Batch Release: A Practical Step-by-Step Guide (Annex 16)

Introduction: Beyond the Signature, the Process

Batch release certification by a Qualified Person (QP) is the final step that transforms a pharmaceutical product from "quarantined material" to "patient-ready medicine." This process isn't just a stamp; it's a systematic and documented investigation.

The operational "bible" that guides the QP in this activity is Annex 16 of the EU GMP: "Certification by a Qualified Person and Batch Release." This document translates the legal obligations of Directive 2001/83/EC into an operational roadmap. Failure to adhere to Annex 16 is one of the most critical non-conformities an inspector can detect.

This practical guide illustrates the operational steps that every QP must follow for an audit-proof batch release.

Phase 1: Assemble and Verify the Batch Dossier

The QP cannot release "on trust." They must base their decision on complete documentary evidence. The first step is to ensure that the release package (often prepared by the QA) is complete.

Mandatory documentation includes:

1. Batch Manufacturing Record (BMR) and Batch Packaging Record (BPR): The batch logbooks. The QP verifies that:
• They should be complete, without blank spaces.
• All critical steps are signed (operator and supervisor - double check ).
• Process parameters (e.g. temperatures, times) are within the validated ranges.
• Yields are within expected limits.
• Corrections are handled according to SOP (single line, signature, date, reason).
2. Test Report and Certificate of Analysis (CoA): The QC results. The QP verifies that:
• All tests required by the AIC have been performed and comply with the specifications.
• The analytical methods used are those approved.
• The CoAs of critical raw materials (especially the API) are available and approved.
3. Logbook and Cleaning Records: Evidence that systems were qualified, calibrated and cleaned (line clearance) before use.

Phase 2: Handle Exceptions (Deviations and OOS)

It's rare for a batch to be perfect. The true expertise of QP lies in evaluating the "exceptions."

Scenario 1: There is a Process Deviation

• What to Do: The QP must review the deviation report.
• QP Mental Checklist:
• Was the investigation (Root Cause Analysis) thorough?
• Has the impact on batch quality been correctly assessed?
• Was the diversion closed before release?
• Have CAPAs (Corrective Actions) been defined?
• Decision: If the deviation is minor and the QRM (Quality Risk Management, ICH Q9) demonstrates no impact on the patient, the QP may release the product, documenting their assessment (as required by Annex 16, Section 3). If the impact is uncertain or critical, the batch should be held or rejected.

Scenario 2: There is an Out-of-Spec (OOS) Result

• What to Do: The QP should review the entire OOS investigation (often the root cause of critical inspection findings ).
• QP Mental Checklist:
• Was the laboratory investigation (Phase 1) scientifically valid?
• Is the invalidation of the OOS (if it occurred) justified by a certain root cause (e.g. demonstrated analytical error)?
• If OOS is confirmed, the batch must be rejected.
• Common Mistake (to avoid): Accepting a release based on "testing into compliance" (i.e., retesting until a compliant result is obtained, ignoring the OOS). This is an act of falsification and is the quickest route to a Warning Letter.

Phase 3: The Final Decision and Certification

After reviewing all documentation and handling exceptions, the QP makes the formal decision.

Step 1: The Pre-Release Checklist Many QPs use an operational checklist (such as the one provided in the GuideGxP Guide) to ensure they haven't missed anything:

• [ ] Complete and signed BMR/BPR?
• [ ] CoA compliant with AIC specifications?
• [ ] All deviations/OOS closed and evaluated?
• [ ] Compliant materials (APIs, excipients, packaging)?
• [ ] In-process controls (IPC) compliant?
• [ ] Stability data to support this?
• [ ] Labelling (RCP/FI) correct for the target market?

Step 2: Certification (Signature) The QP signs the release register or batch certificate. This signature, placed on a legal document (paper or electronic with digital signature), certifies that the QP assumes personal responsibility for that batch. This register must be kept for at least 5 years.

Step 3: Operational Release The QP (or QA at their disposal) formally notifies the warehouse (Logistics) that the batch can be moved from "Quarantine" to "Released" status. In modern ERP systems, this is often an electronic status change that unlocks the batch for shipping.

Special Situations: Conditional Release

Not all releases are standard.

• ATMP (Advanced Therapeutics): For products with a very short shelf life (e.g., CAR-T), the QP may be forced to release the batch before all testing (e.g., sterility) is complete. This is a high-risk conditional release, agreed upon with the authorities, which requires rigorous follow-up .
• Deviations (Annex 16, Section 3): As seen, the QP can release a batch with a minor deviation if the risk has been assessed as negligible. The "condition" is the documentation of this QRM.

Conclusion: Release as an Act of Discipline

The batch release process is a GMP ritual that requires discipline, rigor, and technical expertise. Annex 16 provides the framework, but it's the QP's experience in "reading" the data and identifying risks that makes the difference between a simple signature and true quality assurance.

To master every single item on the release checklist, manage the most complex deviation scenarios, and correctly interpret Annex 16, the " Complete Guide to the Qualified Person (QP) " from GuideGxP.com is the indispensable operating manual.