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

1. VALIDATION
³Validation is a key element of the quality assurance system in a pharmaceutical company´
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For a long time, our understanding of pharmaceutical quality was such that one relied solely on the control of raw materials and final products. The intermediate process was guaranteed by established experience and the professional honesty of longtime employees. Today, our understanding is almost the reverse. Well-tested raw materials from qualified suppliers are used in a process that must be so well controlled that, theoretically, absolutely nothing can result other than a product that conforms to the specifications. In contrast, the place of manufacture and staff carrying out production are interchangeable, as long as they are qualified.

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

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S. Food and Drug Administration) .validation. process. material. part-2 .´ (EU GMP Guideline) ` ³Establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality attributes. (WHO guide to GMP requirements . Geneva 1997) ` "Action of proving. that any procedure. activity or system actually leads to the expected results.´(U.` ³The establishing of documented evidence which provides a high degree of assurance that a planned process will consistently perform according to the intended specified outcomes´. equipment. in accordance with the principles of Good Manufacturing Practice.

It is. therefore. . The basic principles of quality assurance have as their goal the production of products that are fit for their intended use.` Validation is an essential part of good manufacturing practices (GMP). c) Each critical step of the manufacturing process must be validated. These principles are as follows: - ` ` ` a) Quality. an element of the quality assurance program associated with a particular product or process. Other steps in the process must be under control to maximize the probability that the finished product consistently and predictably meets all quality and design specifications. b) Quality cannot be inspected or tested into the product. safety and efficacy must be designed and built into the product.

It is by design and validation that a manufacturer can establish confidence that the manufactured products will consistently meet their product specifications. Documentation associated with validation includes:- ` ` ` ` ` a) Standard operating procedures (SOPs) b) Specifications c) Validation master plan (VMP) d) Qualification protocols and reports e) Validation protocols and reports.` Validation of processes and systems is fundamental to achieving these goals. .

` The implementation of validation work requires considerable resources such as: ` a) Time: generally validation work is subject to rigorous time schedules. comprising quality assurance. depending on the product and process to be validated). engineering. c) Human: validation requires the collaboration of experts from various disciplines (a multidisciplinary team. ` . ` b) Financial: validation often requires the time of specialized personnel and expensive technology. manufacturing and other disciplines.

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

Scope of Validation. ` Principles may be useful: in production and control of active harmaceutical ingredients (APIs) and finished pharmaceutical products ` Validation of specific processes and products (e. sterile product manufacture) requires much more consideration and a detailed approach beyond the scope of the guideline .g.

` Many factors affecting the different types of validation Manufacturers should plan validation to ensure regulatory compliance and product quality. safety and consistency ` ` The general text in the guideline (part 1 of presentation) may be applied to validation and qualification of: premises. utilities and systems processes and procedures . equipment.

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

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

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

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

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

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

` This Validation Master Plan (VMP) specifies and coordinates all qualification/ validation activities to ensure the production of pharmaceutical products according to accepted international standards. . It also specifies the responsibilities for validation procedures and helps to plan the necessary activities. ` A validation master plan is a document that summaries the company¶s overall philosophy. Validation in general requires meticulous preparation and careful planning of the various steps in the process. intentions and approaches to be used for establishing performance adequacy. The Validation Master Plan should be agreed upon by management.

its organizational structure. relevant to product and process controls within a firm should be included in the validation master plan. The validation master plan should provide an overview of the entire validation operation. . all work should be carried out in a structured way according to formally authorized standard operating procedures. It should comprise all prospective. All observations must be documented and where possible must be recorded as actual numerical results.` ` In addition. its content and planning. The main elements of it being the list/inventory of the items to be validated and the planning schedule. All validation activities relating to critical technical operations. concurrent and retrospective validations as well as re validation.

concise and clear. scope. It should not repeat information documented elsewhere but should refer to existing documents such as policy documents. actual status and future planning ` ‡ Key acceptance criteria ` ‡ Documentation format ` ‡ Reference to the required SOP¶s ` ‡ Time plans of each validation project and sub-project. summarized in a matrix format. ` . SOP¶s and validation protocols and reports The format and content should include: ` ‡ Introduction: validation policy.The Validation Master Plan should be a summary document and should therefore be brief. 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. validation approach ` ‡ Re-validation activities.

revision control. The validation process extends from the very basic specifics (how each item works and interacts with another item) to a very broad theological and methodical investigation of how the system and processes perform. validation is a method for building and maintaining QUALITY. Validation is not just a set of procedures and rules to satisfy FDA. and be reflected in the management structure. ` Its scope encompasses documentation. Evidence of validation should be seen at the corporate level. training. and maintenance of thesystem and process.Validation Life-Cycle ` Validation is a continuing and evolving process. .

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TYPES OF PROCESS VALIDATION ` ` ` ` Prospective process validation Concurrent process validation Retrospective process validation Revalidation .

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

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

` GMP compliant procedures must be followed in this stage and successful completion of this stage is necessary before commercial distribution of a product. It confirms that all established limits of the Critical Process parameters are valid and that satisfactory products can be produced even under ³worst case´ conditions.Stage 2: Process Qualification ` This stage is confirmation that the process design is capable of reproducing the manufacturing process. .

and that all SOPs have been followed. deviations. the limitation of the detection of the variation. failures.Stage 3: Continued Process Verification ` The Validation Maintenance Stage requires frequent review of all process related documents. the manufacturer must have full assurance of its performance. A successful validation program depends on the knowledge and understanding and the approach to control manufacturing processes. modifications to the production process. . These include the source of variation. including validation audit reports to assure that there have been no changes. ` Before any batch is distributed for marketing. and the attributes susceptible of the variation. including change control procedures.

