Best Practices for Reviewing Validation Documents

Validation documents go beyond regulatory documentation; they are written proof that the pharmaceutical premises, equipment, utilities, computerized systems, analytical methods, and manufacturing methods work properly on a permanent basis. Validation document quality establishes, among other things, the trust level of regulatory authorities in the company’s performance and products.

However, many companies spend weeks on preparing validation protocols and reports but only a couple of hours on their review. Therefore, even such mistakes as incorrect acceptance criteria, poor traceability of information, calculation mistakes, unsubstantiated conclusions, and inconsistent data are usually revealed during inspection rather than in-house review.

In my opinion, efficient validation document review should not be considered as proofreading; it should rather be viewed as scientific evaluation of the document performance in terms of accomplishing the validation goal. In this case, the reviewer should scrutinize the assumptions made in the document, verify its supporting proof, and check whether the conclusions presented in the document are backed by the documented data.

This paper will consider some useful methods that validation experts may apply to make the validation document review successful before approval.

Understand the Purpose Before Starting the Review

Before starting a protocol or report, make sure you understand what they intend to convey.
For instance:

• Installation Qualification (IQ) indicates that the equipment is installed per approved specifications.
• Operational Qualification (OQ) shows that the equipment works within the specified range.
• Performance Qualification (PQ) acts as a proof of being operational under normal conditions.
• Process Validation shows that the process continuously produces products meeting the determinant quality characteristics.
• Cleaning Validation is a proof of the efficiency of cleaning processes in removing the residues of the product and cleaning agents.

Someone with a clear understanding of the goals of validation is likely to detect flaws better than someone looking at the relevant formatting criteria alone.

Verify Compliance with the Validation Master Plan

All validation activities must be consistent with the validation master plan of the company. Make sure that this file follows:

• Validation strategy approved
• Equipment classification
• Results of the risk assessment
• Requirements of the validation lifecycle
• Appropriate company practices

If the document contradicts the validation plan, the documentation and approval should be featured.

Review Document Completeness First

Prior to analyzing the technical part, make sure the document is complete. Make sure it includes:

• Document number
• Revision number
• Title
• Scope
• Objective
• Roles
• References
• Approval signatures
• History of revisions
• Appendices

Incomplete documents often lead to unnecessary rounds of reviews.

Check Technical Accuracy

Technical aspects need maximum focus. For example, the questions might be:

1. Is the goal of validation clear?
2. Is the basis of acceptance criteria scientifically sound?
3. Are the testing methods fit for the purpose?
4. Are the sampling procedures appropriate?
5. Are the calculations right?
6. Is there evidence to support the conclusions reached?

Do not take it for granted that the calculations or the technical statements in the previous documents are correct.

Evaluate the Acceptance Criteria

Acceptance criteria must, at all times, be:

• Quantifiable
• Scientifically based
• Regulatory compliant
• Product-specific if necessary
• Signed off prior to execution

Avoid using expressions like:
"Results should be satisfactory."
Instead, try to write acceptance criteria in a measurable form. For instance:

• Temperature: 121 ± 2 degrees
• Relative humidity: 45-55%
• Differential pressure: 15 Pa or more
• Recovery: 70% at least

Well-defined acceptance criteria eliminate subjective interpretation.

Ensure Traceability Throughout the Document

One of the important characteristics of a good validation document is full traceability.
The auditor should be able to trace:

User Requirement Specification (URS)
                 ↓
Design Qualification (DQ)
                 ↓
Installation Qualification (IQ)
                 ↓
Operation Qualification (OQ)
                 ↓
Performance Qualification (PQ)
                 ↓
        Running test

Similarly, each requirement should be linked to corresponding tests. Broken traceability often turns into a serious issue during inspection observations.

Verify Supporting Data

Reviewers are supposed to check reported results against original records whenever it is possible.
Some of the sources are:

• Calibration report
• Raw analytical data
• Instrumentation printout
• Environmental monitoring report
• Equipment log book
• Electronic audit trail
• Batch manufacturing records

Reports should not rely on listed information only. Source information gives assurance that results really reflect observations made.

