Validation failures are usually due to improper testing, equipment failure, or mistakes made by the operator. One of the most common causes of validation failures is not mentioned often enough, which is the poor risk assessment done in the planning phase. Inadequate identification and assessment of potential risks can lead to improper validation protocols, which could mean that critical parameters in a process were not challenged, the worst conditions were never taken into account, and other types of failure were unnoticed. That means that besides unsuccessful validation, the process can seem validated while there are many risks that have not been managed properly.
In recent years, regulatory authorities have started to demand that pharmaceutical producers adopt risk-based validation in all stages of the product life cycle. Validation protocols developed without systematic risk assessment will be unsuccessful since they will not be able to identify negative variables and will be subjected to scrutiny from regulatory authorities. Furthermore, such approach would lead to unnecessary quality risks to patients.
Detailed risk assessment can help to:
- Identify Critical Process Parameters (CPPs)
- Define Critical Quality Attributes (CQAs)
- Choose worst-case scenarios
- Specify sampling points
- Set acceptance criteria
- Prioritize validation tests
- Back scientifically valid reasons for your decisions
If there is no such basis, validation tests are likely to give illusory confidence.
Three validation batches were produced successfully, meeting specifications for yield, hardness, and the way the product looks. Thus, the process has been licensed for commercial scale of production.
In six months, several commercial batches failed dissolution tests. Even though yield and uniformity of the content were approved, dissolution tests showed serious deviations among tablets.
An investigation was launched to determine the cause.
They confirmed:
During evaluation, the team analyzed such documents as:
Distribution of granule particle size after milling.
In the course of carrying out the development batches, particle size was virtually unchanged and the project team considered it to be a parameter with low risk.
As a consequence:
Even though the material met all of the pharmacopoeial properties, it was slightly different in terms of physical characteristics.
This impacted:
Key material properties must have been assessed together with the process criteria.
If an interdisciplinary team had been utilized, it might have pointed out the possibility of particle size at a much earlier stage.
Statements like "This has never been problematic before." were used instead of scientific evaluation.
Past achievements should never replace any formal risk analysis.
Hence, the reassessment has shown the inadequacy of the validation plan in reflecting the interplay between raw materials and process performance.
1. One must acknowledge that validation is only as good as the risk evaluation behind it.
2. Obtaining positive results from a validation run does not guarantee the process viability in the long run.
3. One should treat Critical Material Attributes on the same level as the Critical Process Parameters.
4. The risk evaluation must continuously be updated and improved depending on new experience and information gained during production.
It is often difficult to identify inadequate risk management when the validation is initiated, although its ramifications appear during the process of routine commercial manufacturing months later. The example given here illustrates how failure to recognize a critical material quality can lead to process variability and poor product quality, and the need for a costly investigation even after the validation is deemed successful. Hence, it becomes evident that risk assessment is to be conducted thoroughly and systematically to perform effective validations.
From my experience so far, I have found that great validation strategies can hardly be developed without multiple teams working together in order to raise questions regarding certain assumptions, have assessments conducted under the worst-case scenarios, and ensure that risk assessments are continuously updated depending on the amount of process knowledge received.
The Importance of Risk Assessment in Validation
Risk assessment makes it possible to understand where validation focus needs to be placed. Rather than turning all parameters equally important, it helps find those variables that impact the product quality, safety of the patient, and compliance with regulations the most.Detailed risk assessment can help to:
- Identify Critical Process Parameters (CPPs)
- Define Critical Quality Attributes (CQAs)
- Choose worst-case scenarios
- Specify sampling points
- Set acceptance criteria
- Prioritize validation tests
- Back scientifically valid reasons for your decisions
If there is no such basis, validation tests are likely to give illusory confidence.
The Case Study
A pharmaceutical company launched a tablet compression machine that helps to manufacture tablets with immediate release. The IQ and OQ stages have been passed successfully, and the process was ready to move on to the Performance Qualification (PQ) phase.Three validation batches were produced successfully, meeting specifications for yield, hardness, and the way the product looks. Thus, the process has been licensed for commercial scale of production.
In six months, several commercial batches failed dissolution tests. Even though yield and uniformity of the content were approved, dissolution tests showed serious deviations among tablets.
An investigation was launched to determine the cause.
Initial Investigation
The investigation team started looking into the obvious possibilities.They confirmed:
- Analytical method being validated.
- Calibrated dissolution apparatus was satisfactory.
- The raw materials met the specifications.
- The equipment was in the current state of calibration.
- The operators had followed the defined procedures.
