What is Pharmaceutical Validation?
Image: PM Group
Defining Pharmaceutical Validation
Whether we’re talking about a piece of equipment designed to do something, a process/recipe to make something, or a computer programme to control something – the pharmaceutical industry uses validation.
It can be a complicated area to understand if you don’t have direct experience with it. So as we explore the area of validation, we’re going to think about the concepts as if we were baking a batch of cakes.
Keep an eye out for the text in blue boxes (like the one below) for our simplified cake examples and some old-school Great British Bake Off gifs!
At its most simple – validation is testing whether something works, as well as writing down what you did and what happened when you did it.
This means you can prove that it worked to others who weren’t there.
For a more technical answer, let’s look at how the US Food & Drug Administration (the FDA – the US regulatory body for pharmaceutical manufacturing) defines Process Validation (the most common type of validation, used on processes)…
“Process validation is defined as the collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality product. Process validation involves a series of activities taking place over the lifecycle of the product and process.” – FDA
So we can see that there are really 3 main parts in this definition of validation.
creating an evidence trail…
to show that an action, process, or system…
leads to a consistent and reproducible result.
This ‘result’ is usually taking a measurement or assessing product quality. It is then compared against a predetermined specification (the expected outcome – which is always decided before the test is done).
And in pharmaceutical manufacturing, a consistent and reproducible result is very important because medicines are not really like cakes. You can’t have a “good batch” for tablets and a “not so good batch”.
Every tablet, every batch, must be good.
Why do we need Validation in Pharmaceutical Manufacturing?
We need validation in pharmaceutical manufacturing because the medicines we make must be the same high quality every time we make them.
Whether they’re made on a Monday morning or a Friday evening…
whether it’s during the day when everyone is watching or in the middle of the night-shift when no one is looking over your shoulder…
whether you’re a new member of staff or someone with 15 years of experience…
the medicine that you make and the equipment that’s used to make it must always be of the same high quality.
This high quality is important so that the medicine is safe for patients to take, will help to make them better, and will not harm them in any way (i.e. they’ll be fit for use and function as expected).
We can test final medicines at the end of the production process but final end product testing just isn’t enough.
Every time you test medicines you have less to give to patients. If you are just testing quality through final products, you have to test a lot of them.
However, if you can confirm that a medicine is safe to use every time you made it a certain way AND that you made it the same way every time, it’s a reasonable assumption that the medicine you made this time (in the same way) is also safe for patients to use.
This is what happens when you use a “validated process” to make the medicines.
To be sure that the final medicine is safe and effective for patients to take, we also have to check in on it at multiple points along its way to becoming a final product (i.e. are the ingredients used and the “in-process” materials all the same as expected?).
And finally, we have to rigorously scrutinize the processes, systems, and equipment used throughout manufacturing.
We need to confirm that everything we did was the same as on other occasions when we produced safe medicines using this “validated process”.
At all points, validation tests are comparing a result against a predetermined specification (or an expected result range).
Only by looking at – and documenting – the whole manufacturing process in this way, can we say for sure that a final medicine will be safe and effective for patients to take.
“Homogeneity within a batch and consistency between batches are goals of process validation activities.” – FDA
Most medicines are made using a batch process.
This is similar to making a batch of scones/brownies on a baking tray, you get lots of individual end products but they’ve all come from the same mixture in the mixing bowl.
Basically, validation activities are making sure that everything in one batch is the same. BUT they’re also making sure that those things are the same as other batches manufactured by the same process.
To highlight why, you only have to consider our TV baking programme…
Even when contestants are given the same ingredients and the same vague recipe – there can be a huge variation in the cakes that are produced.
While baking shows make for good television, it would be unacceptable if medicines varied that much.
We need much stricter control on the process.
Therefore, consistency between batches is just as important an outcome of validation activities.
To achieve this, each step in the process can be subject to validation.
How Do Companies Actually Achieve This?
When talking about “validation tasks or activities”, we are basically referring to testing, observing, and documenting a measurement and then comparing it against an expected outcome.
We compare what actually happened to what should have happened – to make sure they’re the same.
Validation tasks are carried out during all stages of a product lifecycle – from research and development, through to manufacture and distribution.
As a result, they are tasks that many different departments within a company can have a role in.
“We recommend an integrated team approach to process validation that includes expertise from a variety of disciplines (e.g., process engineering, industrial pharmacy, analytical chemistry, microbiology, statistics, manufacturing, and quality assurance). Project plans, along with the full support of senior management, are essential elements for success.” – FDA
It’s also important to note that validation is not just necessary when building new manufacturing processes.
