Method Validation

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Updated 18 June 2020

Introduction

This article is intended to give you an understanding of the following:

  • What is validation.
  • Why we need validation.
  • What the impact of not having validated processes is.
  • The stages of Validation.
  • The type of validation.
  • How will knowing about validation can assist you.

What is validation?

In regulated industries such as device manufacturing, pharma and food, validated methods and equipment are important.

Validation is proving that a piece of equipment, a computer program, or a test process does what it is designed to do on a consistent and predictable basis. eg

  • Proving a fridge can maintain temperature within a specified range for as long as required with minimal impact from differences in load or accessing of items in fridge an antibiotic assay can consistently yield the same result from the same test sample
  • Media expiry dates are valid
  • a total aerobic count test is capable of recovering microbes that may be present within a sample
  • a computer program will run as predicted without crashing or yielding unexpected outputs

If you buy a fridge, then there is no point using it if it maintains temperature at a range that is not intended. The same goes for freezers/ovens/incubators. With scientific equipment, you need to prove the equipment does what it is purchased to do.

When an antibiotic assay is validated you can be confidant that the results you get are reliable and consistent through the range of samples tested. Minor variations in sample weights and preparations should be shown to not affect the final result.

An unvalidated TMC test that recovers no growth may be producing this result due to toxicity of the product. Validation is meant to show that microbes where present, can be recovered using the test method used.

Computer programs need to work as intended and be able to cope with data input errors without crashing or hanging.   The data must also be shown to have integrity.  i.e. have audit trails and not spontaneously change.

Why do we need validation?

Validation is important for a number of reasons:

  • It shows a process can do what it is supposed to do over and over again.
  • A consistent output means a consistently quality product.
  • A validated and followed method means less product deviations and less time spent investigating losses of control or taking action on audit observations.
  • Validation is essential to the successful development and delivery of many internal processes.

It is a basic requirement of quality control is to ensure that test methods are validated. This is stated in documentation from the BP/EP, USP, TGA and PIC/s PE009-14 chapters 5 and 6.

It is important to note that any validation should reinforce GMP, be carried out to established documented procedures and the data, results and conclusions be fully documented. You want to be show that your processes and equipment are capable of producing a consistent outcome.

Chapter 6 states that testing should be validated and anything provided in the marketing authorisation or technical dossier needs to be tested as written.  Therefore, a change in method might need regulatory approval.

Your critical processes and procedures should so be re-validated periodically to show they remain capable of achieving their goals.

From a functional perspective, it is unwise to incubate samples in an incubator that has not been proven to maintain the temperatures required, or to conduct an assay on a product where the test cannot produce a valid result. Having a validated process makes life easier. Though the initial validation may be tricky, it potentially saves much angst later.

Why is this so? If a manufacturer cannot support the results they obtain, then the product they are selling cannot be purported to be or do what it is supposed to do. Eg, a product is free from microbes, or a stability study was at a certain temp for a certain period.

What is the impact of not having validated processes?

  • Unable to prove equipment is suitable for intended use or that it does what the vendor said it is capable of
  • Unable to prove test results are valid/accurate
  • Can result in difficulties in audits if validation records are not available
  • May lead to products being declared to be adulterated

Why is this so?  If a manufacturer cannot support the results they obtain, then the product they are selling cannot be purported to be or do what it is supposed to do.  Eg, a product is free from microbes, a stability study was at a certain temp for a certain period, a filling machine can fill a set volume when set to that volume for the substance being filled.

Stages of Equipment Validation

  • DQ – design qualification (Details what you want the test or equipment to do. May incorporate a User Requirement Spec)
  • IQ – installation qualification (Confirms you have what you paid for)
  • OQ – operational qualification (Tests that while fallow, the unit does what the DQ/URS requires)
  • PQ – performance qualification (Test that in operation, the unit does what the DQ/URS requires)

Stages of Method Validation

  • Validation protocol (comparable to all four stages of equipment validation in so far as it sets what is done and why.  So the DQ, IQ, OQ and PQ).
  • Validation report (this documents all of the work done and presents valid conclusions which ideally will show the method is suitable for use).

Types of Validation

Prospective validation:

The gold standard.  Equipment or methods are fully characterised before being brought online and validated prior to commissioning.  Here, there would be no production until all validation documentation is approved and signed off.

A Master Validation Plan might be used to encompasses everything at your site.

Concurrent Validation:

This is done under exceptional circumstances only, for example mass producing product for an urgent public health need such as a covid 19 vaccine. Such validation needs approval by reg, QA and the Government (regulatory bodies)

Ideally your test methods and equipment will have undergone prospective validation. Your plant is built and production is underway. Here you conduct tests and gather results while production is underway to show that the facility and documented  processes are performing as intended.

Retrospective Validation:

Here an in place process or item of plant is validated. The bulk of this would be done on old processes and procedures that were either poorly documented before the need to extensively document such things was required. For example, something developed in the 1950’s and were grandfathered meaning that claims as to the processes were accepted at the without review.  In 2006 the FDA introduced an unapproved drugs initiative with recommended retrospective validation be conducted.

Here, the amount of effort you put into validation comes down to a risk assessment. If the equipment has been used for years it will likely have more recent calibration and revalidation documentation so the need for a full validation could be argued against. The same goes for drugs.  A drug sold for years without any recalls probably indicates it is safe (though I would wonder about its efficacy), so complete validation could be waived with a lot of historical data.  The same goes for your test methods.  At the very least you want to show 10CFU in = 10 CFU out for a samples test or that the amount of active ingredient stated on the bottle can be recovered.  You should have a lot of historical data to show this.  If not, the level of validation required might need to go up.

The danger is that a retrospective validation will reveal your equipment and processes are unsuitable which will give you a lot of work to address the situation and justify why you can still sell your products, assuming you are allowed to!

The ultimate aim of the FDA’s unapproved drugs initiative is to ensure no unapproved drugs are on the market.

Where you are transferring a test method across labs or sites, you should review these to ensure they are compliant with the ICH/VICH guidelines, marketing authorisation and there is a protocol for the transfer.

Any protocol deviations should be investigated.

How will knowing about validation assist you?

Day to day, knowing equipment has been validated gives you confidence it will work as expected. For tests, you have confidence in the results produced.

Knowing how an item of equipment or test was validated allows you to determine solutions when validated equipment and processes begin to yield unexpected results. This aids your problems solving skills. Once you have successfully conducted one validation, you are in a good position to conduct further validation.

Temperature mapping on a fridge will allow you to make judgements on temperature excursions where the correct type of mapping has taken place during OQ/PQ.

Validation of TMC tests may allow the microbiologist to determine which products are toxic to microbes. This is helpful in the event of an alert or action level count. Eg, if a validation could not recover Staphylococcus aureus, and a test sample recovered this microbe, it could be argued that the recovery was due to a testing error.

Some companies have dedicated validation departments so being knowledgeable about validation can expand your career opportunities. Validation aids your problem solving, experimental design and report writing skills.

Conclusion

You will now know:

  • What is validation.
  • Why we need validation.
  • What the impact of not having validated processes is.
  • The stages of Validation.
  • The type of validation.
  • How will knowing about validation can assist you.

References / Appendix

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