AN OVERVIEW: VALIDATION AND BASIC CONCEPTS OF ORGANIZATION FOR VALIDATION

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1 52 P a g e International Standard Serial Number (ISSN): International Journal of Universal Pharmacy and Bio Sciences 4(3): May-June 2015 INTERNATIONAL JOURNAL OF UNIVERSAL PHARMACY AND BIO SCIENCES IMPACT FACTOR 2.093*** Pharmaceutical Sciences ICV 5.13*** REVIEW ARTICLE!!! AN OVERVIEW: VALIDATION AND BASIC CONCEPTS OF ORGANIZATION FOR VALIDATION Rashmita A. Dalvi 1*, Megha S. Jadhav, S. B. Gondkar 2, R. B. Saudagar 3 1* Department of Quality Assurance Techniques, R. G. Sapkal College of Pharmacy, Anjaneri, Nashik ,Maharashtra, India. 2 Department of Quality Assurance Techniques, R. G. Sapkal College of Pharmacy, Anjaneri, Nashik ,Maharashtra, India. 3 Department of Pharmaceutics, R. G. Sapkal College of Pharmacy, Anjaneri, Nashik , Maharashtra, India. 4 Department of Pharmaceutical Chemistry, R. G. Sapkal College of Pharmacy, Anjaneri, KEYWORDS: Quality, validation, revalidation, organization for validation. For Correspondence: Rashmita A. Dalvi * Address: Department of Quality Assurance Techniques, R. G. Sapkal College of Pharmacy, Anjaneri, Nashik , Maharashtra, India. Nashik ,Maharashtra, India. ABSTRACT Quality is the primordial intention to any industry and its products manufactured. Multiple views on obtaining such quality are the current interest in the pharmaceutical industry. Acquainted with a practice that puts us in common and routine convention ensured to deliver a quality that sounds globally in terms of a spoken quality is on the dais of pharmaceutical arena. Validation is a systematic approach to gathering and analyzing sufficient data which will give reasonable assurance (documented evidence), based upon scientific judgment, that a process, when operating within specified parameters, will consistently produce results within predetermined specifications. Also, Validation is the art of designing and practicing the designed steps alongside with the documentation. Validation and quality assurance will go hand in hand, ensuring the through quality for the products. Hence, an emphasis made on to review that gives a detailed, overview of validation concept of designing, organizing and conducting validation trials. Additionally a view of validation against the quality assurance, drug development and manufacturing process has been discussed.

2 53 P a g e International Standard Serial Number (ISSN): INTRODUCTION: The concept of validation was first proposed by two FDA officials. Ted Byers and Loftus, in the mid 1970 s in order to improve the quality of pharmaceuticals (Agalloco 1995). The prime objective of any pharmaceutical plant is to manufacture products of requisite attribute and quality consistently, at the lowest possible cost. Although validation studies have been conducted in the pharmaceutical industry for a long time, there is an ever increasing interest in validation owing to their industry s greater emphasis in recent years on quality assurance program and is fundamental to an efficient production operation. The word validation simply means assessment of validity or action of proving effectiveness. Validation isa team effort where it involves people from various disciplines of the plant. This principle incorporates the understanding that the following conditions exist: Quality, safety, and efficacy are designed or built into the product. 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. Validation mainly based on, FDA regulations describing current good manufacturing practice (cgmp)for finished pharmaceuticals are provided in 21 CFR parts 210 and 211. The cgmp regulations require that manufacturing processes be designed and controlled to assure that inprocess materials and the finished product meet predetermined quality requirements and do so consistently and reliably. Process validation is required, in both general and specific terms, by the cgmp regulations in parts 210 and 211. Definitions (3) European commission: 1991 Validation- Act of proving, in accordance of GMPs that Any process actually leads to expectedresults Documented evidence that the process, operated within established Parameters, can perform effectively and reproducibly to produce a Medicinal product meeting its predetermined specifications and quality attributes. US FDA Definition: Process validation is establishing documented evidence which provides a high degree of assurance that a specified process will consistently produce a product meeting its pre-determined specifications and quality characteristics.

