Validation|Process validation

Validation is one of the most important and common terms used in pharmaceutical industries and its simple meaning is to provide a high degree of assurance or confirmation regarding product quality and system reliability.

The concept of validation gives a high level of assurance that products manufactured in pharmaceutical industries are fit for use and the same quality is maintained in all batches of the product. In this article, we will learn about,

• History
• What is Validation?
• Importance of Validation
• Process Validation
• Guidelines & Definitions
• Types Of Process Validation
• What is Prospective Validation?
• When To Perform Prospective Validation?
• What to Do in Prospective Validation?
• What is Concurrent Validation?
• When To Perform Concurrent  Validation?
• What to Do in Concurrent Validation?
• What is Retrospective Validation
• When To Perform Retrospective  Validation?
• What to Do in Retrospective Validation?
• What is Re-Validation
• When To Perform Re-Validation?
• What to Do in Re-Validation?
• Cleaning Validation
• Method Validation
• Computer Validation
  

History 

The concept of Validation in pharmaceutical industries was introduced by FDA due to the problems in the sterility of parenteral products.

It was first adopted for the processes but later on,it spread to the following,

• Equipment 
• Media fill
• Purified water production
• Environment control etc.

Pharmaceutical Validation

 In pharmaceutical industries,Validation is a documented evidence to demonstrate that all the processes, system,utility or facility are designed in such a way that they produce the same results on repeated usage.

To understand the pharmaceutical validation simply and easily we can say that validation means to get the same output results  for all pharmaceutical  products and systems at different time intervals provided that the input should remain the same.

Explanation

Suppose we manufacture a tablet product by wet granulation method using a specific procedure,formulation,area and equipment etc.

During first manufacturing we will check and perform analysis of all critical steps during granulation to observe the results of the product and when we complete our three batches with the same quality using same input we declare that our product is now validated and we can get same quality of product using same input unless and until we do not change any input value.

Importance Of validation

• Validation ensures the product quality.
• Validation reduces the chances of non compliance.
• Validation reduces the chances of product recall.
• Data of validation acts as proof in making decisions.
• During inspection validation data gives assurance to the inspecting bodies that the procedures are reliable.
• Meet regulatory requirements.
• Cost of manufacturing is reduced due to less testing because once the product is validated we do not require intensive testing on all the stages.
• The pharmaceutical industries which do not have a validation system for manufacturing perform testing on all the stages,means after granulation they have to perform the analysis of blend to ensure that the assay of the product is in the range.
• After analysis of blend they compress the tablets and after compression again testing is performed for content uniformity,assay,dissolution and
• disintegration etc.
• In the same manner again testing is required after coating.
• The product is then packed and testing is done for the finish product before its dispatch to the finish good store.
• We repeat testing on all stages because our process is not validated and it makes our process costly.
• Once we validate our process then intensive testing is not required. We build quality in our product by using validated procedures and testing is done only at critical steps which reduces the cost.

Types of Validation

There are following types of validation

• Process Validation
• Cleaning Validation
• Method Validation
• Computer validation
  

Process Validation

It is an establishment of documented evidence which gives assurance that a process will continuously produce a product having predetermined specifications and quality attributes.

•  Validating each individual step of a process is known as process validation in the pharmaceutical industry.

Guidelines for Process Validation

• The concept of process validation was first introduced by the US FDA in 1978.
• (cGMP) of finished products give details of validation.

US FDA Definition

US FDA defines the process validation as follow,

• It is establishing documented evidence(prove)which provides a degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and Quality characteristics.

ICH Definition

• According to ICH It is the process of ensuring and providing documentary evidence that processes within their design parameters are capable of repeatedly and reliably producing a finished product of the required quality.
  

WHO Definition

• The documented action of proving that any procedure,process ,equipment,material,activity or system actually leads to the expected result.

Explanation

• Process validation in pharmaceutical industries starts from the initial developmental stage in research and development and continues till its shelf life in the market to provide assurance of a finished product even after its dispatch to the market.
• When a pharmaceutical company is going to manufacture a new product it has no documents for its manufacturing and testing.
• The development of all the procedures for testing and manufacturing which ensures product quality is known as process validation and method development.
• When the product is manufactured using the developed  procedure and its quality and efficacy is tested by using the analytical method which was developed,we claim that our process for manufacturing and testing is validated.

Also Read

Qualification|FAT|SAT|DQ|IQ|OQ|PQ

When to perform Process Validation?

Process validation is performed in case of following,

• For manufacturing new products.
• In case of any change in the manufacturing process which has a major effect on product quality.

Types Of Process Validation

Process validation in pharmaceutical industries are of following types

1. Prospective Validation
2. Concurrent Validation
3. Retrospective Validation 
4. Revalidation

1.Prospective Validation

• Prospective validation is establishing documented evidence that a system performs as it is intended based on pre-planned protocol.(Before process implementation).
• Prospective validation is performed in a research and development lab on a small scale.

