for older products which were not validated by the fabricator at the time that they were first marketed, and which are now to be validated to confirm to the requirements of division 2, Part C of the Regulation to be Food and Drugs Act. Retrospective Validation is only acceptable for well established detailed processes and will be Inappropriate where there have recent changes in the formulation of the products, operating procedures, equipment and facility. [8] 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. List of process deviations, corrective actions and changes to manufacturing documents. Data for stability testing for several batches. Trend analysis including those for quality related complaints. [9] 177

7 Process Re-Validation Required when there is a change in any of the critical process parameters, formulation, primary packaging components, raw material fabricator, major equipment or premises. Failure to meet product and process specifications in batches would also require process revalidation. Re-Validation becomes necessary in certain situations. The following are examples some of the planned or unplanned changes that may require re-validation. Changes in raw materials (physical properties such as density, viscosity, particle size distribution, and moisture, etc., that may affect the process or product). Changes in the source of active raw material manufacturer. Changes in packaging material (primary container/closure system). Changes in the process (e.g., mixing time, drying temperatures and batch size). Changes in the equipment (e.g. addition of automatic detection system). Changes of equipment which involve the replacement of equipment on a like for like basis would not normally require a revalidation except that this new equipment. Must be qualified. Changes in the plant/facility. Variations revealed by trend analysis (e.g. process drifts). [8] REGULATORY BASIS FOR PROCESS VALIDATION The concept of process validation from its beginning in the early 1970s through the regulatory aspects associated with current good manufacturing practice (cgmp) regulations and the application thereof to various analytical, quality assurance, pilot plant, production, and sterile product and solid dosage forms considerations. In the early 1990s, the concept of preapproval inspection (PAI) was born and had as one of its basic tenets the assurance that approved validation protocols and schedules were being generated and that comprehensive development, scale-up, and bio batch and commercial batch validation data were required in order to achieve a successful regulatory PAI audit. There are several important reasons for validating a product and/or process. First, manufacturers are required by law to conform to cgmp regulations. Second, good business dictates that a manufacturer avoids the possibility of rejected or recalled batches. Third, validation helps to ensure product uniformity, reproducibility and quality

8 Although the original focus of validation was directed towards prescription drugs, the FDA Modernization Act of 1997 expanded the agency s authority to inspect establishments manufacturing over-the-counter (OTC) drugs to ensure compliance with cgmp. Once the concept of being able to predict process performance to meet user requirements evolved, FDA regulatory officials established that there was a legal basis for requiring process validation. The ultimate legal authority is Section 501(a) (2) (B) of the FD&C Act, which states that a drug is deemed to be adulterated if the methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or were not operated or administrated in conformity with cgmp. [10] Regulations mandate compliance with Good Manufacturing Practices (GMP) for the manufacture of clinical trial materials. Validation is one component of the GMPs, but it is not feasible to complete validation before a process is fully developed. Instead, it is important to understand what is required for phase 1, 2, and 3 clinical trials. Understanding the requirements means that the needs of the patient and the expectations of the regulatory agencies are considered. From both patient and regulatory perspectives, safety is critical. An understanding of the risks associated with product source, manufacturing methods, and the product itself is essential for making decisions about what has to be validated for the various clinical trial phases. [11] PREREQUISITE OF 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 prerequisites to successful validation. [12] Process Development Designee shall review the product development report, data from pilot scale, scale up batch and proposed master formula document of product intended for manufacturing

9 Process Development Designee shall review/ensure the availability analytical method transfer report to the plant and plant preparedness for conducting validation testing and routine testing; function shall co-ordinate with QC/QA in this regards. Process Development Designee shall prepare commercial/exhibit batch production and control records which include the operational limits and overall strategy for process control based on development report. The Process Validation is performed after the facility, utility, and equipment, and laboratory test methods have been validated and released fir process validation activities. Where compendia method is used only limited analytical method validation shall be conducted. All raw material and packaging material specification shall be from approved vendors and shall be approved by quality control. All the equipment and instrument to be utilized are calibrated and preventive maintenance programs are in place. Relevant SOPs are in place and training is completed on equipment, operation, manufacturing instruction and sampling strategy. Key process steps and process variables are identified and their operating ranges have been established. All the master formula, manufacturing instruction, packaging instruction, testing procedure and specification shall be approved before execution of process validation batches. The cleaning of the area and equipment has been completed prior to the initiation of process validation. The validation team and operational team shall be trained from process engineer. [13] STRATEGY FOR INDUSTRIAL PROCESS VALIDATION OF SOLID DOSAGE FORMS The strategy selected for process validation should be simple and straightforward. The following five points gives strategy for process validation. The use of different lots of raw materials should be included. i.e., active drug substance and major excipients. Batches should be run in succession and on different days and shifts (the latter condition, if appropriate)