- The environmental conditions had remained in acceptable limits.
Going beyond the Validation Report
The next step in the analysis was documenting the original validation strategy.During evaluation, the team analyzed such documents as:
- Validation protocol
- Risk assessment
- Process development data
- Equipment qualification papers
- Change management records
The Missing Risk Assessment
The risk assessment conducted prior mainly dealt with conventional process variables such as:- Homogeneity of mixture
- Compression pressure
- Tablet weight
- Turret speed
- Lubrication duration
Distribution of granule particle size after milling.
In the course of carrying out the development batches, particle size was virtually unchanged and the project team considered it to be a parameter with low risk.
As a consequence:
- No limits of acceptance were determined.
- No routine measurements were performed.
- No validation samples were gathered exclusively for the investigation of particle size variations.
What Actually Happened?
A new supplier of raw materials was accepted six months after commercial production started for one ingredient.Even though the material met all of the pharmacopoeial properties, it was slightly different in terms of physical characteristics.
This impacted:
- Granule flow property
- Efficiency of milling
- Distribution of the particle size
- Densification of powder during compression
Where the Risk Assessment Failed
The analysis pointed out multiple shortcomings.1. Failure to Identify Critical Material Attributes
The team concentrated mainly on machinery criteria at the expense of the material properties.Key material properties must have been assessed together with the process criteria.
2. Inadequate Worst-Case Analysis
The batches being validated have been produced with:- One API batch
- One excipient manufacturer
- Nominal working conditions
- Skilled workers
3. Limited Cross-Functional Participation
The original risk assessment included:- Verification
- Manufacturing
- Quality Control
If an interdisciplinary team had been utilized, it might have pointed out the possibility of particle size at a much earlier stage.
4. Overreliance on Historical Experience
Considering the previous success in the production of similar products, many unconfirmed hypotheses were accepted.Statements like "This has never been problematic before." were used instead of scientific evaluation.
Past achievements should never replace any formal risk analysis.
Root Cause Analysis
An analysis was conducted using FMEA which allowed to rank the six high risks:- Variability in particle size
- Differences in suppliers
- Efficiency of the milling process
- Flow of granules
- Uniformity in compression
Hence, the reassessment has shown the inadequacy of the validation plan in reflecting the interplay between raw materials and process performance.
Corrective Actions
The company put into action numerous corrective measures.1. Updated Risk Assessment
A new FMEA was conducted which included:- Production
- Quality Control
- Engineering
- Formulation Development
- Validation
- Quality Control
2. Revised Validation Protocol
The new guideline consisted of:- Particle Size Measurement
- The Usage of Varied Materials
- Different Operator Shifts
- Upper and Lower Limits of Operation Range
- Enhanced Sampling
3. Improved Supplier Qualification
Supplier verification processes were modified to take into account, along with chemical parameters, also the physical properties of the material.4. Continued Process Verification
The regular monitoring was expanded and included:- Particle Size Characteristics
- Compression Strength Measurement
- Dissolution Profiles
- Process Capability Stats
- Statistical Process Control Charts
Lessons Learned
There are a few key takeaways from this case study.1. One must acknowledge that validation is only as good as the risk evaluation behind it.
2. Obtaining positive results from a validation run does not guarantee the process viability in the long run.
3. One should treat Critical Material Attributes on the same level as the Critical Process Parameters.
4. The risk evaluation must continuously be updated and improved depending on new experience and information gained during production.
Validation Risk Assessment Mistakes
In internal reviews, a series of common issues has been noted which include:- Using previous projects' assessments as references
- Concentrating exclusively on data regarding equipment
- Failing to take into account variability in materials
- Omitting expert viewpoints
- Providing insufficient reasoning behind the assigned risk levels
- Not checking historic manufacturing records
- Not relaying any changes in previously completed risk assessments or calculations
- Interpreting FMEA scores as if they were not subject to any changes
It is often difficult to identify inadequate risk management when the validation is initiated, although its ramifications appear during the process of routine commercial manufacturing months later. The example given here illustrates how failure to recognize a critical material quality can lead to process variability and poor product quality, and the need for a costly investigation even after the validation is deemed successful. Hence, it becomes evident that risk assessment is to be conducted thoroughly and systematically to perform effective validations.
From my experience so far, I have found that great validation strategies can hardly be developed without multiple teams working together in order to raise questions regarding certain assumptions, have assessments conducted under the worst-case scenarios, and ensure that risk assessments are continuously updated depending on the amount of process knowledge received.
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