Common FDA 483 Observations Related to Process Validation

The validation of processes is one of the major cornerstones of manufacturing in the pharmaceutical industry. The process of Validation provides a documented record that demonstrates a manufacturing process is capable of producing products that consistently meet predetermined quality attributes as well as regulatory criteria. Since valid processes can impact product quality, as well as patient's safety, the FDA routinely evaluates the process validation programs during inspections.

In my experience, the basis for most of the process validation findings is not from a failure of an individual validation study, but more from issues related to broader problems in the quality systems, scientific decision making, documentation practices and lifecycle process management. A number of companies have been successfully completing validation protocols, however, these companies have not been able to maintain their validated state during commercial manufacturing.

FDA investigators evaluate validation for both if validation was performed as well as if validation was designed and executed scientifically and documented correctly and continuously.

By understanding what are the most generally seen FDA 483 observations associated with process validation, pharmaceutical companies will be able to take an active approach to improving their compliance programs prior to regulatory inspections.

FDA Expectations for Process Validation

The FDA has established general principles and practices for establishing process validation through the Lifecycle Approach of Process Validation. There are three stages involved in the lifecycle of process validation, these are:

• Process Design
• Process Qualification
• Continued Process Verification (CPV)

Inspectors are looking for manufacturers to demonstrate that they have control over each of these three stages and to verify that validation is not a one-time activity. The validated process should be monitored continuously across the entire product lifecycle.

Observation 1: Inadequate Process Validation Protocols

Most of the time, the most common FDA observation is that the validation protocol is poorly designed. There are a lot of common deficiencies found during evaluations of the validation protocols as they relate to:

• Acceptance criteria are not defined
• Sampling plans have been omitted
• Statistically inadequate
• Responsibilities are unclear
• Testing requirements have not been completed

In my experience many times have I found that protocols have been copied from previous products without regard for process-specific risks resulting in an inspection finding. A validation protocol must clearly define what will be evaluated and also state the purpose for each evaluation activity.

Observation 2: Lack of Supporting Scientific Evidence

FDA investigators will frequently question validation decisions made without a scientific basis. Examples of lack of scientific basis for validation decisions:

• Arbitrarily set acceptance limits
• Sample sizes that are not scientifically based
• Hold times that have not been scientifically justified
• Worst-case selection that is not scientifically based
• Operating ranges that have not been scientifically justified

A scientific justification should be based on these elements:

• Development studies (as described in the previous paragraph)
• Historical process data (as described in the preceding paragraph)
• Risk assessments
• Statistical analysis
• Technical expertise

Each validation decision must have supporting evidence.

Observation 3: Not Identifying Critical Process Parameters

Critical Process Parameters (CPPs) have an immediate impact on Critical Quality Attributes (CQAs). FDA observations have repeatedly stated that manufacturers have not been able to:

• Properly identify CPPs
• Justify the ranges of their parameters
• Monitor their critical parameters
• Evaluate the capability of their processes

Without having identified their CPPs it is difficult for organizations to demonstrate that they are controlling their processes. An organization should establish scientific linkages between CPPs and their product quality.

Observation 4: Incomplete Process Qualification

The purpose of PQ is to confirm that equipment, utilities, people and manufacturing processes produce consistent output of product under routine operating conditions. FDA observations reveal the following common deficiencies:

• Insufficient number of qualification batches
• No challenge studies conducted
• Sample locations not adequately distributed
• Production conditions not representative of actual manufacturing process

Validation batches must provide a true representation of typical commercial manufacturing rather than an optimum situation as achieved in the laboratory.

Observation 5: Weak Continued Process Verification (CPV)

The emphasis on continued process verification (CPV) is one of the major changes in the FDA's expectations. There are numerous 483s issued by the FDA to companies that performed an initial validation (for example, the successful manufacture of three consecutive batches) but did not continue to monitor the ongoing performance of the process. Deficiencies found in CPV include:

• No statistical process control
• Limited process monitoring
• Failure to review quality metrics
• No annual product reviews
• Delayed responses to process changes

Validation does not stop after three successful batches. The continued evaluation of manufacturing process performance must continue throughout commercial production.

Observation 6: Poor Sampling Plans

A good sampling strategy is very important to validation. FDA inspectors frequently find the following when reviewing validation:

• Insufficient number of samples
• Poor location of samples
• Unrepresentative samples
• No worst case samples

For example, blend uniformity studies should contain scientifically justified locations to represent expected variability and not just convenient locations. Sampling plans should be based upon existing process knowledge and risk assessment.

Observation 7: Inadequate Statistical Analysis

Descriptive summary data is included in most validation reports, but meaningful statistical analysis is not always provided. Typical FDA issues noted with validation statistical analysis include:

• No Capability Analysis
• No Variability Analysis
• Inadequate Trend Analysis
• Unsubstantiated Conclusions

Today many validation programs depend heavily upon the use of statistical analysis to prove process consistency. Examples of statistical analysis tools are:

• Process Capability Indices
• Control Charts
• Trend Analysis
• Confidence Intervals

Statistical Analysis provides evidence that is more robust than visual analysis alone.

