The Four Types of Process Validation

Process validation is defined as the collection and evaluation of data, from the process design stage throughout production, which establishes scientific evidence that a process is capable of consistently delivering quality products. Process validation is a requirement of current Good Manufacturing Practices (GMPs) for finished pharmaceuticals (21CFR 211) and of the GMP regulations for medical devices (21 CFR 820) and therefore applies to the manufacture of both drug products and medical devices.

Process validation involves a series of activities taking place over the lifecycle of the product and process.

The U.S. Food and Drug Administration (FDA) has proposed guidelines with the following definition for process validation: – “PROCESS VALIDATION” is establishing documented evidence which provides a high degree of assurance that a specific process consistently produces a product meeting its predetermined specifications and quality attributes.

The Process validation activities can be described in three stages.

Stage 1 – Process Design: The commercial process is defined during this stage based on knowledge gained through development and scale-up activities.

Stage 2 – Process Qualification: During this stage, the process design is confirmed as being capable of reproducible commercial manufacturing.

Stage 3 – Continued Process Verification: Ongoing assurance is gained during routine production that the process remains in a state of control.

Types Of Process Validation

The guidelines on general principles of process validation mentions four types of validation:

A) Prospective validation (or premarket validation)

B) Retrospective validation

C) Concurrent validation

D) Revalidation

A) Prospective validation

Establishing documented evidence prior to process implementation that a system does what it proposed to do based on preplanned protocols. This approach to validation is normally undertaken whenever the process for a new formula (or within a new facility) must be validated before routine pharmaceutical production commences. In fact, validation of a process by this approach often leads to transfer of the manufacturing process from the development function to production.

B) Retrospective validation

Retrospective validation is used for facilities, processes, and process controls in operation use that have not undergone a formally documented validation process. Validation of these facilities, processes, and process controls is possible using historical data to provide the necessary documentary evidence that the process is doing what it is believed to do. Therefore, this type of validation is only acceptable for well-established processes and will be inappropriate where there have been recent changes in the composition of product, operating processes, or equipment.
This approach is rarely been used today because it’s very unlikely that any existing product hasn’t been subjected to the Prospective validation process. It is used only for the audit of a validated process.

C) Concurrent validation

Concurrent validation is used for establishing documented evidence that a facility and processes do what they purport to do, based on information generated during actual imputation of the process. This approach involves monitoring of critical processing steps and end product testing of current production, to show that the manufacturing process is in a state of control.

D) Revalidation

Revalidation means repeating the original validation effort or any part of it, and includes investigative review of existing performance data. This approach is essential to maintain the validated status of the plant, equipment, manufacturing processes and computer systems. Possible reasons for starting the revalidation process include:

  • The transfer of a product from one plant to another.
  • Changes to the product, the plant, the manufacturing process, the cleaning process, or other changes that could affect product quality.
  • The necessity of periodic checking of the validation results.
  • Significant (usually order of magnitude) increase or decrease in batch size.
  • Sequential batches that fail to meet product and process specifications.
  • The scope of revalidation procedures depends on the extent of the changes and the effect upon the product.

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  • vicky_yadav88

    is there any difference between process qualification and process validation?

  • Danielle Wood

    Great post. Unfortunately, a lot of products out today aren’t FDA regulated and people are getting sick from these drugs. It’s surprising how many places accept and display drugs that aren’t regulated by the FDA. I wish most of the drugs out now go through these processes of pharmaceutical manufacturing and process validation, because it would make all users feel safer. I still have to do my research every time I buy any type of supplement and I try to stick to FDA regulated supplements most of the time.

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The Difference Between Prospective, Concurrent and Retrospective Validation

Unless you’re starting a new company you will need to plan on a variety of approaches.

Prospective validation occurs before the system is used in production, concurrent validation occurs simultaneously with production, and retrospective validation occurs after production use has occurred.

In this article we will discuss all three and also discuss the role the master validation plan (MVP) performs for each one.

1. Prospective Validation

Prospective validation is establishing documented evidence, prior to process implementation, that a system performs as is intended, based on pre-planned protocols.

This is the preferred approach.

Production is not started until all validation activities are completed.

The MVP need not go into much detail about this approach since it’s the standard method, however, prospective validation follows a step wise process illustrated here.

The process commences with the development of a Validation Plan and then passes through the DQ, RA, IQ, OQ and PQ phases after which process, computer, analytical and cleaning validations are performed which are followed by a final report.

After which the instrument or equipment will be subject to preventative maintenance and requalification on a routine basis.