` Prospective Validation Defination : Establishment of documentary evidence. It is a pre-planned scientific approach and includes the initial stages of formulation development. setting of process specifications. where the modifications are significant and may affect the product¶s characteristics. transfer of technology from scale-up batches to commercial size batches. developing in-process tests. defining raw material specifications. listing major process equipment and environmental controls. designing of batch records. prior to process implementation. Prospective validation is conducted prior to the distribution of either a new product or a product made under a modified production process. ` ` . completion of pilot runs. process development. sampling plans. that a process does what it purports to do based on validation master plan.

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

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

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

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

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

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

Verification of the developed process . Challenging of critical process parameters 3.` ` ` ` Stages of Process development 1. Design 2.

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

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

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

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

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and offers limited assurance regarding consistency of quality from batch to batch. This method is effective only if the development stage has resulted in a proper understanding of the fundamentals of the process. ` A process where current production batches are used to monitor processing parameters. . It gives assurance of the present batch being studied.` Concurrent process validation: Definition: Establishment of documentary evidence of what a system does or purports to do based on information generated during implementation of system. Concurrent validation is carried out during normal production.

(This careful monitoring of the first three production batches is sometimes regarded as prospective validation. Concurrent validation together with a trend analysis including stability should be carried out to an appropriate extent throughout the life of the product.` ` The first three production-scale batches must be monitored as comprehensively as possible. Examples of these may be when: · A previously validated process is being transferred to a third party contract manufacturer or to another manufacturing site. Concurrent validation may be the practical approach under certain circumstances. ` .) The nature and specifications of subsequent in-process and final tests are based on the evaluation of the results of such monitoring.

anti-cancer) · Process of manufacturing urgently needed drugs due to shortage (or absence) of supply. radiopharmaceuticals. .g.The product is a different strength of a previously validated product with the same ratio of active/inactive ingredients. · Process with low production volume per batch ( e..g. orphan drugs). · The number of lots evaluated under the Retrospective Validation were not sufficient to obtain a high degree of assurance demonstrating that the process is fully under control · The number of batches produced is limited (e.

The justification for conducting concurrent validation must be documented and the protocol must be approved by the Validation Team. . giving the product the desired quality would constitute a proper validation of the process. A report should be prepared and approved prior to the sale of each batch and a final report should be prepared and approved after the completion of all concurrent batches. that the systems and equipment to be used have been fully validated previously.` ` ` It is important in these cases however. It is generally considered acceptable that a minimum of three consecutive batches within the finally agreed parameters.

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

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

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

Batch size/strength/manufacturer/year/period. Some of the essential elements for Retrospective Validation are: Batches manufactured for a defined period (minimum of 10 last consecutive batches).` ` ` ` ` ` ` ` ` For the purpose of retrospective validation studies. it is considered that the data are not sufficient to demonstrate retrospectively that the process is fully under control. When less than ten batches are available. In such cases the study should be supplemented with data generated with concurrent or prospective validation. Master manufacturing/packaging documents. Data for stability testing for several batches. List of process deviations. it is considered acceptable that data from a minimum of ten consecutive batches produced be utilized. Number of lots released per year. corrective actions and changes to manufacturing documents. Current specifications for active materials/finished products. . Trend analyses including those for quality related complaints.

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

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

` Unexpected changes and deviations may be observed during self-inspection or audit. revalidation/requalification may be necessary. may affect the process. may result in changes in the process. or during the continuous trend analysis of process data. such as ventilation. ` Changes in the production area and support system.` Changes in equipment. The repair and maintenance of support systems. such as the replacement of major equipment components. the rearrangement of manufacturing areas and/or support systems. as a consequence. including measuring instruments. may change the environmental conditions and.g. may affect both the process and the product. . e. mainly in the manufacture of sterile products. repair and maintenance work.

temperature. utilities.e. drawings and manuals Software documentation Spare parts list Environmental conditions (such as clean room requirements. functionality. cleaning schedules Safety features Supplier documentation. materials of construction cleanability. Simply put. IQ means is it installed correctly? Important IQ considerations are: Equipment design features (i. prints. etc.` 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 recommendations of the supplier of the equipment are suitably considered.) Installation conditions (wiring. etc. preventative maintenance.) Calibration. humidity) ` ` ` ` ` ` ` ` ` ` .

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

worst case testing.` ` Operational qualification . During routine production and process control.´ ` ` . it is desirable to measure process parameters and/or product characteristics to allow for the adjustment of the manufacturing process at various action level(s) and maintain a state of control. These action levels should be evaluated. established and documented during process validation to determine the robustness of the process and ability to avoid approaching ³worst case conditions..e.(OQ) Establishing by objective evidence process control limits and action levels which result in product that meets all predetermined requirements. i. In this phase the process parameters should be challenged to assure that they will result in a product that meets all defined requirements under all anticipated conditions of manufacturing.

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

Assurance of process capability as est ablished in OQ Process repeatability.Performance qualification . ³Methods and tools for process validation´. long term process stability ` ` ` ` ` . PQ considerations include: Actual product and process parameters and procedures established in OQ Acceptability of the product. In this phase the key objective is to demonstrate the process will consistently produce acceptable product under normal operating conditions.(PQ) ` Establishing by objective evidence that the process. under anticipated conditions. consistently produces a product which meets all predetermined requirements.

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

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

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