When To Perform

• Prospective validation is performed for developing new products.
• Prospective validation is performed if we make any change in the manufacturing process which has a major effect on the product quality.
• This type of validation is performed before starting the routine batches of production.
• Prospective validation is performed at the stage of product development.
• In this type of validation all the process is divided into different steps and each step is monitored critically.
• The impact of different parameters is observed.
  

What to Do in Prospective Validation?

• As we know, prospective validation is carried out in the research and development stage so its start from developing formulation.
• Formulation of a new product is developed at this stage.
• Specification of raw materials are defined.
• Procedure for manufacturing is developed in the form of validation protocol.
• Procedure for cleaning validation is defined.
• All the critical points are observed on risk based analysis.
• Process parameters like mixing time,drying time etc are defined and adjusted to get desired results.
•  Batch Manufacturing Record  is prepared.
• Testing method for analysing the product is developed.
• Sampling plan is prepared.
• Technology transfer documents are  prepared.
• Environmental factors like temperature and humidity and storage conditions are defined.

Results 

• Usually three batches are manufactured at this stage and all should produce desired results using the same parameters.
• If we have to make changes in parameters of the first batch to adjust the results,these changes are made through proper change control procedure.
• The batch in which we make changes will not be considered the validation batch.
• We will have to take the next three batches with the same parameters to build confidence that our procedures and methods are reliable.

2.Concurrent Validation

• The word concurrent can be remembered by a simple word current,which means this type of validation is performed on current production batches.
• Concurrent validation is performed in the production area after getting satisfying results of prospective validation.
• In concurrent validation the product is manufactured in the production  area using the production facility and equipment.

When to Perform Concurrent?

Concurrent validation is performed in following,

• Product which has completed its prospective stage,is validated in the production area during concurrent validation.
• When there is a change in process which has no significant effect on product quality.
• Change in a raw material source.
• When a validated batch is required to be manufactured in other facilities(Plant) then no need to perform prospective validation only to do is to perform concurrent validation.
• When there is change in equipment used.
• When there is only change in tablet strength and previous strength was validated by the prospective validation and change strength has the same ratio of API and Excipients.

What to Do?

• Before starting the concurrent validation it is ensured that the operators involved in the manufacturing process are trained.
• All the equipment,utility and systems are qualified.
• Three batches are manufactured  to ensure the same product quality.
• In concurrent validation all the critical parameters of batches which are under manufacturing are observed.
• All the parameters are adjusted according to prospective validation.
• Sampling plan is followed as provided by the product development department.
  

Summery

In concurrent validation we manufacture the large scale batches using the same parameters as manufactured in small scale during prospective validation to ensure that our process developed is capable of producing the quality results.

• Samples are checked at specified time intervals.
• Prospective validation is done for three batches.
  
• Also Read

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3.Retrospective Validation

Retrospective validation is documented evidence that products manufactured in the pharmaceutical industry using validated procedure maintain its quality and purity in the market during the period of its shelf life.

Retrospective validation is performed after the dispatch of product in the market.

What to Do?

• In the pharmaceutical industries the reference samples are withdrawn from the finish product batches before its dispatch to the market.
• After the specified time period the sample is taken from the reference samples and is tested.
• It is done to ensure that our product in the market is still meeting a quality attribute during its shelf life.

Following type of data is also collected during Retrospective validation,

• Number of  batches manufactured for a defined period of time.
• Batch size
• Strength of the product.
• Manufacturing and expiry date of the product.
• Master documentation.
• List of deviations and corrective actions.
• Stability testing data for different batches.

It is used for audits of validated processes.

4.Re-Validation

Validation is done once in the product life cycle until there is no change in the product manufacturing parameters.

In some specific circumstances we have to revalidate our products.

When To Re-validate

The revalidation of process is required in following cases,

• When there is a change in critical parameters.
• When there is a change in product formulation.
• When there is a change in the product process.
• When there is a change in equipment.
• When there is a change in the facility.
• When there is a change in primary packaging.
• When there is a change in raw material density,particle size etc.
• Source change of API.
• Change in any process parameter like mixing time,drying temp,etc
• When there is a change in batch size.
• When there is a change in the plant.(Shifting from one plant to other)
• Periodically checking the validation results.
• When the product fails to meet the specification.

Also Read

Pharmaceutical Questions and Answers.

Cleaning Validation

• Cleaning validation is documented evidence that method developed for cleaning is capable of removing the chemical,biological residues and all traces of excipients, API and detergent are properly removed.
  

Method Validation

Method validation is documented evidence that the method developed for analysis of pharmaceutical products is suitable for producing the desired results.

Computer Validation

Computer validation is documented evidence that all the computer-based operations will produce the desired results.

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