In our example, we have broken this into 3 parts.
System Impact Assessment:
In this section you describe why the CIP System is considered a ‘direct impact’ system.
For the identified equipment, instruments, and piping, you must determine if the components are critical or non-critical – and if critical, whether they are product-contact critical, operationally critical, or both.
Let’s take a look at how you differentiate between by product-contact critical items, operationally critical items, and non-critical items
Product-contact critical items come into direct contact with the product OR are part of the chain of surfaces through which there is a risk of contamination being carried to the product.
The first part of that is quite self-explanatory but the second part can take a bit of thinking about. So let’s consider an everyday example…
You’re in the kitchen and you cut raw chicken. Once you’ve finished, you don’t wash your hands. Instead you go to the fridge and take out salad items. You cut them, and serve the salad to your friend. Your friend gets ill from salmonella after eating the salad.
Your friend was never near the raw chicken but there was a chain of surfaces (e.g. the skin on your hands, and the outer surface of the salad items) that brought the salmonella directly from the raw chicken to your friend.
Our clean in place system has that type of product-contact critical items. The final medicine or its ingredients never come near the clean in place system but the system is part of a chain of surfaces that can pass contamination to the product.
Think of the detergent tank of our system. The inner surface of the tank touches the detergent liquid. That detergent liquid passes along a system of pipes and into the reactors during a drawdown. That same liquid then touches the inner surface of the reactor. After a cleaning cycle is finished and manufacturing restarts, the inside of that reactor will come into direct contact with product ingredients.
So although no final products (or even ingredients) are ever in direct contact with the inside of the detergent tank, there is a chain of surfaces that leads from the tank to a surface that will come into contact with the product. If there was contamination in the detergent tank, there is a possibility it could ultimately reach the product via this chain of surfaces. Therefore, our detergent tank is product-contact critical.
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 (e.g. temperature, flow, level, concentration) in our Clean in Place system.
If any of these 4 key factors are out of specification in our CIP system (e.g. liquid is not hot enough or detergent concentration isn’t strong enough), we cannot guarantee that the system is working as intended. Operationally critical items are involved in controlling, monitoring, or reporting these 4 factors so it’s essential that we validate them.
(Note that these key factors may be different depending on the system you’re validating, the 4 listed are specific to controlling our CIP system.)
Non-critical items do not come into contact with the product, nor can they influence the factors that are essential for the correct functioning of the system.
For any component identified as operationally critical, you’ll then complete the summary table of the operational critical components and include rationale.
How this would “look” in the real world:
When you begin in the field – the component impact assessment will probably have been completed for you . However, over time, you are expected to be able to conduct an impact assessment on your own. This is one of the most critical parts of a protocol.
The examples above and your knowledge of ISPE Guide Baseline 5 will be key when it comes to making decisions about criticality, and what needs validation as a result.
It’s important to remember the remit of the FDA at this point and instil it in your work ethic – to ensure the “manufacture safe medicines” and “at an affordable cost”.
You should always keep in mind that the more items that need to be validated, the costlier the validation process will be, and the costlier the medicine will be for the patient. You need to validate the key items, but you cannot just validate everything “just incase”. It’s this balancing act you will need to perform in the field.
You have to be able to justify your decisions around which things you deemed critical if questioned by an FDA auditor.
Always remember, that while an FDA auditor might hold a different opinion on which items are critical, they will respect your decisions if you use scientific-based risk management tools to reach them. There can be different opinions as there is often no single right answer to what is critical and what is not. There are wrong answers of course, but many decisions on critical items are shades-of-grey rather than black or white.