Risk-Based Validation refers to the process of organizing validation activities of pharmaceutical process, system or method based on the actual risks for product quality, patient safety and data integrity. It assumes that scientific knowledge and quality risk management (QRM) should help in identification of critical points and areas of validation, to which the organization should pay the maximum attention.
In practice, being involved in the pharmaceutical manufacturing process, it does not mean that the process of validation should be minimized or even skipped in terms of the GMP requirements. It means that scientific approach should help to create the proper validation scheme and define the right controls based on the identified risks.
Using the same process validation for all systems may lead to unnecessary tests for low-impact systems but not highlight crucial process variables or failure modes of high-impact systems. The risk assessment process can show you what needs to be qualified, which characteristics to put in the validation, the type of sampling to choose, and many other important aspects of the process.
This is the case, for instance, of the temperature sensor responsible for a significant production process, this sensor can directly influence one of the critical quality attributes (CQA). It is quite clear that a sensor used only for maintaining good temperature in a company's office has a different quality impact. Therefore, different qualification approaches have to be used.
This process is based on cause-and-effect reasoning. It is not acceptable to make a risk-based decision only because it is easy or cheap.
The concept of quality risk management is discussed in ICH Q9(R1) which also provides some methods of carrying out quality risk management. Some of the possible methods of risk management include FMEA, which is a structured approach to risk analysis, risk filtering and ranking, as well as fault tree analysis.
In the case of FMEA, the team will have to analyze the following aspects:
1. Severity: This refers to the possible consequence of failure in terms of quality of product and safety of patients.
2. Occurrence: This refers to the possibility of failure occurring.
3. Detectability: This is the likelihood of failure being detected before it causes harm.
Some companies utilize a Risk Priority Number (RPN) arrived through rating different parameters. However, it is important to remember that an RPN serves only as the means and cannot be treated as a mandatory standard. The method of rating and all the parameters must be set up in accordance with the policy of the facility. A low rating will not amount to a justification for ignoring the risk of failure with serious negative effects.
Persons who can contribute to the process risk assessment should possess the necessary knowledge of the processes being evaluated. Depending on the subject matter of the analysis, various departments such as QA, Validation, Production, QC, Engineering, Microbiology, and IT may take part in the risk analysis.
With regard to qualification of equipment, risks may define the degree of attention to be given to construction features and type of operation, alarms, safety locks, and complexity of performance. In the case of validation of processes, risk evaluation may help decide on the evaluation of critical product parameters (CPP), critical product indicators (CQA), and plans of material sampling and monitoring of a process.
Taking into account the granulation process as an example, moisture content, impeller operation, addition of binder, and granulation time might affect granule parameters and tablet quality which follows. Therefore, the validation team has to rely on knowledge of the process and perform risk assessment in order to define which parameters should be assigned specific limits and should face deliberate challenge. This refers to the parameters which are believed to influence CQAs and thus require justification and regulation.
A risk assessment should account for such factors as product features, composition, design of the equipment, production scale, process variability, previously available information, and production experience. The changes in any of these factors will make a new assessment necessary.
The explanation of worst-case selection should be recorded. In that sense, choosing the product only for being the strongest or the one produced most can be insufficient for understanding the cleaning risk.
The volume of testing needs to be justified by the purpose of the use, the design of the equipment, and the amount of risk. Any modifications to studies of the functional components should undergo an impact assessment process through the change control procedures.
A technique designed to identify a hazardous contaminant at a tight limit may need to be specifically examined for reliability, sensitivity, and specificity. The risk-based approach helps concentrate on scientific investigation, without undoing the process of analytical validation.
QA has to determine whether the assessment is scientifically adequate and whether the risk with high levels of significance has been managed properly. Moreover, QA will review if all final conclusions are validated adequately as well as whether unresolved issues should be followed up.
One of the main problems of the completion of risk assessment is conducting this exercise after the testing phase to validate the existing scope instead of using the assessment beforehand in order to inform on how implementation should take place.
There should be a periodical auditing process of evaluation to verify whether the earlier stated assumptions are still currently valid. The relevant elements in this case can be interpreted as deviations, OOS and OOT results, maintenance records, events of calibration, complaints, dynamics of the processes, and the efficiency of CAPA.
For instance, the repetitive occurrence of deviations of the previously low-risk indicator can also imply that the evaluation should be reviewed. The company should analyze the situation, determine the effect of the risk, and decide if there is a demand for some additional control measures.
At an inspection, an inspector may ask why a particular parameter was deemed non-critical, how the extreme product was chosen, and what proof substantiates the range of validation. A properly executed risk assessment that demonstrates connections with available protocols, data, and quality decisions clarify the rationale.
Why Validation Scope Should Be Risk-Based
Pharmaceutical plants run several systems with different degrees of impact. The operation of a tablet-compressing machine, a purified-water system, a temperature-controlled storage facility, an HPLC analyzer, or an office printer does not carry the same number of risks for product quality.Using the same process validation for all systems may lead to unnecessary tests for low-impact systems but not highlight crucial process variables or failure modes of high-impact systems. The risk assessment process can show you what needs to be qualified, which characteristics to put in the validation, the type of sampling to choose, and many other important aspects of the process.
This is the case, for instance, of the temperature sensor responsible for a significant production process, this sensor can directly influence one of the critical quality attributes (CQA). It is quite clear that a sensor used only for maintaining good temperature in a company's office has a different quality impact. Therefore, different qualification approaches have to be used.
This process is based on cause-and-effect reasoning. It is not acceptable to make a risk-based decision only because it is easy or cheap.