It is also used to make sure that any changes to systems, equipment, or processes within an established (and previously validated) manufacturing system, do not change the quality or consistency of the medicine that is produced.
What and when do we validate?
If we consider a range where one end is “validate nothing” and the other is “validate everything”, where should we aim for?
Well “validate nothing” isn’t an option. We’ve already established that validation activities are essential for manufacturing safe and effective medicines.
What about “validate everything”?
It seems like a sensible option – we’d know our process worked and we could prove it.
BUT validating things takes time and money. The more we validate within any given process, the more manufacturing will cost. And if manufacturing costs more, the medicine will cost more. If the medicine costs more, fewer patients will have access to it.
So the goal is to validate to a point where we can be sure we’re consistently delivering safe medicines (always the highest priority) but not validating beyond that, where manufacturing costs rise without any additional product safety benefits.
The next question then is how do we decide what is critical to validate, in a way that’s transparent and objective?
The answer is risk management tools.
By applying risk management tools you can decide (in a scientific way) which items are critical, and should therefore be validated. This scientific approach also means that these decisions can be justified to an FDA auditor (or other regulatory bodies) if necessary.
An FDA auditor might have a different opinion about which items are critical – there is often no single right answer to the question of what is critical and what isn’t. BUT the auditor will respect your decision-making process if you can show an analysis using science-based risk management tools.
Using risk management tools, we can define a list of Critical Quality Attributes (CQA) for making safe medicines.
“A CQA is a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality.” ICH
Critical quality attributes are the things that are essential for a pharmaceutical product (the medicine) to have its desired effect.
Any variation in these product qualities would alter how well the medicine performs for the patient. So it’s essential that throughout the manufacturing process, these critical quality attributes are monitored and remain the unchanged.
To achieve this, we validate every point where a CQA could be altered.
When making medicines, identifying the critical quality attributes begins in early product/process development. The FDA understands this and requires that…
- Understand the sources of variation
- Detect the presence and degree of variation
- Understand the impact of variation on the process and ultimately on product attributes
- Control the variation in a manner commensurate with the risk it represents to the process and product” – FDA
Basically – manufacturers have to establish the things that MUST be controlled for the medicine to be safe to use and to function as expected (remembering that pharmaceutical products will already have gone through extensive clinical trials to prove their safety for patients and to determine how much of the medicine is needed to achieve the desired effect).
Finally, they have to validate the parts of the process that could impact the CQAs, to make sure that all CQAs remain unchanged throughout.
Here’s how the ICH talks about this in relation to Active Pharmaceutical Ingredient (API) manufacturing…
“The critical parameters/attributes should normally be identified during the development stage or from historical data, and the necessary ranges for the reproducible operation should be defined. This should include:
- Defining the API in terms of its critical product attributes
- Identifying process parameters that could affect the critical quality attributes of the API
- Determining the range for each critical process parameter expected to be used during routine manufacturing and process control
Validation should extend to those operations determined to be critical to the quality and purity of the API.” – ICH
And that last part is important to note – validation occurs at points where critical quality attributes are ‘at risk’ of alteration/variation.
Of course, there are many other factors that a company might be trying to control throughout the manufacturing process that are not CQAs (e.g. things that relate to the cost of manufacturing the medicine but not the quality of the medicine that is made).
One example might be minimising energy consumption within the manufacturing process.
While this might be important to the company to reduce costs it isn’t essential for maintaining product quality (by maintaining critical quality attributes).
Therefore it does not fall into the category of being a validation activity.
As well as identifying the critical quality attributes, companies must establish the acceptable range for each attribute – the high and low values that the critical quality attribute cannot go beyond.
Examples might include the high/low temperature range for the manufacturing process, the specific quantity of ingredients that are used in a batch, and how long they are to be reacted together.
Validation activities will check that the process does not interfere with these critical quality attributes outside the predetermined acceptable levels.
While the initial list of CQAs are produced in early product/process development – further CQAs can be identified and added, as knowledge and experience about how best to consistently make the medicine grows over time.
Becoming A Validation Engineer
The Application DEADLINE for our next Validation Technician Program – For Starter Validation Roles and Validation Technician Program – For Senior Validation Roles is April 29th.
This is the first is a series of posts about Validation in the pharmaceutical industry.
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