10 Batches should be manufactured in the equipment and facilities designated for eventual commercial production. Critical process variables should be set within their operating ranges and should not exceed their upper and lower control limits during process operation. Output responses should be well within finished product specifications. Failure to meet the requirements of the Validation protocol with respect to process input and output control should be subjected to process requalification and subsequent revalidation. [14] PROCESS VALIDATION WITHIN THE QUALITY MANAGEMENT SYSTEM Process validation is part of the integrated requirements of a quality management system. It is conducted in the context of a system including design and development control, quality assurance, process control, and corrective and preventive action. The product should be design robustly enough to withstand variations in the manufacturing process and the manufacturing process should be capable and stable to assure continued safe products that perform adequately. Corrective actions often identify inadequate processes/process validations. Each corrective action applied to a manufacturing process should include the consideration for conducting process validation/ revalidation. [13] REASON FOR PROCESS VALIDATION There are two main reasons for validating a process. The first is to reduce production costs of sorting and rework due to the manufacture of non-conforming products [products that do not meet their specification(s)]. The second is to meet regulatory requirements. [15] The possible reason of performing process validation may include: New product or existing products as per SUPAC changes. Change in site of manufacturing. Change in batch size. Change in equipment. Change in process existing products. Change in composition or components. Change in the critical control parameters. Change in vendor of API or critical excipient. Change in specification on input material

11 Abnormal trends in quality parameters of product through review during Annual Product Review (APR). Trend of Out of Specification (OOS) or Out of Trend (OOT) in consecutive batches. [16] BENEFITS OF PROCESS VALIDATION Consistent through output. Reduction in rejections and reworks. Reduction in utility cost. Avoidance of capital expenditures. Fewer complaints about process related failure. Reduced testing in process and finished goods. More rapid and accurate investigations into process deviation. More rapid and reliable start-up of new equipment. Easier scale-up from development work. Easier maintenance of equipment. Improve employee awareness of processes. More rapid automation. [14] STAGES OF PROCESS VALIDATION Process Validation is defined as the collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality products. Process Validation involves a series of activities taking place over the lifecycle of the product and process. The activities relating to validation studies may be classified into three stages. Stage 1 Process Design Focusing exclusively on qualification efforts without also understanding the manufacturing process is defined during this stage based on knowledge gained through development and scale-up activities.. [17] The first step in the process requires four main activities be performed: Definition of Quality Target Product Profile or (QTPP), in other words, how you want your product to look like and behave. Definition of Critical Quality Attributes (CQAs), the features that are important to you in meeting the target profile. Definition of Critical Process Parameters (CPPs) which 182

12 are the limitations or restrictions that may impact your product during manufacturing. When defining your CPPs you will also consider the features of machinery and equipment, such has operating ranges, speed, compression force etc. Finally, a risk assessment based on the anticipated interaction of your Raw Materials and Process Components and their impacts on CQAs. At the end of stage 1 you will have 5 major outputs. The determination and verification of the critical process parameters A high degree of understanding of the interaction between the CPPs, Material Attributes and the CQAs. Established process limits and operating ranges through your design of experiment activities. Risk assessment and mitigation, or control strategy. A report that contains all the information required for Stage 2 or Process Qualification. [18] Stage 2 Process Qualification During this stage, the process design is evaluated to determine if the process is capable of reproducible commercial manufacturing. [17] The focus of the process qualification stage is to evaluate if the process is capable of reproducible commercial manufacturing. This is accomplished through the manufacturing of a number of commercial batches. Remember that we design our protocols based on the product and process understanding gathered in the design stage. A lot of the information that goes into the protocol can be extracted from your Technical Transfer Reports developed in stage 1. Information such as the Critical Process Parameters (CPPs), Critical Quality Attributes, and your control strategy or the testing that will be required at the different stages of manufacturing. The results of the testing will provide the evidence and confidence that the process is capable of yielding reproducible quality product, within the established parameters. The major output at the end of this phase is the Stage 2 Report. This report documents adherence to the process qualification protocol, provides a summary of data collected and the result of the analysis providing evidence of process control. [18] 183