Observation 8: Failure to Investigate Validation Deviations

There needs to be a thorough investigation for all unexpected validation results Companies have been issued 483 for:

• Closing deviation investigations without identifying root cause
• Re-testing one or more sample without justification
• Ignoring outlier values
• Poor CAPA execution

In my experience as an investigator, I have found that most of the time the investigators highlight the focus of their investigation on how they conducted the investigation and not the deviation itself.

An unexpected result should require the following:

• Conduct a risk assessment
• Conduct a root cause analysis
• Evaluate product impact
• Execute a CAPA

Observation 9: Inadequate Change Control Following Validation

It is inevitable that validated processes will undergo numerous changes during the course of commercial manufacturing. Some of the changes are as follows:

• Equipment
• Raw materials
• Utilities
• Computer software
• Manufacturing facilities

The FDA inspector frequently identifies:

• Changes to equipment without a risk assessment
• No evaluation of the effect to the validation from the change
• No revalidation performed
• Inadequate documentation of the change process

All changes that have a major impact to the validated process should have a formal change process with an evaluation of the effect of the change on the validity of the validation study should be documented.

Observation 10: Poor Validation Documentation

One of the most frequently cited deficiencies found by the FDA during an inspection is that of documentation. Some examples of inadequate or missing documentation include:

• Raw data missing
• Reports incomplete
• Records not signed
• Calculations inconsistent
• Approvals missing

Documentation that supports the validation process must clearly establish the following:

• Protocols have been executed
• Results achieved
• Deviation encountered
• Evaluation statistically
• Conclusions reached

As I often state to validation teams, if validations are poorly documented but well-executed, it appears as though they never occurred.

Observation 11: Lack of Proper Qualification for Equipment

The process of validating equipment relies heavily upon properly qualifying the equipment. Inspectors at the FDA have frequently noted:

• lack of installation qualification
• weakness with operational qualification
• lack of full performance qualification
• lack of qualification of instruments

Each piece of equipment must be qualified prior to conducting validation on any processes.

Observation 12: The Failure to Keep Validated State

Once a validation is completed, it is an ongoing process and not a finite period. Many of the observations made by FDA are caused by failures by companies to maintain a validated process following completion of approval. A few examples of maintaining the state that is validated include:

• Drift in process parameter
• Increase in trend/deviation
• Deterioration of equipment
• Utility performance changed

Maintaining the validation state requires continuous monitoring, preventive maintenance, calibration and periodic assessment.

Common Root Causes Behind Validation Observations

Validation Observations are common, and many of the reasons for them stem from the same basic issues. The most common root causes of validation observations include:

• Weak oversight of quality
• Processes not being fully understood or not documented properly
• Poor management of risks associated with the validation process
• Inadequate training of personnel performing processes subject to validation
• Incomplete validation lifecycle of product being validated
• Lack of resources to support the validation process
• Lack of effective management oversight during validation

Correcting these systemic causes will have an impact on preventing many future observations.

Prevention of Process Validation Observations

A proactive, rather than reactive, approach to the validation process is necessary for organizations.

Best Practice Recommendations

1. Develop validation protocols that are designed with scientific justification.
2. Conduct comprehensive risk assessments prior to executing the validation protocol.
3. Identify and track Critical Process Parameters (CPPs) and Critical Quality Attributes (CQAs) throughout the validation process.
4. Utilize statistically established sampling plans to determine the number of samples to be analyzed.
5. Execute Continued Process Verification (CPV) robustly.
6. Investigate all validation deviations thoroughly.
7. Strengthen change control processes.
8. Review validation trends regularly.
9. Maintain appropriate documentation of the validation process.
10. Train all personnel involved in the validation process on current regulatory requirements regularly.

Adopting these best practices will greatly improve both compliance and operational reliability.

Preparing for FDA Inspections

Facilities need to consistently assess their validation systems in anticipation of an FDA inspection. The internal audit must include:

• Validation Master Plan
• Protocol Quality
• Process Monitoring Data
• Statistical Analysis
• CPV Reports
• Change Control Record
• Revalidation Activity

Frequent mock inspections can reveal areas of weakness before an FDA inspection.

The area of process validation is, without a doubt, the most scrutinized entity during FDA inspections because it directly relates to how well the product has been produced, how consistently the product has been produced, and how safe the product is for patients. The majority of FDA Form 483 observations are not due to isolated technical failures; instead, they represent a failure to accurately understand processes, validate processes throughout their lifecycle, maintain appropriate documentation, have in place proper change controls, and ensure ongoing verified processes.

My experience has shown that organizations whose validation programs include a scientific risk management component, prompt documentation, an effective change control system, and ongoing monitoring of their processes will consistently have better inspection results. Understanding and recognizing the common observations that FDA investigators are issuing will help pharmaceutical companies develop better quality systems, maintain validated product state, and create greater confidence in their manufacturing process.

Regulatory References

1. FDA Process Validation: General Principles and Practices

https://www.fda.gov/media/71021/download
2. ICH Q10 Pharmaceutical Quality System

https://database.ich.org/sites/default/files/Q10_Guideline.pdf
3. EU GMP Guidelines Volume 4, Annex 15: Qualification and Validation

https://health.ec.europa.eu/medicinal-products/eudralex/eudralex-volume-4_en

Get ready to use editable Validation Protocols in MS-Word FormatView List

Share

Tweet

Share

Pin it

Share