The purpose of validation in pharmaceutical production is to give documented proof that the processes and instruments being used are in compliance with their intended utilization and capable of being carried out successfully. This can, however, stop being true once the focus shifts from scientific proof to filling in the necessary documents only.
Typical mistakes in validation are lack of clearly defined acceptance criteria, the risk assessment not being performed thoroughly enough, incomplete protocol execution, inadequacies in the deviation investigations, untrustworthy data collected, and inability to keep the process in its validated state. All these mistakes may lead to deterioration in the product quality, delays in product licensing, and problems during the inspections by the state.
It is important to note that even the most severe mistakes may not necessarily be evident protocol mistakes. More often than not, that will be evident when the validation was declared successful in theory but not actually carried out.
Any process validation planning should utilize all the necessary information about the product, raw materials, equipment, manufacturing steps, critical process parameters and critical quality attributes to devise a proper validation strategy. Otherwise, the research might not contribute to any meaningful understanding of the process.
An illustration of this is illustrated by tablet making. When preparing the validation protocol, parameters such as the compression force, machine speed, tablet weight, and hardness are included. The team must have been able to assess the relationship among these parameters and significant quality attributes.
Common faults include:
For instance, stating that the process parameter is supposed to remain in “the normal range” would be pointless unless the protocol defined the limits of this range or described the grounds for its determination. The protocol must specify the expected range and the way to determine the results.
Additionally, it is necessary to verify the adequacy of the sampling plan. Even though a large amount of sample might seem supportive, it will provide less useful evidence than a risk-based sampling plan covering a number of process stages and variability.
An appropriate risk assessment is supposed to examine the possible outcomes of failure in terms of product quality, patient safety, process performance, and data integrity. There should also be a provision of justification for the risk rating assigned.
To illustrate it with a practical case, it should be highlighted that the process of cleaning validation risk assessment should take into account the product solubility, toxicity and potency, equipment design, the places difficult to clean, and the type of sampling process applied.
It is wrong to opt for sampling locations that are easily reachable; indeed, they may leave some important risks outside the scope of risk assessment.
Risk assessment must be revised as new data appear, e.g. repeated deviations, changes in the process and adverse trends that happen.
Examples include failure to adhere to the specified sampling sites, making use of a different instrumental method in case of non-compliance with the original conditions, failure to conduct a procedure because it is deemed unnecessary, or conducting further tests without any reason.
Not all deviations from protocol execution invalidate the study but those must be duly documented and dealt with as per the procedures at the site approved. Where approval is required beforehand, changes must not be implemented before getting the approval first.
Let us discuss the delivery of a validation process as an example. Let’s assume that the time for sampling was missed, and the team has to document what happened, determine whether the sample is still valid, and check if the criteria and objectives of the validation are met. It is not correct to make alterations to the protocol requirements in the final report in order to show that the methodology was followed.
There is a common misconception that in case of a deviation being spotted, there is no need to investigate since the final product testing results were satisfactory. Finished-product data may not be enough to clarify if a process failure took place or whether the goals of the validation process are achieved.
A thorough investigation should consider the following:
Justification is a must for repetition of the test. In case repeating the test results in a passing result, and no explanation for the failure is available, the validation evidence becomes suspect.
The reviewers should ensure that the results match the original documents, devices, worksheets or approved electronic records. The data must comply with the ALCOA+ principles.
For computerized systems, validation needs to include information concerning relevant access codes, audits, calculations, interfaces, electronic documents, and recovery systems. For laboratory experiments, chromatographs, integration changes, the documentation about the preparation of samples and calculation worksheets should be included.
Validation needs to give not only summarized information but references that support the evidence. If the data can not be retrieved, the conclusion is not valid.
The most frequent mistake is to approve a report and validate all its components because they are present and signed. The quality assurance experts and technical reviewers should analyze the actual findings of the research, protocol deviations, acceptance criteria, and unresolved limitations of the research.
The report should indicate very clearly:
Some typical errors:
The extent of revalidation should be decided based on the impact of the changes made rather than by ensuring that the entire validation process is repeated.
