Revalidation Triggers in Pharmaceuticals | When and Why Required

Pharmaceutical manufacturers must validate their manufacturing processes. It is going to provide proof that a pharmaceutical company's equipment, utilities, systems and processes operate according to proper procedures consistently. Validation may not be a repetitive process and as time goes by your validated condition may be affected by one or more variables, i.e. Change, Deviation, Trends, etc. This is why it's important to implement revalidation.

Revalidation guarantees that the validated state of a system is maintained throughout its entire life cycle. The requirements of Good Manufacturing Practices (GMPs) for this maintained validated condition have been well established and reinforced by both the FDA and the EU and therefore the need to know when and why revalidation is required by a pharmaceutical company is paramount.

What is Revalidation?

The term "revalidation" refers to the repeated or confirmed validation of a process or system to ensure that they remain in a controlled state. It will verify if the conditions that were previously validated still hold true after changes or over the period of time. There are two types of revalidation:

• Full Revalidation (where all validation activities are repeated in their entirety)
• Partial Revalidation (reporting upon validation activities for some limited aspect of the system; for example, a particular parameter or in response to an event)

The type and extent of revalidation will be determined by the degree and effect of the change or event.

Why Revalidation is so Important

Systems that have been validated historically remain in a validated state over time under controlled conditions. But over a period of years even the best controlled systems will deviate from their validated state; this may be due to wear and tear on equipment, process variation or other changes made to the systems. Revalidation should be conducted to:

• Provide assurance that the products manufactured from the process will conform to specifications
• Maintain compliance with relevant regulatory requirements
• Detect out-of-control processes in the early stages of deviation
• Assure that a change made to a system had the desired impact

Without revalidation, the processes may no longer meet the required specifications that were developed during the validation.

Types of Revalidation

There are three categories for revalidation based on the motive behind initiating a revalidation.

1. Revalidation Based on Changes

This type of revalidation is performed when there is a change to a system, process, or piece of equipment.

2. Periodic Revalidation

This type of revalidation is conducted periodically as specified to confirm that the system continues to perform as intended.

3. Trigger-based Revalidation

Trigger-Based Revalidations are initiated due to occurrences of defined events (i.e., deviations or failures).

Common Revalidation Triggers

Staying compliant by understanding revalidation triggers.

1. Changes in Critical Process Parameters

Any changes made to any one critical process parameter will have an effect on the product's final quality. Examples of these changes include:

• Temperature changes
• Changes to mixing times
• Changes in compression forces
• Evaluation of these changes will help the organization determine if the changes are required for re-validation.

Revalidation may need to be performed to re-confirm the impact of those changes.

2. Equipment Modification or Replacement

Any changes made to equipment can have a large impact on the performance of the process. The most common examples would be:

• Replacing a major piece of equipment
• Installing new equipment
• Upgrading existing equipment

These minor modifications may also require evaluation to confirm the need for re-validation.

3. Changes in Raw Materials

Raw material properties can change from batch to batch and affect how the process will perform or affect the quality of the final product. Some examples of these types of changes would be:

• Changing suppliers
• Changing grades or other specifications
• Changing the particle size of raw material

These changes could require revalidation due to potentially changing how the process behaves.

4. Changes to Facilities or Utilities

Changes made to the manufacturing environment or utilities could impact validation status. Some examples of these types of changes would be:

• Changing the HVAC system
• Changing the water system
• Changing cleanroom classification

Any of these changes could affect the quality of the product and should be evaluated carefully before continuing manufacture of the product.

5. Deviation & Out of Specification Results

When repeated deviations or out of specification (OOS) results occur, it typically indicates that the process is not in control. Examples of when an organization may have to revalidate due to deviation or OOS results could be when:

• Trends are showing an increase in variability
• Results of performing root cause analysis are focused on an issue with the process

Revalidation should help return the confidence in the system.

6. Change Control Implementation

A formal change control process is used for all changes. All changes must be evaluated for their effect on validation.

If there is a significant effect on the validation process, revalidation is required to ensure compliance with Good Manufacturing Practices.

7. Software or Computerized System Changes

Changes or updates to computerized systems may affect the integrity of data and the functionality of the system. Examples of system changes include:

• Changes to software (upgrading)
• Changes to configuration
• Integrating with new systems

21 C.F.R. Part 11 requires validation of these types of changes to systems.

8. Scale-up or Process Transfer

A process may have different requirements when scaling up or transferring to another site. Examples of process changes due to a change in scale or location include:

• Increasing the batch size
• Transferring to different manufacturing units

Revalidation confirms that a process will produce consistently when the environment changes.

9. Trends from the Annual Product Review (APR)

Data obtained through an Annual Product Review can show trends that indicate a drift in process. Examples of drift include:

• Changing over time in critical quality attributes
• Increase in the variability of process parameters

Trending may be used to initiate revalidation.