3 54 P a g e International Standard Serial Number (ISSN): ICH Definition: Process Validation is the means of ensuring and providing documentary evidence that processes within their specified design parameters are capable of repeatedly and reliably producing a finished product of the required quality. WHO Definition: The documented act of proving that any procedure, process, equipment, material, activity or system actually leads to expected result. Market requirements- (2) The demands in the health care industry are greater than ever because customers(government, physicians, pharmacists, patients, and health insurance companies) are more interested in product safety, efficacy, and potency and asking value for money. Pharmaceutical products quality must be consistent and meet the health and regulatory requirements. The pharmaceutical industry has the obligation to validate GMP to their process to be in compliance with GMP requirements. SCOPE OF VALIDATION (3) Pharmaceutical Validation is a vast area of work and it practically covers every aspect of pharmaceutical processing activities, hence defining the Scope of Validation becomes a really difficult task. However, a systematic look at the pharmaceutical operations will point out at least the following areas for pharmaceutical validation; Analytical Instrument Calibration Process Utility services Raw materials Packaging materials Equipment Facilities Manufacturing operations Product Design Cleaning Operators IMPORTANCE OF VALIDATION (2) 1) Increased throughput 2) Reduction in rejections and reworking 3) Reduction in utility costs 4) Avoidance of capital expenditures 5) Fewer complaints about process-related failures 6) Reduced testing in-process and in finished goods

4 55 P a g e International Standard Serial Number (ISSN): ) More rapid and reliable start-up of new equipment 8) Easier scale-up from development work 9) Easier maintenance of equipment 10) Improved employee awareness of processes 11) More rapid automation 12) Fewer complaints about process related failures. 13) Reduced testing in process and If finished goods. 13). More rapid and reliable start-up of new equipments 14). Easier scale-up form development work. 15). Easier maintenance of equipment. 16) Improved employee awareness of processes. 17) More rapid automation. 18) Government regulation (Compliance with validation requirements is necessary for obtaining approval to manufacture and to introduce new products) Types and methods of validation- 1) Prospective validation 2) Concurrent validation 3) Retrospective validation 4) Revalidation 1)Prospective validation- (1,3,) It is defined as the established documented evidence that a system does what it purports to do based on a pre-planned protocol. This validation usually carried out prior to distribution either of a new product or a product made under a revised manufacturing process. This approach to validation is normally undertaken whenever a new formula, process or facility must be validated before routine pharmaceutical formulation commences. In Prospective Validation, the validation protocol is executed before the process is put into commercial use. During the product development phase, the production process should be categorized into individual steps. Each step should be evaluated on the basis of experience or theoretical considerations to determine the critical parameters that may affect the quality of the finished product. A series of experiment should be designed to determine the criticality of these factors. Each experiment should be planned and documented fully in an authorised protocol. All

5 56 P a g e International Standard Serial Number (ISSN): equipment, production environment and the analytical testing methods to be used should have been fully validated. Master batch documents can be prepared only after the critical parameters of the process have been identified and machine settings, component specifications and environmental conditions have been determined. During the processing of the validation batches, extensive sampling and testing should be performed on the product at various stages, and should be documented comprehensively. Detailed testing should also be done on the final product in its package. Upon completion of the review, recommendations should be made on the extent of monitoring and the in-process controls necessary for routine production. These should be incorporated into the Batch manufacturing and packaging record or into appropriate standard operating procedures. Limits, frequencies and action to be taken in the event of the limits being exceeded should be specified. Prospective validation should include, but not be limited to the following: Short description of the process. Summary of the critical processing steps to be investigated. List of the equipment/facilities to be used (including measuring, monitoring/recording equipment) together with its calibration status. Finished product specifications for release. List of analytical methods, as appropriate. Proposed in-process controls with acceptance criteria. Additional testing to be carried out, with acceptance criteria and analytical validation, as appropriate. Sampling plan. Methods for recording and evaluating results. Functions and responsibilities. Proposed timetable. Batches made for process validation should be the same size as the intended Industrial scale batches.

