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Mr. Diptesh A. Patel1*, Mrs. Pinkal H. Patel1, Mr. Rohit K. Patel2
1Department of Quality Assurance, Baroda college of pharmacy, Vadodara, Gujarat, India.
2Department of Quality Assurance, Kaptab Pharmaceutical, Vadodara, Gujarat, India.

The purpose of the research investigation was to study concurrent Process Validation of Cefixime Dispersible TabletI.P. These processes should be controlled in order that the finished product meets all quality specifications. The critical process parameters were identified with the help of process capability and evaluated by challenging its lower and upper release specifications. Three initial process validation batches of same size, method, equipment and validation criteria were taken. The critical parameter involved in sifting, sizing and compression stages were identified and evaluated as per validation plan. Uniformity of mixing is optimum in 30 min as standard deviation was between ±0.20% to ±0.99%. Compression speed of 16 RPM was suitable for IPQC as  % standard deviation limits was found for Thickness was ±1.8 % to ±3 %, Hardness ±16.6 % to ±37 %, Weight Variation ±0.3% to ±7.1 %, Friability ±2.4 to ±7.1 %, Diameter ±0.9 % to ±1.2 % and Disintegration time NMT 3 min. The outcome indicated that this process validation data provides high degree of assurance.


Validation Principles1-11
The basic principle of quality assurance is that a drug should be produced that is fit for its intended use. In order to meet this principle, a good understanding of the processes and their performance is important. Quality cannot be adequately assured by in-process and finished product inspection and testing but it should be built into the manufacturing processes. These processes should be controlled in order that the finished product meets all quality specifications. Therefore, building of the quality requires careful attention to a number of factors, such as the selection of quality materials/components, product and process design, control of processes, in-process control, and finished product testing. Careful design and validation of system and process controls can establish a high degree of confidence that all lots or batches produced will meet their intended specifications.

As per the ICH guidelines defines as Process validation: ‘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 required quality’.

Process validation is intended to establish that the proposed manufacturing process is a suitable one and yields consistently a product of the desired quality. i.e. that the process is suitable and under control.

Importance of Process validation
The main advantages to be obtained from validation are assurance of quality and process optimization, both resulting in a reduction of total costs.

Assurance of Quality
Validation is an extension of the concepts of quality assurance since close control of the process is necessary to assure product quality and it is not possible to control a process properly without thorough knowledge of the capabilities of that Process Without validated and controlled processes, it is impossible to produce quality products consistently. End product testing, in the absence of validation, gives little assurance of quality for variety reasons, among which are,

1. Very limited sample size.
2. The limited number of tests performed on a sample. For example, it is impractical to test for all potential impurities or contaminants.
3. The limited sensitivity of the test.

Process Optimization
The optimization of a process for maximum efficiency, while maintaining quality standards, is a consequence of validation. Literal meaning of word to optimize is “To make as effective, perfect or useful as possible”. The optimization of the facility, equipment, systems, and processes results in a product that meets quality requirements at the lowest cost.

Reduction of quality costs
Quality costs are divided in to four categories.

They are:
a) Preventive costs.
b) Appraisal costs.
c) Internal failure costs.
d) External failure costs.

E.g.: of internal failure costs: Any validated and controlled process will result in fewer internal failures like

* Fewer rejects

* Reworks

* Re-tests

* Re-inspection

Process validation makes it possible to do the job right the first time. Also, a scientifically studied and controlled process  makes it unlikely that defective products will be dispatched to market thus no recalls or market complaints.

Validation can also result in increased operation safety. eg: gaues used on equipment that designed to operate at certain temperature and pressures must be reliable i.e. they must be calibrated.

Validation Master Plan
A validation master plan is a document that summarizes the company’s overall philosophy, intentions and approaches to be used for establishing performance adequacy. The Validation Master Plan should be agreed upon by management. Validation in general requires meticulous preparation and careful planning of the various steps in the process. In addition, all work should be carried out in a structured way according to formally authorized standard operating procedures. All observations must be documented and where possible must be recorded as actual numerical results. The validation master plan should provide an overview of the entire validation operation, its organizational structure, its content and planning. The main elements of it being the list/inventory of the items to be validated and the planning schedule. All validation activities relating to critical technical operations, relevant to product and process controls within a firm should be included in the validation master plan. It should comprise all prospective, concurrent and retrospective validations as well as re-validation.

The Validation Master Plan should be a summary document and should therefore be brief, concise and clear. It should not repeat information documented elsewhere but should refer to existing documents such as policy documents, SOP’s and validation protocols and reports. The validation protocols for equipment and systems are normally divided into three segments: Installation Qualification, Operational Qualification and Performance Qualification, abbreviated as IQ, OQ, PQ. For systems and equipment, Performance Qualification is often synonymous with Validation. Depending on the function and operation of some equipment, only IQ/OQ are required. For equipment whose correct operation is a sufficient indicator of its function, and that are monitored and/or calibrated on a regular schedule (e.g. pH meter, incubator, centrifuge, freezer), the installation and operational qualifications are performed. Systems such as air, water, steam, and major equipment which perform critical support processes, such as sterilization (autoclave, oven), depyrogenation (oven or tunnel), or lyophilization, require installation, operational and performance qualifications. Each IQ, OQ, and PQ protocol provides the specific procedure to follow, information to be recorded, a set of acceptance criteria, and a list of materials, equipment and documents needed to perform the validation.


1.      Prospective validation

2.      Concurrent validation

3.      Retrospective validation

4.      Re-validation

1) Prospective Validation
The objective of the prospective validation is to prove or demonstrate that the process will work in accordance with validation protocol prepared for the pilot production trials. Prospective validation should normally be completed prior to the distribution and sale of the medicinal product. 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 broken down 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 experiments should be designed to determine the criticality of these factors. Each experiment should be planned and documented fully in an authorized protocol. All 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. Using this defined process a series of batches should be produced. In theory, the number of process runs carried out and observations made should be sufficient to allow the normal extent of variation and trends to be established to provide sufficient data for evaluation. 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. Some considerations should be exercised when selecting the process validation strategy. Amongst these should be the use of different lots of active raw materials and major excipients, batches produced on different shifts, the use of different equipment and facilities dedicated for commercial production, operating range of the critical processes, and a thorough analysis of the process data in case of Requalification and Revalidation. 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 actions to be taken in the event of the limits being exceeded should be specified.



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