10. Time-Based or Periodic Requirement

Many organizations use revalidation on a regular basis as a preventative measure. Regular revalidation will ensure the following:

• Systems are continually controlled
• No unintended drift has occurred

Periodic revalidation is usually based on a risk assessment.

Approach to Risk-Based Revalidation

Not all changes necessitate the performance of full revalidation. A risk-based approach can assist in determining the amount of revalidation that is required.

According to ICH Q9 Quality Risk Management, when carrying out a risk assessment, the following considerations should be taken into account:
1. The impact that the change will have on product quality
2. The impact that the change will have on patient safety
3. Complexity of the change
Using a risk-based approach will allow for proper use of resources while ensuring compliance.

Process for Revalidation

A well-structured revalidation process is necessary for effective revalidation. The major components of a structured revalidation process:

• Identify the trigger
• Conduct an impact assessment (if needed)
• Define the scope of revalidation
• Develop the protocol
• Execute the revalidation activities
• Review the results and approve.

Each step of the revalidation process must have adequate documentation to provide evidence of compliance and to support any regulatory inspection.

Documentation Requirements

Sufficient documentation to support revalidation activities is critical. Some key types of documentation:

• Change control records
• Risk assessment documentation
• Revalidation protocols
• Test results and reports

Documentation is critical in providing evidence that the activities are compliant, but it also serves to support any potential regulatory inspections that may occur.

Common Mistakes in Revalidation

There are many problems that organizations encounter when they do not manage revalidation properly. Here are some of the most common mistakes:

• Not considering all of the smaller changes
• Not completing impact assessments
• Not revalidating promptly after changes
• Poor documentation
• Not completing periodic reviews

Reducing these common mistakes will help an organization continue to demonstrate that their products are still in a validated state.

Best Practices for Effective Revalidation

A company can have a successful revalidation by taking a proactive approach to maintain validated conditions of their products and processes. Some of the best guidelines to accomplish this are:

• Establish strong change control systems
• Make risk-based decisions
• Continuously monitor processes
• Perform regular reviews
• Train all employees on the validation process and requirements

By following and applying these guidelines there will be timely and effective revalidation of product(s) or process(es).

Role of Quality Assurance in Revalidation

Quality Assurance (QA) is instrumental in the entire revalidation process. QA is responsible for the following:

• Reviewing all change control and risk assessment for an organization
• Approving all revalidation protocols
• Ensuring that all elements of Good Manufacturing Practices are met at the time of revalidation
• Monitoring the implementation of corrective actions following revalidation

But QA can ensure that all revalidation activities are performed in accordance with regulatory expectations.

Regulatory Expectations for Revalidation

Regulatory bodies expect that all pharmaceutical companies continue to maintain their manufacturing process or product(s) in a validated state. Some of the expectations of regulatory bodies in the area of revalidation:

• Timely revalidation of change(s)
• Use of a risk-based approach
• Proper documentation
• Continual monitoring

Organizations that fail to meet these expectations run the risk of regulatory observations during a regulatory inspection; therefore, can expect non-compliances related to revalidation activities.

The re-validation of pharmaceutical manufacturing is an essential element of maintaining control over any aspect of the pharmaceutical process such as process, systems and equipment still functioning as intended after there have been changes to either the process, systems or equipment or simply because of their age.

If organizations understand the trigger for re-validation, they can be proactive in their response to maintaining compliance with regulations and best practices through a risk-based methodology and ultimately maintaining consistent levels of quality with their products while also being ready for regulatory agencies.

Re-validation is more than a regulatory requirement; it's also a vital mechanism for sustaining quality and reliability in a highly regulated industry.

Frequently Asked Questions on Revalidation in Pharmaceuticals

Q1. What is revalidation?

Answer: Revalidation is the confirmation process of a validated system still in control.

Q2. When is revalidation required?

Answer: Revalidation is warranted when a system has gone through change, including deviation from the original specifications, or at regular intervals (i.e., periodical review).

Q3. What triggers revalidation?

Answer: Revalidation is initiated due a change in process, a modification to equipment, or out of specification (OOS) results.

Q4. Is revalidation always full?

Answer: Revalidation is not always full revalidation of the validated system; it can be partial depending on the level of risk associated with the system.

Q5. What is the role of change control?

Answer: Change control's role in relation to revalidation is to evaluate how a change will affect the previously performed validation assessment.

Q6. What is 21 CFR Part 11?

Answer: 21 CFR Part 11 describes regulations concerning electronic systems.

Q7. Why is risk assessment important?

Answer: Risk Assessment is important as it aids in determining the amount of revalidation that must occur.

Q8. What happens if revalidation is not done?

Answer: If you do not perform revalidation on a validated system, you are potentially non-compliant and may risk the quality of the product.

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