6 57 P a g e International Standard Serial Number (ISSN): If it is intended that validation batches be sold or supplied, the conditions under which they are produced should comply fully with the requirements of Good Manufacturing Practice, including the satisfactory outcome of the validation exercise and the marketing authorization. 2) Concurrent Validation (1,3,) It is similar to prospective, except the operating firm will sell the product during the qualification runs, to the public at its market price, and also similar to retrospective validation. This validation involves in-process monitoring of critical processing steps and product testing. This helps to generate and documented evidence to show that the production process is in a state of control. In exceptional circumstances it may be acceptable not to complete a validation programme before routine production starts. The decision to carry out concurrent validation must be justified, documented and approved by authorized personnel. Documentation requirements for concurrent validation are the same as specified for prospective validation. 3) Retrospective validation- (1,3,) It is defined as the established documented evidence that a system does what it purports to do on the review and analysis of historical information. This is achieved by the review of the historical manufacturing testing data to prove that the process has always remained in control. This type of validation of a process for a product already in distribution. Retrospective validation is only acceptable for well-established processes and will be inappropriate where there have been recent changes in the composition of the product, operating procedures or equipment. Validation of such processes should be based on historical data. The steps involved require the preparation of a specific protocol and the reporting of the results of the data review, leading to a conclusion and a recommendation. Records of personnel changes, process capability studies, finished product data, including trend cards and storage stability results. Batches selected for retrospective validation should be representative of all batches made during the review period, including any batches that failed to meet the specifications, and should be sufficient in number to demonstrate process consistency. Additional testing of retained samples may be needed to obtain the necessary amount or type of data to retrospectively validate the

7 58 P a g e International Standard Serial Number (ISSN): process. For retrospective validation, generally data from ten to thirty consecutive batches should be examined to access process consistency, but fewer batches may be examined if justified. 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. 4) Revalidation- (3,4,) It is repetition of validation process or specific parts of it. This is carried out when there is a any change or replacement in formulation and equipment plant or a site location batch size an in the case of sequential batch they do not meet product and specification. Revalidation becomes necessary in certain situations. Some of the changes that require validation are as follows: 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 revalidation except that this new equipment must be qualified. Changes in the plant/facility. ORGANISATION FOR VALIDATION Introduction (5) In the WHO GMP it has been stated that any aspect of operation including significant changes to the premises, facilities, equipment or processes which may affect the quality of the product directly or indirectly should be qualified and validated. It has been further stated that qualification and validation should not be considered as one off exercise, and this should be an ongoing program. From this requirements it may be seen that scope of qualification and validation work is quite large. therefore, if a pharmaceutical manufacturer can afford to establish a department of validation, it would be ideal. However if it is not possible, the qualification and validation work can be organized employing one of the following structures:

8 59 P a g e International Standard Serial Number (ISSN): The consultant; - The task force; - The dedicated group. Purpose (2) To describe the functions and responsibilities of the validation team to meet the cgmp compliance. Responsibility (2) It is the responsibility of all concerned departments to follow the procedure. The QA manager is responsible for SOP compliance. Procedure (2,4,) 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 task force concept refers to organization structure within the company in which person proficient in different fields are drawn from different department. When qualification and validation work is to be carried out this persons are drawn from different department meets as a committee group eq. person are from each of the production, engineering, & quality assurance and research and development department. the head of this committee is the person responsible for validation work. He delegates work to different members of the committee. The salient advantages of this approach are: Since task force members, experts in their fields are drawn from different departments, they bring experience from a range of departments, they bring experience from a range of departments to apply to related topics. Member in task force can be changed depending on the work to be carried out. For example, if the work relating to solid dosage form and sterile product is to be carried out by the task force, person drawn from production of solid dosage form can be replace with person from production of sterile products, once the work relating to solid dosage form is over. 3) The dedicated group The disadvantages of task force approach can be overcome in the dedicated group approach. In this approach, person drawn from different departments are relieved of their routine functions.

