On the protocol approvals page, you would complete a list of necessary protocol approvers – the people who need to “sign off” on the validation activities.

How this would “look” in the real world:

This section is where validation team members have their responsibilities summarised, and sign to state that everything they’ve written in the document is correct and accurate. Each of the relevant personnel would be listed on this page.

While this is the first page of a protocol, it is the last page that will be signed. Signatures on this page confirm that everything in the rest of the document is accurate and that you are happy with the results and recommendations.

You should never sign anything unless you know it to be an accurate reflection of the situation. You would never sign anything that was not your own work. Always remember that in an FDA audit, the auditor could ask to speak to you about your specific role in the validation process, and you would have to be able to defend the decisions you made.

Additional Reading

What Types of Jobs are there in the Pharmaceutical Industry?
What Is a Validation Engineer?

In this section, you need to prepare a summary ‘System Description’. You might include things such as:

• Drawing a process flow / block diagram
• Listing critical operational features
• Describing the major equipment components in the context of their installation and functional features.

How this would “look” in the real world:

In an FDA audit, this is where the auditors will go first to understand the system being validated. It provides a high-level overview of the equipment system. It needs to be short, but also provide the level of detail they need to understand the rest of the protocol.

When you first begin in a Validation team, this will probably already be completed for you. However, as you gain seniority, you will need to understand the purpose of a system description and be able to write one of your own.

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.

In this section you include a copy/scan of the P&ID and either draw a ‘scope bubble’ or yellow-highlight the ‘in-scope’ components.

How this would “look” in the real world:

This section builds on the decisions you made earlier. In the field, the decisions you made regarding the scope of the protocol (i.e. what equipment elements, instrumentation components, and line and piping elements are part of the system you are validating) determine what you include in the scope bubble here. Again, as a new member of a validation team, you will likely be told what is included but over time you will be expected to make the decisions yourself.

Make a list of abbreviations that are used in the protocol and their definitions. This is something you should fill up as you complete the protocol. Once you have finished, read back through the protocol and make sure to add any abbreviations you have missed.

How this would “look” in the real world:

The purpose of this section is so that the person who comes along after you can understand any abbreviations you have used throughout the protocol. We all routinely use some abbreviations, this is no different in companies. But an abbreviation used on the factory floor that people around you understand is not necessarily something an outsider or someone new to the company will know. When it comes to an FDA auditor, they need to be able to understand exactly what you are referring to with your abbreviations – so make sure this is as comprehensive as possible.

In this section, you identify subject matter experts. These are the people responsible for the development, review, approval, and execution of the protocol. Complete a list of project responsibilities for each of the specific subject matter experts.

How this would “look” in the real world:

When you begin in a Validation Team, you will be told exactly who needs to sign off on your work and what responsibilities each team member has. If you go on to be a Validation Engineer and begin to write protocols from scratch, you could then be responsible for deciding what each department in the company is responsible for, who the subject matter experts are, and what responsibilities each person has.

An FDA auditor will turn to this protocol section to see each department or individual’s responsibilities so they know who to talk to if they have specific questions about a test or procedure. It is therefore important that this section is detailed and accurate.

This is also one of the sections that is closely linked to other protocol sections. Your Approvals Page (Section 2), Your Responsibilities Page (Section 10) and Your Progression Approval Page (Section 12), should all align. If they do not, an auditor is going to have serious questions.

In this section, you need to give a summary of the ‘Calibration Program Verification’ procedure that is used to guide the creation of calibration check sheets (these are usually located in the protocol appendix). Make sure you write this from the perspective of someone who is entirely new to the system you are validating.

How this would “look” in the real world:

After you have identified the Operationally Critical Components (remember we did this in Section 3), you need to make sure that any operationally critical instruments you have identified become part of the maintenance team’s calibration rota.

Calibration is where you test to make sure the operationally critical instruments are working. For example, you would test to make sure that the temperature gauge is measuring the temperature correctly. This is done on a routine and ongoing basis to make sure everything is operating as intended for the whole length of the system life cycle. Commissioning, Qualification & Validation (CQV), Commissioning & Qualification (C&Q) Engineers and Maintenance personnel are responsible for calibration testing in a plant. It falls into “Continued Process Verification”, the purpose of which is to ensure that the previously validated system remains in a reliable and validated state.

Your job in the field would be to write this summary, then use the information from this to create a checksheet to be completed during calibration activities. Finally, the CQV Engineers and Maintenance Personnel would be told to add this list of instruments to their regular calibration schedule.

Additional Reading

• What are IQ OQ PQ? And why are they critical to the pharmaceutical industry?
• What is Process Validation?