Periodic Basis

On a periodic basis all instrumentation and equipment should be reviewed. This review is intended to identify any gaps which may have developed between the time it was last qualified and current requirements.

If any gaps are identified a remediation plan will be developed and the process will start again.

The MVP

The MVP may need to describe what is done with product produced during prospective validation. Typically, it is either scrapped or marked not for use or sale.

The product may be suitable for additional engineering testing or demonstrations, but appropriate efforts need to be made to ensure this product does not enter the supply chain.

Ideally, all validation is done prospectively; i.e., the system is validated before use. However, there are cases and conditions which may prevent this.

2. Concurrent Validation

Concurrent validation is used to establish documented evidence that a facility and process will perform as they are intended, based on information generated during actual use of the process.

In exceptional circumstances (for example, in a case of immediate and urgent public health need) validation may need to be conducted in parallel with routine production. The MVP needs to define how product is managed throughout the process.

Typically, the product batches are quarantined until they can be demonstrated (QC analysis) to meet specifications.

The Right Decision?

The decision to perform concurrent validation should not be made in a vacuum. All stakeholders including management, Quality Assurance and the government regulatory agencies should all agree that concurrent validation is an acceptable approach for the system under consideration.

As always the principal requirement is patient safety is not compromised. The rationale to conduct concurrent validation should be documented along with the agreement to do so by all the stakeholders. This can be part of the Validation Plan or documented as a deviation.

The Process

The concurrent validation process is identical to that of prospective validation. The process starts with the development of a Validation Plan, followed by the DQ, RA, IQ, OQ and PQ phases after which process, computer, analytical and cleaning validations are performed, ending with a final report.

Again, routine preventative maintenance, requalification and periodic review are performed.

3. Retrospective Validation

Retrospective validation is validating a system that has been operating for some time. There are various schools of thought on how to approach retrospective validation. Some may feel that a full-blown validation is required to assure the system is functioning properly.

Others may feel that since the system has been in use, presumably without issues, validation is not necessary and a memo to file justifying why validation is not necessary may be issued.

Doing a full validation may not be required, since you already have proof that the system functions as required – at least in the situations in which production was conducted. Doing nothing, though, is a risk.

It’s likely that the controls haven’t been challenged so there may be some hidden flaws that haven’t been identified that could lead to non-conforming product, hazardous operating conditions, extended delays, etc.

Historical Data

Historical data can certainly be used to support validation. For example, if there is detailed and statistically-significant evidence that production runs are well controlled you could rationalize and justify not doing full validation.

During retrospective validation, it’s advisable that existing product be quarantined, and production put on hold until validation is complete.

As an exception, producing product as part of the validation exercise would follow concurrent validation. This may not be practical since product may have already been distributed, but caution is advised for the reasons outlined.

General Process

The general process for retrospective validation follows the same process as for prospective and concurrent validation except DQ is seldom performed, as the system has already been in use for some time.

Instead a survey and review of available information is performed. This normally occurs before the validation plan is created.

The MVP should also provide guidance on managing inventory during retrospective validation.

One Major Issue

One potential major problem that can occur with retrospective validation the determination of what action should be taken if an issue is found with the system during retrospective validation?

As with everything else, a risk-based decision is warranted. This could be anything from product recall, to customer notifications, to just documenting the justification of the decision why nothing was done.

Again, the MVP should provide guidance on dealing with situations concerning out of specification conditions revealed during retrospective validation, which should also definitely include involving regulatory support.

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International Conference on Harmonization (ICH) in a Nutshell [Video]

The ICH is a common project of regulatory authorities and representatives of pharmaceutical industries in EU, Japan and the US.

Its mission is to discuss issues related to approval and marketing authorization of new medicinal products in these three regions.

Namely, the six parties involved are the:

  • European Commission
  • The European Federation of Pharmaceutical Industry Associations
  • The Japanese Ministry of Health and Welfare
  • The Japanese Pharmaceutical Manufacturers Association
  • The US FDA
  • The US Pharmaceutical Manufacturers Association

In addition to these principals, there are three observers representing non-ICH countries:

  • World Health Organisation (WHO)
  • The European Free Trade Association (EFTA)
  • Health Canada

Primary Objective

The primary objective of ICH is to harmonize regulatory requirements related to quality, safety and efficacy of medicinal products and to support mutual recognitions between the three regulatory authorities.

Exchange of Data

Mutual recognitions are based on the exchange of data and assessment reports which are intended to eliminate duplicative testing and inspection procedures, and thus decrease costs of, and speed up, the introduction of new medicinal products to the markets.

cGMP – Cases from History and the Regulations

If you would like to learn more about the regulations governing the GMP’s click here.

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