13 There are two aspect of Process Qualification. Design of Facilities and Qualification of Equipment and Utilities a. Proper design of manufacturing facility is desired under 21 CFR part 211, subpart C, of the cgmp regulation on Buildings and Facilities. b. Activities performed to assure proper facility design and commissioning precede Process Performance Qualification. Here, the term qualification refers to activities undertaken to demonstrate that utilities and equipment are suitable for their intended use and perform properly. These activities necessarily precede manufacturing products at the commercial scale. Process Performance Qualification Criteria and process performance indicators that allow for a science and risk-based decision about the ability of the process to consistently produce quality products. a. Part of the planning for stage 2 involves defining performance criteria and deciding what data to collect when, how much data, and appropriate analysis of the data. b. Likely consist of planned comparisons and evaluations of some combination of process measures as well as in-process and trial product attributes. c. Manufacturer must scientifically determine suitable criteria and justify it. d. Objective measures, where possible. e. May be possible to leverage earlier study data if relevant to the commercial scale. [17] Figure 1: Stages of Process Validation 184

14 Stage 3 Continued Process Verification The goal of the third validation stage is continual assurance that the process remains in a state of control (the validated state) during commercial manufacture. A system or systems for detecting unplanned departures from the process as designed is essential to accomplish this goal. Adherence to the CGMP requirements, specifically, the collection and evaluation of information and data about the performance of the process, will allow detection of undesired process variability. Evaluating the performance of the process identifies problems and determines whether action must be taken to correct, anticipate, and prevent problems so that the process remains in control. [17] This phase requires a state of control be maintained during routine commercial production, in tandem with continuous monitoring and verification of each step in the process. Any deviations encountered will trigger the need for further testing and risk assessment. Ultimately, this type of process validation aims to verify the critical activities of production to ensure standardization, efficiencies, and quality throughout the entire product lifecycle. [18] PHASES IN PROCESS VALIDATION The activities relating to validation studies may be classified into three. Phase1: Pre-Validation Qualification Phase This phase is 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 and storage, and handling of in-process and finished dosage forms, equipment qualification, installation qualification master production document, operational qualification and process capacity. Phase 2: Process Validation Phase It is designed to verify that all established limits of the critical process parameter are valid and that satisfactory. Products can be produced even under the worst conditions. Phase 3: Validation Maintenance Phase It requires frequent review of all process related documents, including validation of audit reports, to assure that there have been no changes, deviations failures and modifications to the production process and that all standard operating procedures (SOPs), including change control procedures, have been followed. At this stage, the validation team comprising of 185

15 individuals representing all major departments also assures that there have been no changes/deviations that should have resulted in requalification and revalidation. [19] Fig. 2: Phases in Process Validation ONGOING PROCESS VERIFICATION DURING LIFECYCLE Manufacturers should monitor product quality to ensure that a state of control is maintained throughout the product lifecycle with the relevant process trends evaluated. The extent and frequency of ongoing process verification should be reviewed periodically and modified if appropriate, considering the level of process understanding and process performance at any point in time in the product lifecycle. Ongoing process verification should be conducted under an approved protocol and a corresponding report should be prepared to document the results obtained. Statistical tools should be used, where appropriate, to support any conclusions with regard to the variability and capability of a given process and ensure a state of control. Ongoing process verification should be used to support the validated status of the product in the Product Quality Review, however, incremental changes over time should also be considered and the need for any additional actions (e.g. enhanced sampling) should be assessed. Ongoing process verification should be considered where any individual change or successive incremental changes during the product lifecycle could have an impact on the validated status of the process. [20] 186

16 VALIDATION OF PHARMACEUTICAL PACKAGING LINES To manage a packaging line, adequate standard operating procedures (SOPs) will be required. It is vital that there are clear and unambiguous instructions on how to operate, adjust, and maintain each piece of equipment. In addition, there will be procedures to detail how a batch is packaged, SOP usually explains how each material is received on the line and checked for correctness, quantity, etc. by the operators. Details of In Process Control (IPC) tests will be given in these SOPs. Involving the line operators in developing the SOPs will result in documents that more accurately reflect what is actually happening on a day to day basis. Operators will also take ownership of the SOPs ensuring better compliance and hence less problems on the line. [21] VALIDATION PROTOCOL Detailed protocols for performing validations are essential to ensure that the process is adequately validated. Process validation protocols should include the following elements: o Objectives, scope of coverage of the validation study. o Validation team membership, their qualifications and responsibilities. o Type of validation: prospective, concurrent, retrospective, re-validation. o Number and selection of batches to be on the validation study. o A list of all equipment to be used; their normal and worst case operating parameters. o Outcome of IQ, OQ for critical equipment. o Requirements for calibration of all measuring devices. o Critical process parameters and their respective tolerances. o Process variables and attributes with probable risk and prevention shall be captured. o Description of the processing steps: copy of the master documents for the product. o Sampling points, stages of sampling, methods of sampling, sampling plans. o Statistical tools to be used in the analysis of data. o Training requirements for the processing operators. o Validated test methods to be used in in process testing and for the finished product. o Specifications for raw and packaging materials and test methods. o Forms and charts to be used for documenting results. o Format for presentation of results, documenting conclusions and for approval of study results. [9] 187