In this section, you need to give a summary of a ‘Preventative Maintenance Program Verification’ procedure that is used to guide the creation of a check sheet (that is usually located in the protocol appendix). Make sure you write this from the perspective of someone who is entirely new to the system you are validating.

How this would “look” in the real world:

Each plant has a preventative maintenance program. Preventative maintenance is how you ensure that all the operationally critical components you have identified, are working properly at all times.

The preventative maintenance team performs maintenance checks on equipment before there is a problem – like changing the tires on your car before they become bald. On a car, your tires should be good for 25,000 miles, and therefore if you change them at 20,000 miles they should have enough thread to be safe to drive on. The preventative maintenance system identifies the critical items that need to be maintained, and the duration between each maintenance check.

CQV Engineers, C&Q Engineers and Maintenance Personnel are responsible for the preventative maintenance program and it is your job here to complete the form with what components they need to add to preventative maintenance rota

Preventative Maintenance is also part of the stage of Validation called Continued Process Verification. Failure to complete this stage of validation could result in compromised batches of unreliable quality medicine that are not safe for patients to use.

The activities of this stage focus on two key goals:

1. To maintain equipment and facilities in their validated state
2. To quickly highlight variation in product or process data, allowing corrective action to be taken

Activities involved in Continued Process Verification might include things such as:

• Regular equipment maintenance
• Routine testing of in-process materials and final product sampling (comparing both within and between batches)
• Routine gathering and analysis of in-process data
• Equipment swabbing
• Cleaning

Additional Reading

Process Validation

In this section, you’ll propose a list of necessary standard operating procedures for the ‘Clean in Place’ system.

The information you outline here will be used to create an SOP checksheet in the protocol appendix.

How this would “look” in the real world:

As you know by now, no matter what role you have in the Pharma or MedTech industries, a key part of your job will always involve following strict internal protocols and Standard Operating Procedures (SOPs) as well as following current Good Manufacturing Practices (cGMP).

When you start in a Validation Team, you are going to be told which SOPs are going to be implemented because of the validation protocol that has been written. As you go up the career ladder, you will be expected to make the decision regarding what SOPs are needed.

This section basically tells an auditor that at this stage of the protocol, you were thinking of implementing the following list of SOPs to make sure the equipment functions as intended. When you get to later sections, you are then going to tell an auditor (and your colleagues) the finalised list of SOPs that are to be followed.

Writing SOPs is an advanced-level task but it’s important that you understand where they come from and how they integrate with the rest of the protocol.

Additional Reading

How to Save Money with SOPs that Stand the Test of Time

In this section, suggest a list of test instruments that may be required for the testing phase.

The information you outline here will be used to create a test-instrument calibration verification checksheet in the protocol appendix.

How this would “look” in the real world:

This section is very simple. You want to document that all test instruments used to validate the readings on the instruments of the Clean in Place system are functioning correctly. We’ve already talked about the importance of calibration but in this case, in the future, if there was a problem with any of the instrument readings on the CIP system, you want to rule out the possibility that it was a problem that stemmed from a faulty test instrument reading

Align the signatories in this section “Progression Approval to Proceed” with the section 2 signatures on the ‘Approvals Page’, section 6 Responsibilities / Subject Matter Experts, and the protocol signature log which will be contained in the appendix.

How this would “look” in the real world:

This section is where you would sign your name stating that everything you have written is correct and accurate as you move into functional verification. You’ll see again that all relevant personnel have to sign at this stage, and responsibilities for each are summarised.

Remember, you should never sign anything unless you are sure it’s an accurate reflection of the situation – and you would never sign anything that was not your own work. In an FDA audit, where an auditor was looking at this specific piece of equipment, the auditor could ask to speak to you about your specific part validating the equipment, and you could have to justify decisions you made, to them.

This is a section that builds on what you have written previously. What is written here should match what you wrote in section 2 and 10. And again, an auditor would have questions for you if it didn’t.

Enter the same list of instruments into the ‘Operational-Critical-Instrument Calibration Verification Form’ in this section as those listed in Section 3 ‘Summary Table – Operational Critical Components’.

How this would “look” in the real world:

The purpose of this form is to ensure that critical instruments associated with the system are in a calibrated state during the operational qualification (OQ) phase.

Operational Qualification is used to confirm that the overall CIP system will operate as intended

To carry this out, C&Q engineers must carry out various tests on the equipment to make sure the system functions is meeting the expectations outlined in the User Requirement Specification (URS) for flow, temperature etc.

Prepare functional test procedures for Temperature, Flow and Level for the Clean in Place System.