Confirm Data Integrity

The validation documentation must indicate adherence to ALCOA principles. Accert the following data is:
1. Attributable
2. Legible
3. Contemporaneous
4. Original
5. Accurate
6. Complete
7. Consistent
8. Enduring
9. Available

Special attention must be paid to
1. Calculations
2. Electronic data
3. Audit trail
4. Consistency of time and dates
5. Versioning of documents
Weaknesses in data integrity can result in failure of validation studies.

Review Deviations Carefully

Few validation studies do not have deviations. It is necessary that the reviewer finds out:

• Has the deviation been documented?
• Was the investigation of the reasons for the deviation conducted?
• What corrective actions were taken?
• Did the deviation influence the results of the validation?

The statement "No impact on validation." must be proven with technical evidences.

Assess Statistical Evaluation

Statistical evaluation forms an essential part of some validation reports. Consider the following:

• Sample size
• Average value
• Standard deviation
• Capacity of a process
• Trend evaluation
• Confidence range
• Control charts

Make sure statistics are relevant and used correctly.

Evaluate Conclusions Critically

One of the most common problems with many validation reports is their conclusions. Try to avoid conclusions that only restate the results of the testing. Make sure, instead, that your conclusions help answer the initial question of the validation. For instance, avoid:
"All tests were successful."
But write the claim:

• Whether acceptance criteria were satisfied
• Whether the system is adequate for the purpose of its usage
• Any limitations
• Recommendations on monitoring processes
• Whether qualification of the system is needed.

Conclusions should reflect a scientific judgement instead of simply summarizing the data.

Review Language and Consistency

While grammatical correctness holds less weight than technical accuracy, proper communication makes any document better. Be sure to check for consistency in:

• Identifiers
• Brands
• Numbers of batches
• Measurements
• Terms used
• Abbreviations used

For instance, it is best not to mix:
- Purified Water
- PW
- P/W
- Water System
Pick one of the terms and stick to it.

Use a Structured Review Checklist

The structured review checklist guarantees that reviewers agree on critical points. Sample review items include:

Review Area	Questions
Scope	Is the objective clearly defined?
Protocol Compliance	Was every approved test executed?
Acceptance Criteria	Are limits scientifically justified?
Raw Data	Does source data support reported results?
Calculations	Have formulas been verified?
Deviations	Were all deviations assessed appropriately?
Conclusions	Are they supported by evidence?
Approvals	Are all required signatures present?

A standardized checklist is also great for ensuring that vital details are not missed.

Common Review Deficiencies

Listed below are common errors that are found during inspection by various regulatory agencies:

• Referring to protocols that have been copied without being checked.
• Using erroneous equipment identifiers.
• Not providing a sufficient amount of raw data.
• Presenting conclusions that have not been supported.
• Not having acceptance criteria in place.
• Not properly assessing deviations.
• Not being able to prove the results being tested.
• Not implementing proper revision control.
• All required approval signatures obtained before completion of the required review process.

Most of these errors are avoidable once proper review of the documents is done.

Strengthen the Review Process

To improve the quality of validation documents, organizations can do the following things:

• Assigning technically competent reviewers.
• Making sure that technical review is kept apart from format review.
• Utilizing independent reviewers when available.
• Conducting peer reviews prior to the QA.
• Looking at past validation results.
• Training reviewers about risk-based approach.
• Keeping the validation templates uniform.
• Conducting audits of validation documents from time to time.

An effective review process ensures that document quality improves continuously in future validation projects.

The act of reviewing validation papers is an integral part of pharmaceutical quality systems. The review can ascertain not just that the tests have been carried out but that the validation also has a scientific basis for the conclusion reached.

I have come to understand that the validation processes based on thorough document reviews result in a stronger system than the one based on repetitive validation studies. The improvement in the quality of validation documents can be attained only when reviewers evaluate not only acceptance criteria, raw data, and final conclusions but also whether the assumptions are correct, backed by evidence and the application of science in similar cases.

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