9 60 P a g e International Standard Serial Number (ISSN): They from a group which is made responsible for validation work. The advantages of this approach the group is totally dedicated to validation work. This group may be placed under a department but with autonomy. Perhaps some additional space may be required for the smooth function of the group. The departments from which the experts should be drawn and number of persons will depend on the size of the company and organizational structure of the company. Members from following departments: -Production -engineering -calibration laboratory -quality control laboratory -maintenance -HVAC -Product development. The team should consist of managers of the departments involved in the validation and outside vendors (if applicable); For example: Quality assurance managers Production managers Technical services manager Product development manager Calibration manager Quality control manager Approved vendors (outside) Validation organisation can be divided into three basic areas (1) 1. Establishing the organisation. 2. Operating it from a quality and cost effectiveness basis. 3. Maintaining a functioning organisation. 1) Establishing the organization

10 61 P a g e International Standard Serial Number (ISSN): Formulating a department mission is necessary so that, not only process validation staff members understand the breadth of their job, but also the other corporate groups with whom there is interaction, can also understand. In some organization senior staff members representing the process validation, R&D, Quality Assurance, Production and Engineering functions combine to form advisory or steering committees for the validation programme. This committee can prove extremely valuable to the validation program by defining the mission, as well as by making decisions on specific issues of concern; validation professionals provide sufficient technical information to this committee. Quality Assurance Committee (Head of quality control/quality assurance, Production, Engineering and GMP section) Validation Steering Committee (Members represent the above departments) Fig-1 Department interactions (4) Validation Team (Those responsible from Quality control, production and engineering Once the validation team has been constituted and mission have been formulized, the team will interact with different departments. Usually interactions are made with the following departments: -Research and development department; - Engineering Department; - Production Department; - Maintenance Department; - Quality control Department. In some companies maintenance is the responsibility of the engineering Department. In such cases only engineering department is to be involved.

11 62 P a g e International Standard Serial Number (ISSN): Research and development (R&D) Department is usually involved with introduction of new products and with improvement of existing process. The R&D department will be having development data regarding the product and/or process development. Such data will be useful input to the validation team. Validation team (1) A multidisciplinary team is primarily responsible for conducting and supervising validation studies. Personnel qualified by training and experience in a relevant discipline may conduct such studies. Responsibilities of validation team (1) Creates updates and reviews/approves individual project validation plans and validation deliverables. Ensures validation compliance with the company validation master plan and project validation plan. Coordinates, implements, verify elements of VMP. Consults on, evaluates and approves changes. Reviews and approves IQ/OQ/PQ procedures and plans.ss Reviews test results and makes recommendations regarding release. Assess risks and develops contingency plan. Department Designation Responsibility Research and development (R&D) Quality Assurance Executive/ Officer Officer Table 1: Validation Team Responsibilities (3) To coordinate the entire validation process by scheduling meetings and discussions with production, quality control and quality assurance. Preparation of preliminary validation protocol, master formula record, monitoring the process, compiling and analyzing data and test results and preparing the final report. To review the preliminary validation documents. To coordinate the entire validation process by scheduling meetings and discussions with the team. Preparation of validation protocol, monitoring the process, compiling and analyzing data and test results and preparing the final report. To review of validation documents. Production Officer To participate in performing the validation steps during manufacturing processes. To assist in collection of data. Quality Control Officer To test and report the test results. Quality Assurance General manager Quality assurance To approve the process validation protocol and report. To review of validation documents. To approve the process.