Applying Quality Risk Management to Validation
Risk assessment comprises both a comprehensive understanding of the process and identifying its purposes and the interactions occurring within the process. Teams will be tasked with determining how the process could fail and what its failure consequences would be.The concept of quality risk management is discussed in ICH Q9(R1) which also provides some methods of carrying out quality risk management. Some of the possible methods of risk management include FMEA, which is a structured approach to risk analysis, risk filtering and ranking, as well as fault tree analysis.
In the case of FMEA, the team will have to analyze the following aspects:
1. Severity: This refers to the possible consequence of failure in terms of quality of product and safety of patients.
2. Occurrence: This refers to the possibility of failure occurring.
3. Detectability: This is the likelihood of failure being detected before it causes harm.
Some companies utilize a Risk Priority Number (RPN) arrived through rating different parameters. However, it is important to remember that an RPN serves only as the means and cannot be treated as a mandatory standard. The method of rating and all the parameters must be set up in accordance with the policy of the facility. A low rating will not amount to a justification for ignoring the risk of failure with serious negative effects.
Persons who can contribute to the process risk assessment should possess the necessary knowledge of the processes being evaluated. Depending on the subject matter of the analysis, various departments such as QA, Validation, Production, QC, Engineering, Microbiology, and IT may take part in the risk analysis.
Defining the Validation Strategy and Testing Depth
Risk-based validation affects the breadth and intensity of qualification and validation procedures. The strategy should specify what will be measured, reasons of the importance, and how the criteria of approving will confirm the suitability for the intended application.With regard to qualification of equipment, risks may define the degree of attention to be given to construction features and type of operation, alarms, safety locks, and complexity of performance. In the case of validation of processes, risk evaluation may help decide on the evaluation of critical product parameters (CPP), critical product indicators (CQA), and plans of material sampling and monitoring of a process.
Taking into account the granulation process as an example, moisture content, impeller operation, addition of binder, and granulation time might affect granule parameters and tablet quality which follows. Therefore, the validation team has to rely on knowledge of the process and perform risk assessment in order to define which parameters should be assigned specific limits and should face deliberate challenge. This refers to the parameters which are believed to influence CQAs and thus require justification and regulation.
Risk-Based Validation Across Different Activities
1. Process Validation
The purpose of a risk assessment in the process validation stage is to determine the critical process parameters, CQAs, and the locations for sampling, as well as to establish which aspects have to be qualified. Furthermore, it may provide information on the approach to continue process verification.A risk assessment should account for such factors as product features, composition, design of the equipment, production scale, process variability, previously available information, and production experience. The changes in any of these factors will make a new assessment necessary.
2. Cleaning Validation
Cleaning validation risk may include not only carryover but also insufficiently effective removal of cleaning agents and microbial contamination. Moreover, the assessment may help to choose the product with the highest risk based on the parameters of the product including its potency, solubility, cleanability, and toxicity.The explanation of worst-case selection should be recorded. In that sense, choosing the product only for being the strongest or the one produced most can be insufficient for understanding the cleaning risk.
3. Equipment and Utility Qualification
Qualification for equipment and utilities should be risk-based and should consider aspects like functionality and components that have an influence on product quality, process control, and operational reliability. An example in regard to a pharmaceutical water system might include considerations such as water quality, conditions of storage and distribution, performance of sterilization processes at different points of measurement, and design of the system.The volume of testing needs to be justified by the purpose of the use, the design of the equipment, and the amount of risk. Any modifications to studies of the functional components should undergo an impact assessment process through the change control procedures.
4. Analytical Method Validation
When establishing analytical methods, it is required to assess risk considering the purpose of implementation, limits of specifications, matrix of testing samples, properties of analytes, and results of incorrect analysis. It is necessary to define validation characteristics and criteria acceptable for the validation based on the guidance and on the method of analysis used.A technique designed to identify a hazardous contaminant at a tight limit may need to be specifically examined for reliability, sensitivity, and specificity. The risk-based approach helps concentrate on scientific investigation, without undoing the process of analytical validation.
Documentation and QA Oversight
To carry out a risk-based approach, it needs to be documented and made completely transparent. For instance, an adequate risk assessment must be made to provide justification for such aspects as scope of work, major characteristics that have to be tested, methodology of testing, acceptance criteria, and exceptions that require justification.QA has to determine whether the assessment is scientifically adequate and whether the risk with high levels of significance has been managed properly. Moreover, QA will review if all final conclusions are validated adequately as well as whether unresolved issues should be followed up.
One of the main problems of the completion of risk assessment is conducting this exercise after the testing phase to validate the existing scope instead of using the assessment beforehand in order to inform on how implementation should take place.
Maintaining the Validated State
Validation that is targeted on risk does not wrap up with the approval of a report. There is potential for an alteration of processes and systems because of changes in the machines, newly developed products, revisions in procedures, or deviations throughout maintenance and performance.There should be a periodical auditing process of evaluation to verify whether the earlier stated assumptions are still currently valid. The relevant elements in this case can be interpreted as deviations, OOS and OOT results, maintenance records, events of calibration, complaints, dynamics of the processes, and the efficiency of CAPA.
For instance, the repetitive occurrence of deviations of the previously low-risk indicator can also imply that the evaluation should be reviewed. The company should analyze the situation, determine the effect of the risk, and decide if there is a demand for some additional control measures.
At an inspection, an inspector may ask why a particular parameter was deemed non-critical, how the extreme product was chosen, and what proof substantiates the range of validation. A properly executed risk assessment that demonstrates connections with available protocols, data, and quality decisions clarify the rationale.
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