Published on 07/12/2025
What FDA and EMA Expect from Pharma on Change Control and Revalidation Activities
In the pharmaceutical industry, compliance doesn’t end after initial validation. The FDA and EMA both emphasize the importance of ongoing control throughout the product lifecycle, especially when changes are made to validated systems, processes, or equipment. At the heart of this continuous oversight lie two interlinked pillars of pharmaceutical quality systems: Change Control and Revalidation.
This article presents a detailed overview of how global regulators expect pharmaceutical companies to manage change and revalidation activities in alignment with Good Manufacturing Practice (GMP), risk management principles, and the validation lifecycle model.
1. The Regulatory Foundation
The fundamental expectation is that manufacturers maintain a validated state. Any changes — planned or unplanned — must be systematically evaluated for their potential impact on product quality, and revalidation must be performed where necessary.
Key regulations include:
- FDA Guidance: Process Validation – General Principles and Practices
- EU GMP Guidelines Annex 15: Qualification and Validation
- ICH Q8 (R2), Q9, and Q10
- EU GMP Chapter 1: Pharmaceutical Quality System
All these documents stress that changes should be scientifically evaluated, risk assessed, and, where applicable, subjected to revalidation to
2. Change Control Expectations: What Regulators Look For
Change control is not merely a documentation step. Regulatory bodies expect it to be a proactive quality assurance mechanism embedded in the pharmaceutical quality system (PQS). During inspections, they look for:
- Clearly defined change control SOPs with escalation pathways
- Evidence of cross-functional assessment (QA, validation, production, engineering)
- Formal impact assessment on validated systems, processes, CQAs, and CPPs
- Justification for changes not requiring revalidation
- Documented linkage to deviation, CAPA, and risk management systems
- Final QA approval and closure with effectiveness checks
Common Change Types Requiring Assessment
- Process parameter modification (e.g., granulation time, temperature)
- Introduction of new equipment or utilities (e.g., HVAC upgrade)
- Raw material supplier changes
- Software upgrades in computerized systems
- Facility modifications or layout changes
3. Revalidation: When and Why It Must Be Triggered
According to both FDA and EMA, revalidation is required when a change could affect the quality, safety, or efficacy of the product. This includes any change that may impact:
- Process reproducibility
- Equipment performance
- Cleaning effectiveness
- Control strategy or monitoring points
EMA Annex 15 explicitly mentions that revalidation is necessary when “a change control system identifies a change which requires revalidation.” Similarly, FDA’s guidance requires manufacturers to “evaluate data and trends from monitoring and control systems” to determine when revalidation is needed.
4. Lifecycle Integration: Validation Stage and Change Control
Regulators expect validation to follow the lifecycle model:
- Stage 1: Process Design
- Stage 2: Process Qualification
- Stage 3: Continued Process Verification (CPV)
Changes must be evaluated in light of this model. For example:
- Changes in Stage 1 may require complete revalidation
- Changes in Stage 2 may require partial requalification or bracketing studies
- Changes identified in Stage 3 (via CPV) may trigger retrospective revalidation
5. Quality Risk Management (QRM) in Revalidation Decisions
Per ICH Q9, risk management tools such as FMEA, HACCP, and Risk Ranking must be employed to assess whether a change warrants full or partial revalidation. This ensures scientific decision-making and avoids over- or under-validation.
Sample Revalidation Decision Matrix
| Change Type | Risk Level | Revalidation Action | Documentation Required |
|---|---|---|---|
| Change in excipient supplier | High | Full process revalidation | Protocol, report, raw data, risk assessment |
| Equipment software update | Medium | Partial PQ requalification | Impact assessment, protocol, addendum |
| Routine facility maintenance | Low | No revalidation | QA note to file with rationale |
6. Documentation Expectations
FDA and EMA expect traceability from change initiation through revalidation completion. Key documents include:
- Change Request Form with cross-functional review
- Impact assessment signed by QA and validation
- Risk assessment record (FMEA, decision tree, etc.)
- Validation protocol (if applicable)
- Execution data and final validation report
- QA approval and closure summary
All documentation should be archived according to data integrity principles such as ALCOA+ and must be accessible for audits and inspections.
7. Common Inspection Findings
- No impact assessment performed for changes to critical equipment
- Failure to revalidate after major process parameter change
- Change control open beyond defined closure timelines
- Justification for not revalidating is not data-driven
- Lack of traceability between change control and VMP
These findings can lead to 483 observations or Warning Letters from FDA, or Non-Compliance Reports (NCRs) from EMA.
8. How to Ensure Compliance
To meet regulatory expectations, companies should implement the following best practices:
- Embed risk-based evaluation in your change control SOP
- Link VMP, change control, and CPV data streams
- Train cross-functional teams on revalidation criteria
- Use standardized templates and traceability matrices
- Review closure effectiveness and audit trail completeness
Resources like PharmaSOP.in and pharmaregulatory.in offer templates and SOP examples to align documentation with regulatory expectations.
Conclusion
Change control and revalidation are not optional — they are cornerstones of a compliant pharmaceutical quality system. The FDA and EMA expect manufacturers to proactively assess, document, and control changes throughout the lifecycle using QRM and data-driven justifications. By following the guidance in this article, companies can avoid regulatory pitfalls and ensure a validated state is consistently maintained across systems and processes.
For more templates and compliance tools, visit PharmaValidation.in.