17 VALIDATION MASTER PLAN All validation activities should be planned. The key elements of a validation programme should be clearly defined and documented in a validation master plan (VMP) or equivalent documents. [22] The validation master plan should provide an overview of the entire validation operation, its organizational structure, its content and planning. The core of the VMP 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 revalidation. The Validation Master Plan should be a summary document and should therefore be brief, concise and clear. It should not repeat information documented elsewhere but should refer to existing documents such as policy documents, SOP s and validation protocols and reports. The format and content should include. Introduction: validation policy, scope, location and schedule. Organizational structure: personnel responsibilities. Plant/process/product description: rational for inclusions or exclusions and extent of validation. Specific process considerations that are critical and those requiring extra attention. List of products/ processes/ systems to be validated, summarized in a matrix format, validation approach. Re-validation activities and actual status Key acceptance criteria. Documentation format. Reference to the required SOP s. Time plans of each validation project and sub-project. [23] PROCESS VALIDATION AND QUALITY ASSURANCE Process validation is part of the integrated requirements of a quality management system. It is conducted in the context of a system including design and development control, quality 188

18 assurance, process control, and corrective and preventive action. The product should be design robustly enough to withstand variations in the manufacturing process and the manufacturing process should be capable and stable to assure continued safe products that perform adequately. Corrective actions often identify inadequate processes/process validations. Each corrective action applied to a manufacturing process should include the consideration for conducting process validation/ revalidation. [24] The relationship of quality assurance and process validation goes well beyond the responsibility of any quality assurance (QA) function. Nevertheless, it is a fair to say that process validation is a QA tool, because it establishes a quality standard for the specific process. Quality assurance in pharmaceutical companies embodies the effort to assure that products have the strength, purity, safety and efficacy represented in the company s new drug application (NDA) filings. Although quality assurance is usually designated as a departmental function, it must also be an integral part of an organization s activities. When process validation becomes a general objective of the technical and operational groups within an organization, it becomes the driving force for quality standards in development work, engineering activities, quality assurance, and production. The quality assurance associated with the pharmaceutical development effort includes the following general functions. To ensure that a valid formulation is designated. To qualify the process that will be scaled up to production-size batches. To assist the design of the validation protocol. To manufacture the bio batches for the clinical program, which will become the object of the FDA s preapproval clearance. To work with production and engineering to develop and carry out the qualification program for production equipment and facilities/process systems. To develop validated analytical methods to allow. The stability program to be carried out. The testing of raw materials and finished product The development of release specifications for the raw materials and finished product

19 The testing of processed material at certain specified stages. Quality assurance is the effort taken to ensure compliance with government regulations for the systems, facilities, and personnel involved with manufacturing products. QA audits will be quite varied in scope to achieve this assurance. These responsibilities include batch record reviews, critiques of product design, process validation activity, and, possibly, audits of other departments operations. [25] VALIDATION REPORT Validation Report provides an overview of the entire validation project. Once the summary report is signed, the validation project is considered to be complete. When regulatory auditors review validation projects, they typically begin by reviewing the summary report. When validation projects use multiple testing systems, some organizations will produce a testing summary report for each test protocol, then summarize the project with a final Summary Report. The amount of detail in the reports should reflect the relative complexity, business use, and regulatory risk of the system. The report is often structured to mirror the validation plan that initiated the project. The report is reviewed and signed by the system owner and Quality. The collection of documents produced during a validation project is called a Validation Package. Once the validation project is complete, all validation packages should be stored according to your site document control procedures. Summary reports should be approved by the System Owner and Quality. [26] A written report should be available after completion of the validation. If found acceptable, it should be approved and authorized (signed and dated). The report should include at least the following. Title and objective of study. Reference to protocol. Details of material. Equipment. Programmes and cycles used