Before the execution of the process, one must ensure that the protocol is approved, acceptance criteria justified, equipment qualified, instruments calibrated (if applicable), staff trained, and sampling ready.
When you run the execution you should make contemporaneous notes/result of what you see. If there are any surprises you should report them in good time. And after you have executed you should ensure the deviations are investigated, data is traceable, conclusions justified, actions after are controlled.
The regulators could ask you at an inspection how you derived your acceptance criteria, justification for your sample plan, how you treat failed results, how you conclude that a process is still under control? It should not be a post facto explanation; there should be evidence that you have documented them.
The worst mistakes in validation are to make documentation the objective, rather than evidence of control. The ability to demonstrate control through scientifically justifiable protocol, significant risk assessment, rigorous execution, good data, and review of the critical parts of the report, is essential for a justifiable validation outcome. The ultimate concern for the pharmaceutical person involved should be the true demonstration of control, and continued control in the life cycle of the process.
It is important to note that even the most severe mistakes may not necessarily be evident protocol mistakes. More often than not, that will be evident when the validation was declared successful in theory but not actually carried out.
Starting Validation Without Sufficient Process Understanding
One of the major errors in validation is launching qualification or validation of the process before there is a proper understanding of the process itself.Any process validation planning should utilize all the necessary information about the product, raw materials, equipment, manufacturing steps, critical process parameters and critical quality attributes to devise a proper validation strategy. Otherwise, the research might not contribute to any meaningful understanding of the process.
An illustration of this is illustrated by tablet making. When preparing the validation protocol, parameters such as the compression force, machine speed, tablet weight, and hardness are included. The team must have been able to assess the relationship among these parameters and significant quality attributes.
Preparing Weak Validation Protocols
Validation protocol is essential to the study. A bad protocol can result in inconsistent implementation, ambiguous acceptance criteria, and complicated reporting procedures.Common faults include:
- Unclear or unjustified acceptance criteria
- Incomplete sampling plans
- Lack of equipment and/or instrument identification
- Unclear responsibilities for the implementation and reporting process
- Insufficient description of the tests used
- Ambiguous handling of deviations or unforeseen results
- Lack of sufficient information on operating conditions
For instance, stating that the process parameter is supposed to remain in “the normal range” would be pointless unless the protocol defined the limits of this range or described the grounds for its determination. The protocol must specify the expected range and the way to determine the results.
Additionally, it is necessary to verify the adequacy of the sampling plan. Even though a large amount of sample might seem supportive, it will provide less useful evidence than a risk-based sampling plan covering a number of process stages and variability.
Treating Risk Assessment as a Documentation Exercise
In some cases, risk assessment is treated like a mere formality since every aspect is classified as low or moderate risk without proper explanations in place.An appropriate risk assessment is supposed to examine the possible outcomes of failure in terms of product quality, patient safety, process performance, and data integrity. There should also be a provision of justification for the risk rating assigned.
To illustrate it with a practical case, it should be highlighted that the process of cleaning validation risk assessment should take into account the product solubility, toxicity and potency, equipment design, the places difficult to clean, and the type of sampling process applied.
It is wrong to opt for sampling locations that are easily reachable; indeed, they may leave some important risks outside the scope of risk assessment.
Risk assessment must be revised as new data appear, e.g. repeated deviations, changes in the process and adverse trends that happen.
Executing the Protocol Differently From the Approved Plan
One of the most common mistakes made is permitting the protocol execution to differ from the approved one without sufficient documentation to support this.Examples include failure to adhere to the specified sampling sites, making use of a different instrumental method in case of non-compliance with the original conditions, failure to conduct a procedure because it is deemed unnecessary, or conducting further tests without any reason.
Not all deviations from protocol execution invalidate the study but those must be duly documented and dealt with as per the procedures at the site approved. Where approval is required beforehand, changes must not be implemented before getting the approval first.
Let us discuss the delivery of a validation process as an example. Let’s assume that the time for sampling was missed, and the team has to document what happened, determine whether the sample is still valid, and check if the criteria and objectives of the validation are met. It is not correct to make alterations to the protocol requirements in the final report in order to show that the methodology was followed.
