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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An Alternative View of the ICH Q10 Pharmaceutical Quality System (PQS)

The image below is that depicted by the International Conference of Harmonisation (ICH) Q10, Annex 2, and is supposed to depict a PQS or Pharmaceutical Quality System.

Typically, I really love the ICH. When we have to deal with outdated regulations from different global organizations it becomes a real nightmare trying to keep track of the nuances and the ICH has done a pretty good job of bringing several of the key organizations together and aligning them on how best to organize and meet the expected requirements.

That being said the diagram below and the depiction in Q10 of what a PQS should look like is greatly lacking.

Development Phases

In section 1.8 under the Quality Manual the ICH Q10 guidance states, “The description of the PQS should include: …(c) Identification of the pharmaceutical quality system processes, as well as their sequences, linkages and interdependencies.

Process maps and flow charts can be useful tools to facilitate depicting the pharmaceutical quality system processes in a visual manner”.

I completely agree.

The problem is using the graphical depiction they present in Annex 2 is completely worthless.

Basically they listed some of the PQS elements in a bar and then said they all apply to the entire product lifecycle, which simply isn’t true.

When we are in the development phase of our product lifecycle why would we do that under the change management system, or monitor process performance?

 

Controlling Change – No Value Add

There is no point in controlling changes for a product that is purposely being changed, nor does it offer any value to monitor the process performance for a process that has yet to be developed.

This isn’t a graphic depiction of the PQS, but rather a graphic of how they depict the lifecycle management (which also has some issues).

The PQS is the quality system and its subsystems and how they interrelate.

While it’s useful to look at how the PQS and product Lifecycle Management overlap and what elements of the PQS system are relevant at each lifecycle stage, it is not the point of the PQS, and even if that’s the end goal it’s not depicted here at all.

This image offers almost no value.

A Better Approach

So, what should this graphic look like?

While this is not a perfect view of a PQS, I would propose that the image below is a much better depiction of how the PQS should be visualized and a good place to start.

At the core of any quality system should be management. This goes back to Deming, who said, “Quality begins with the intent that is fixed by Management”.

Quality has to be rooted in the executive management team.

Define Core Quality Systems

Core quality systems then need to be defined. These are systems that impact all aspects of the business and include a Risk Management Policy, Resource Management, Document Control and CAPA systems.

All of the other subsystems, Deviations, Supplier Management, Equipment Qualifications, Validation, Material Management, etc, etc. all should be risk based or involve risk assessment, they all require resources and training, they call require documents (procedures, policies, records), and the CAPA system of course drives for process improvement regardless of the process.

Subsystems

All subsystems feed back into the main Management module. The subsystems listed, all are interconnected, with the exception of Post Market Systems.

The subsystems are important too, but they are farmed out to different groups and have different levels of importance depending on the stage of the product lifecycle.

Post Market Systems

The one exception is the Post Market Systems. This includes complaint management, product reviews, recall processes and other systems to support marketed products.

These generally do not interact with the other subsystems unless it is through the CAPA system or other management functions, but still utilizes all the systems under the management umbrella.

Alternate View

The PQS presented here, isn’t intended to be perfect, but I thought it was worth presenting an alternate view to the one presented by the ICH.

The ICH concept is a good one, and the ideas are fairly well laid out in the ICH, but the graphical representation of the PQS leaves a lot to be desired.

When establishing a PQS, it is better to start with something to what we’ve depicted here, and customize it as needed for the organization.

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How 21 CFR Part 11.3(7) Applies to Electronic Batch Records [Video]

When dealing with Part 11 it’s important to understand what an electronic signature actually means

The definition of electronic signatures or e-sigs can be found in 21 CFR Part 11.3(7).

Electronic Signature

An electronic signature or e-sig means a computer data compilation of any symbol or series of symbols executed, adopted, or authorized by an individual to be the legally binding equivalent of the individual’s handwritten signature.

Handwritten Signatures

We also need to understand what a handwritten signature means in the context of Part 11.
The definition of handwritten signatures can be found in 21 CFR Part 11.3(8).

Handwritten signature means the scripted name or legal mark of an individual handwritten by that individual and executed or adopted with the present intention to authenticate a writing in a permanent form.

The act of signing with a writing or marking instrument such as a pen or stylus is preserved. The scripted name or legal mark, while conventionally applied to paper, may also be applied to other devices that capture the name or mark.

Electronic Batch Records

Eric works in a Pharmaceutical company and he is responsible for the filling process of the batch been manufactured.

Each time Eric performs the filling process he has to populate a batch record with the appropriate details

After each step Eric must also fill in his signature and date to verify that he actually performed each task.

Eric is manually handwriting these details and they are legally binding to Eric.

21 CFR Part 11.3(8)

This is when 21 CFR Part 11.3(8) applies.

Fast forward 12 months and Eric’s company has implemented a brand new Manufacturing Execution System (MES) where all details around the batch manufacturing process are recorded electronically.

21 CFR Part 11.3(7)

Now when Eric performs the filling process he now populates everything electronically and signs with his username and password combination to verify that he has performed those tasks.

This is when 21 CFR Part 11.3 (7) applies.

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