12 63 P a g e International Standard Serial Number (ISSN): Elements of validation (1) The validation of a process requires the qualification of each of the important elements of the process. The relative importance of an element may vary from process to process. Some of the elements commonly considered in a process validation study are presented below. Regulations of Validation (6) The three basic and most important reasons for validation are quality assurance, economics and compliance. 1. Quality assurance Product quality cannot be assumed for a process by routine quality control testing because of the limitation of statistical sampling and the limited sensitivity if the finished product testing. Quality variations among units within a batch, or among different batches, are seldom detected by testing of finished product samples. Validation challenges the adequacy and reliability of a system or process to meet pre-determined criteria. A successful validation, therefore, provides a high degree of confidence that the same level of quality is consistently built into each unit of the finished product, from batch to batch. The Pharmaceutical Manufacturers Association (PMA) and the FDA have recognized the product quality assurance concept of validation.

13 64 P a g e International Standard Serial Number (ISSN): Economics (1) The direct economic benefit of validation is a reduction in the cost associated with process monitoring, sampling and testing. The consistency and reliability of a validated process to produce a quality product provide indirect cost savings resulting from a decrease or elimination of product rejections, reworks and retesting. Final release of the product batch would be expedited and free of delays and complications caused by lengthy investigations of process or analytical variances. In addition, product quality complaints and potential product recalls would be minimized. 3. Compliance (1) Specific current Good Manufacturing Practices (cgmp) references to variation are found in following sections of 21CFR (d) Variation of suppliers test result for components when these results are accepted in lieu of in-house testing after receipt (a) Validation of manufacturing process to ensure batch uniformity and integrity of drug products (e) Validation of analytical methodologies. The requirement of validation is also implied in (a). This section of GMP requires that written procedures and process controls be established to ensure that the drug products have to identify strength, quality and purity are represented to possess. The FDA s draft Mid Atlantic Pharmaceutical Inspection Guidance Program for Prescription Drug Plants, issued in January 1990,emphasisthe importance of validation in the Manufacturing process. CONCLUSION Validation is the most widely used word in the areas of drug development, manufacturing and specification of finished products. It is necessary, before approval of a new drug, that an accurate and reliable assessment for its effectiveness and safety for the intended indication and target patient population is demonstrated. Validation has been proven assurance for the process efficiency and sturdiness and it is the full fledged quality attributing tool for the pharmaceutical industries.

14 65 P a g e International Standard Serial Number (ISSN): Validation is the commonest word in the areas of drug development, manufacturing and specification of finished products. It also renders reduction in the cost linked with process monitoring, sampling and testing. Apart from all the consistency and reliability of a validated process to produce a quality product is the very important for an industry. Also, validation is a team effort and required environment and support of several departments. The validation team may make a subgroup, like qualification group, process validation group, Cleaning validation group etc. these subgroup should make a programs these programs should be approved and reviewed by validation reviewed team. REFERENCES: 1. L.Nandhakumar, G.Dharmamoorthy, S. Rameshkumar and S. Chandrasekaram., an overview of pharmaceutical validation; quality assurance view point., International journal of research in pharmacy and chemistry,201, 4(1), ISSN , page no , HaidersyedImtiaz, pharmaceutical master validation plan, st. Lucie press first Indian reprint, Page no , Dr. Keyur B. Ahir, Khushboo D. Singh, Sushma P. Yadav, Hetal S. Patel, Chetan B. polyahari., Overview of validation and basic concept of process validation., Scholars Academic journal of pharmacy(sajp). 2014;3(2): , ISSN , page no , Pandita Rachna, Rana A C, Seth, Nimrata, BalaRajni., Introduction and general overview of pharmaceutical process validation a review., international research journal of pharmacy, 2012,3(6) ISSN , page no P.P. Sharma., Validation in pharmaceutical industry, concept approaches and guideline., Vandana publication Pvt. Ltd., new Delhi, First edition 2007., Page no Neelam Sharma, A.C.Rana, Nimarata Seth; Process validation: Impact on pharmaceutical industry, International journal of pharmaceutical science,jul-sep 2013,volume-4, ISSN , page no Good manufacturing practices for pharmaceutical products; main principals, WHO Technical Report series, 908, WHO Geneva.

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