Ignoring Deviations, Failed Results, or Unexpected Trends
Validation should test and confirm the performance of the process. Thus deviations and unexpected results should not be ignored.There is a common misconception that in case of a deviation being spotted, there is no need to investigate since the final product testing results were satisfactory. Finished-product data may not be enough to clarify if a process failure took place or whether the goals of the validation process are achieved.
A thorough investigation should consider the following:
- What happened and when did it take place?
- What might have caused the incident?
- What is the impact of the unexpected results in the validation study and on the batches concerned?
- Whether there are any other runs, products, or systems that would be affected by the incident.
- Whether it is necessary to conduct any additional tests or redo the validation study.
- Whether there is a need for CAPA and effectiveness checks.
Justification is a must for repetition of the test. In case repeating the test results in a passing result, and no explanation for the failure is available, the validation evidence becomes suspect.
Overlooking Data Integrity and Traceability
The credibility of validation outcomes relies on the dependability of information. Failure to have available raw data, lack of transparency in calculations, different timestamps, unknown changes, and record difficulties can ruin a technically strong project.The reviewers should ensure that the results match the original documents, devices, worksheets or approved electronic records. The data must comply with the ALCOA+ principles.
For computerized systems, validation needs to include information concerning relevant access codes, audits, calculations, interfaces, electronic documents, and recovery systems. For laboratory experiments, chromatographs, integration changes, the documentation about the preparation of samples and calculation worksheets should be included.
Validation needs to give not only summarized information but references that support the evidence. If the data can not be retrieved, the conclusion is not valid.
Approving Reports Without Evaluating the Conclusion
Validation reports should provide a clear explanation of whether the study goals have been accomplished and if the provided data confirm the conclusion made.The most frequent mistake is to approve a report and validate all its components because they are present and signed. The quality assurance experts and technical reviewers should analyze the actual findings of the research, protocol deviations, acceptance criteria, and unresolved limitations of the research.
The report should indicate very clearly:
- The outcomes that either were confirmed or rejected according to the acceptance criteria;
- The deviations that have taken place and their effect assessment;
- The limitations of the investigation;
- The follow-up actions that should be implemented and the assigned people responsible for executing them;
- Reasons to confirm that the process, system, or equipment is fit for use.
Failing to Maintain the Validated State
Validation should be considered an ongoing activity and not as a one-off measure. A process may initially be validated but then become less controlled during subsequent operations due to equipment modifications or variations in raw material, maintenance issues, operators' actions, or process drift.Some typical errors:
- Introducing changes without conducting a validation influence assessment.
- Disregarding repeated deviations and negative trends.
- Not performing necessary calibration and maintenance checks.
- Not conducting reviews of continuous process verification data.
- Not conducting periodic inspection of systems or equipment (if applicable).
The extent of revalidation should be decided based on the impact of the changes made rather than by ensuring that the entire validation process is repeated.
Building a More Reliable Validation Approach
One way to avoid these errors is by improving the validation plan and cross-functional review. The team from QA, Production, QC, Engineering, and Validation should know their roles and offer relevant experience.Before the execution of the process, one must ensure that the protocol is approved, acceptance criteria justified, equipment qualified, instruments calibrated (if applicable), staff trained, and sampling ready.
When you run the execution you should make contemporaneous notes/result of what you see. If there are any surprises you should report them in good time. And after you have executed you should ensure the deviations are investigated, data is traceable, conclusions justified, actions after are controlled.
The regulators could ask you at an inspection how you derived your acceptance criteria, justification for your sample plan, how you treat failed results, how you conclude that a process is still under control? It should not be a post facto explanation; there should be evidence that you have documented them.
The worst mistakes in validation are to make documentation the objective, rather than evidence of control. The ability to demonstrate control through scientifically justifiable protocol, significant risk assessment, rigorous execution, good data, and review of the critical parts of the report, is essential for a justifiable validation outcome. The ultimate concern for the pharmaceutical person involved should be the true demonstration of control, and continued control in the life cycle of the process.
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