20 Details of procedures and test methods. Results (compared with acceptance criteria). Recommendations on the limit and criteria to be applied on future basis. [27] DOCUMENTATION Good documentation is an essential part of the quality assurance system and, as such, should exist for all aspects of GMP. Its aims are to define the specifications and procedures for all materials and methods of manufacture and control; to ensure that all personnel concerned with manufacture know what to do and when to do it; to ensure that authorized persons have all the information necessary to decide whether or not to release a batch of a drug for sale, to ensure the existence of documented evidence, traceability, and to provide records and an audit trail that will permit investigation. It ensures the availability of the data needed for validation, review and statistical analysis. The design and use of documents depend upon the manufacturer. [28] The degree and type of documentation required by cgmp is greatest during process qualification, and continued process verification. Studies during these stages must conform to cgmps and must be approved by the quality unit in accordance with the regulations. [17] All the documentation which is part of the validation process should be maintained by the document control system and retained for a minimum of 15 years or the life time of the process, equipment, facilities or systems, whichever is the longest. SOPs should be written and authorised prior to the equipment/method/system being brought into routine use. [29] CONCLUSION It is mandatory before authorization of a new product, that a reliable evaluation for its potency and safety for the preconceived indication and target patient population is demonstrated. The Process Validation is intended to facilitate the manufacturers in understanding quality management system (QMS) requirements concerning process validation and has substantial applicability to manufacturing process. The product designed should have characteristics, which enables it to withstand alterations in manufacturing process and the manufacturing process should be efficient and stable to ensure continued safe products. The end product testing is not sufficient to assure quality of a product, therefore validation has become a vital aspect of quality assurance. Persisted knowledge of validation requirements and conscientious implementation of validation 191

21 principles will thus help to ensure that pharmaceutical products will be produced with reproducible attributes required from the regulatory agencies across the globe. REFERENCES 1. Kaur H, Singh G, Seth N Pharmaceutical Process Validation: A Review, Journal of Drug Delivery & Therapeutics., 2013; 3(4): Katz P and Campbell C FDA 2011 Process Validation Guidance: Process Validation Revisited, Journal of GXP Compliance, Autumn., 2012; 16(4): Tandel JM, Dedania ZR and Vadalia KR Review on Process Validation of Pyrazinamide Tablets, International Journal of Advances in Pharmacy, Biology and Chemistry., 2012; 1(3): Quality Management System Process Validation Guidance GHTF/SG3/N99-10: 2004 (Edition 2): Supplementary guidelines on good manufacturing practices: validation; Annex 4, WHO Technical Report Series, 2006; 937: Validation Master Plan Installation and Operational Qualification Pharmaceutical Inspection Convention, Pharmaceutical Inspection Co-Operation Scheme 2007; PI 006(3): Kathiresan K, Moorthi C, Prathyusha Y, Gade B. R, Reddy B. K, Manavalan R An overview of pharmaceutical validation, Research Journal of Pharmaceutical, Biological and Chemical Sciences; ISSN: ; October December 2010; 1(4): Health Canada / Health Products and Food Branch Inspectorate Validation Guidelines for Pharmaceutical Dosage Forms (GUI 0029) / December, Guidelines for Process Validation of Pharmaceutical Dosage Form Saudi Food & Drug Authority; Version 2.1; August, Singh H, Rana AC, Saini S, Singh G Industrial Process Validation of Solid Dosage Form: A Review, International Journal of Research Pharmacy., 2012; 3(4): Rathore AS, Noferi JF, Arling ER, Sofer G, Watler P, and O Leary R Process Validation How Much to Do and When to Do It, Bio Pharm., 2002; Jatto E, Okhamafe AO An Overview of Pharmaceutical Validation and Process Controls in Drug Development, Tropical Journal Pharmaceutical Research., 2002; 1(2): Mohammed SA Pharmaceutical Process Validation: An Overview, Journal of Advanced Pharmacy Education and Research., 2012; 2(4):

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23 28. WHO Expert Committee on Specifications for Pharmaceutical Preparations: thirtyseventh report; WHO technical report series; 908, World Health Organization, Geneva., Allard S, Burgess G, Cuthbertson B, Elliott C, Haggas R, Jones J, et al. Guidelines for Validation & Qualification, including Change Control for Hospital Transfusion Laboratories; British Committee for Standards in Haematology,