What is a Critical Components List Used For In Pharma? How do you Use Impact Assessments to Build an Effective List?

This component list will form the foundation for our “Equipment Qualification Protocol” which is a written plan stating how equipment qualification will be conducted. The protocol lists factors such as:

• product characteristics
• production equipment
• test scripts and methods
• test parameters
• acceptance criteria
• test checksheets
• final approval

The objective of a protocol is to prove “fitness for use”( i.e. the system works) of the critical components within an equipment system.

BTW, if you need to learn how to develop an IQ IQ PQ equipment qualification protocol, check out our Equipment Validation (IQ OQ PQ) Training Course – For Starter Validation, CQV and C&Q Roles.

Imagine you have to qualify a new manufacturing facility.

Let’s think about this – your factory is made up of numerous different systems such as:

• Parking facilities
• Elevators
• Office air conditioner
• Chilled water production
• Air conditioner
• Building management system
• Autoclave
• Purified water system
• Clean-In-Place (CIP) system

Each one of these systems is made up of lots of different items, components, subsystems and instruments.

There can be a tendency, especially amongst novice CQV, C&Q, validation technicians and engineers to err on the side of caution and qualify 100% of the components in every system. After all, surely that’s the safest approach.

But as the economist Thomas Sowell said;

“There are no solutions, there are only trade-offs”

And there are certainly some huge trade-offs with a “qualifying 100% of items in every system” approach.

For example:

Some of the systems and the items within them will have a disproportionately large impact on product quality, while other systems and items will have none at all. Qualifying items that don’t directly impact product quality or patient safety simply wastes time and resources. It makes far more sense to focus your attention and resources on the crucial systems and items.

Ultimately your goal is to make safe medicines at an affordable cost. The qualification process, while necessary, is enormously time-consuming and document-heavy. Qualifying 100% of items would drive the cost of the project and the subsequent final price of the medicine way higher than necessary.

All items on the critical components list will be focused on by the regulatory authorities (FDA, EMA, etc) when they come to approve the medicines that are being manufactured in that facility. So every single item you add to the list increases the regulatory burden and cost of compliance.

There is a huge operational cost with qualification. Every item on the list becomes strictly controlled and any subsequent change or modification to the item must be documented and managed as per the change control procedure. Details might include a description of the current situation, an outline of the change, justification for the change, an impact assessment based on the areas it affects, a risk assessment, an action plan and a final evaluation of the change (European Medicines Agency 2007, p.13).

This is arguably the biggest trade-off of all.

You may have heard the expression,

“If everything is important, then nothing is.”

If you place all your attention equally on all systems and all items within every system, you increase the chances of something critical being missed which could in turn harm the patient. Not every system or item has a critical impact on product quality and patient safety and, from a risk assessment perspective, it makes no sense to treat all equipment items as if they do.

So if 100% qualification is not the answer, what is?

The solution is to conduct impact assessments.

This is a procedure where the effects of different systems (and the components of each system) on product quality and patient safety are assessed, to uncover the most critical items. You then focus your qualification efforts solely on those critical items.

Impact assessments are conducted on two levels.

STAGE 1 – Conduct a system-level impact assessment to figure out which systems within the plant are crucial. This process will help you determine what systems have:

• Direct Impact – has a direct impact on product quality
• Indirect Impact – doesn’t have a direct impact on product quality but supports a system that does
• No Impact

Our qualification efforts will only focus on those systems with “Direct Impact” and “Indirect Impact”.

STAGE 2 – Conduct a component-level impact assessment within those systems identified in STAGE 1, to figure out which components within those critical systems are crucial to product quality. This process will help you determine what components are:

• Product Contact Critical – the item has direct or indirect contact with the product
• Operationally Critical – the item is crucial to the correct operation of the process
• Non Critical

Our qualification efforts will only focus on those components that are deemed “Product Contact Critical” and “Operationally Critical” within “Direct Impact” and “Indirect Impact” systems.

Typically, the system-level impact assessments and component-level impact assessments are performed during the preparation of the protocol.

Based on this assessment, the critical elements are determined and these are included within the scope of the equipment qualification protocol. This helps strike a balance between product quality and patient safety and excessive cost.

Let’s take a look at these steps in more detail.

We conduct a system-level impact assessment to figure out which systems within the plant are crucial using the following steps.

1) Determining System Boundaries 

First, using the ISPE Baseline Guide Volume-5 “Commissioning and Qualification”, you determine the system boundaries and define what is, and is not, included in the system. You need to have an understanding of system functionality in order to define a system. 

2) Evaluate the impact

Once boundaries are logically defined, you apply the guide to evaluate systems as: 

• Direct Impact –  where the system “is expected to have a direct impact on product quality” 
• Indirect Impact – where the “system is not expected to have a direct impact on product quality, but typically will support a Direct Impact System”
• No Impact – where the system “will not have any impact, either directly or indirectly, on product quality” 

A system is generally determined to be of direct or indirect impact if it:

• Affects the product’s safety, integrity, strength, purity, or quality
• Produces/delivers a gas or liquid that has direct contact with the product or is used as an ingredient in the product
• Is used in cleaning, sanitizing, and sterilizing direct product contact surfaces of process equipment (e.g. clean steam)
• Preserves product status (e.g. environmental control systems, nitrogen purge for oxygen-sensitive products)
• Produces data, which is used to make quality decisions (accept/reject) regarding product status (e.g. electronic batch record system, critical process parameter chart recorder)

An example of a completed system impact assessment might look something like this:

On the chart below, we see that some of these systems like the “purified water system” have a direct impact on patient safety. Others like the “office air conditioner” have none. But the distinction between “direct impact”, “indirect impact” or “no impact” is not always clear-cut.

Rather the system impact falls on a spectrum. And this is where judgement and experience come into play to make the distinction between types of impact.

We use Good Engineering Practices (GEPs) to manage the design, installation and commissioning of systems and their components within our facility. GEPs have been developed over decades of trial and error and hard-won experience and are a set of industry practices used to manage engineering projects.

In addition to GEPs, we must also qualify all systems that have a “direct impact” or “indirect impact” on product quality and patient safety.

The regulatory authorities (FDA, EMA, etc) will focus on these qualified systems when they come to approve the medicines that are being manufactured in that facility.

A component-level impact assessment evaluates the criticality of the components within the system by considering their impact on product quality.

You conduct this assessment on the items within systems you’ve identified as critical, to figure out what specific components are critical to product quality and patient safety. The ultimate goal will be to only qualify the items that are critical within the system.

We apply the following criteria to each item within the system to determine its criticality.

Operationally critical items don’t come into direct contact with the product and they’re not part of that chain of surfaces that can introduce contamination.

But they contribute to maintaining a state of balance (dynamic equilibrium) for the key factors (i.e. temperature, flow, level, concentration) and are critical to the operation of the system.

If an operationally critical component/instrument fails, product quality is immediately affected.

If a component matches any of the 6 criteria taken from our qualification course, it is deemed “Operationally Critical”:

1. The component is used to demonstrate compliance with a process
2. The normal operation or control of the component has a direct effect on product quality
3. Failure or alarm of the component will have a direct effect on product quality or efficacy
4. Information from this component is recorded as part of the batch record, lot release data, or other GMP-related documentation
5. The component controls critical process elements that may affect product quality, without independent verification of the control system performance
6. The component is used to create or preserve a critical status of a system