Analysis and testing Flashcards
What is analytical method transfer? How do you transfer assay of a tablet?
- Change Control:
Initiate a change control process to evaluate and document the need for the transfer, assessing regulatory and quality impacts.- Gap Analysis & Impact Assessment:
Compare key aspects between the transferring and receiving laboratories, including equipment (e.g., HPLC models), columns, environment, and analyst competence. Any identified gaps are addressed before transfer. - Transfer Protocol Development:
A detailed method transfer protocol is drafted, including:
• Scope and responsibilities of both labs.
• Acceptance criteria, typically covering parameters such as accuracy, precision, linearity, and specificity, aligned with ICH Q2.
• Sample transport conditions to maintain integrity (e.g., temperature, humidity).
• Training requirements for analysts at the receiving lab. - Method Transfer Execution (Assay Example):
For an HPLC assay of a tablet:
• Samples (e.g., reference standards and tablet batches) are analyzed at the receiving lab.
• Method performance is assessed against ICH Q2 parameters, including:
• Accuracy: Using spiked placebo samples at 80%, 100%, and 120% of the label claim with 3 replicates per level. Evaluate % recovery, aiming for 98-102%, with %RSD ≤ 2%.
• Precision:
• Repeatability: Same analyst, same day, %RSD ≤ 2%.
• Intermediate precision: Different analysts and days within the same lab, %RSD ≤ 3%.
• Linearity: At least 5 concentration levels across the working range, calculate coefficient of determination (r² ≥ 0.99).
• Specificity: Confirm separation of the analyte from excipients, impurities, or degradation products, with resolution > 1.5 between peaks. - Data Analysis and Comparison:
• Use statistical tools, such as t-tests or ANOVA, to compare results between the transferring and receiving labs, ensuring no significant difference.
• All data are reviewed against the predefined acceptance criteria in the protocol. - Deviation and CAPA Management:
Any deviations during the method transfer (e.g., out-of-specification results or method performance failures) are investigated, root causes identified, and CAPAs implemented. Depending on the findings, the method transfer may be repeated.
- Gap Analysis & Impact Assessment:
Analytical method transfer to India
- Change Control:
Initiate a formal change control to document and manage the method transfer, evaluating the impact on regulatory licenses, GMP certificates, and product quality.- Gap Analysis:
A senior analyst from the transferring laboratory conducts a gap analysis, comparing critical factors such as equipment, facilities, analytical techniques, and staff competence between the two laboratories. - Impact Assessment:
Assess the potential impact of the transfer on:
* Marketing Authorizations (MA) if applicable,
* GMP compliance and certification,
* GCP requirements (for clinical products),
* Finished product quality. - Transfer Protocol Development:
Develop a detailed protocol covering:
* The method to be transferred,
* Acceptance criteria,
* Staff training at the receiving lab,
* Sample transportation conditions,
* Handling of deviations and CAPA during the transfer process. - Validation Activities:
Validation of the method at the receiving lab should cover key ICH Q2 elements, including:
* Accuracy:
* Assess recovery at 3 concentrations (e.g., 80%, 100%, 120%) with 3 replicates each.
* Acceptance: Mean recovery within predefined limits (e.g., 98–102%) and %RSD ≤ 2%.
* Linearity:
* Demonstrate a linear relationship between concentration and response across 5 levels.
* Acceptance: Coefficient of determination (r²) ≥ 0.99.
* Precision:
* Repeatability: Same analyst, same day, multiple replicates;
* Intermediate Precision: Different analysts and/or days;
* Reproducibility: If applicable, comparison across different laboratories.
* Acceptance: %RSD typically ≤ 2–3%.
* Specificity:
* Confirm the method can separate the analyte from excipients, impurities, or degradation products.
* Acceptance: Resolution between critical peaks ≥ 1.5.
* LOD and LOQ:
* Determine based on signal-to-noise ratio:
* LOD ~3:1,
* LOQ ~10:1.
* Robustness:
* Evaluate the method’s reliability under small deliberate variations (e.g., minor flow rate, temperature changes). - Sample Transport:
Define transport and storage conditions for sample transfer from the manufacturing site to both transferring and receiving labs, ensuring sample integrity. - Comparative Study:
Analyze the same batch samples at both labs and perform a paired t-test to statistically confirm there are no significant differences between results. - Prospective (Traditional) Validation:
Conduct a prospective validation at the receiving laboratory using at least 3 production batches, to demonstrate consistent method performance. - Deviation Handling:
Any deviations during the transfer must be investigated promptly, root causes identified, CAPAs implemented, and documented in the final transfer report.
- Gap Analysis:
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Summary:
Although regulatory guidance (e.g., MHRA blog, Orange Guide) mainly emphasizes transfer process controls, it is considered best practice to include relevant ICH Q2 validation parameters such as accuracy, precision, linearity, specificity, LOD/LOQ, and robustness. This ensures that the method is scientifically sound, fit for purpose, and compliant at the receiving laboratory.
Where would you find guidance on how to validate chromatographic testing methods (HPLC)
To validate chromatographic testing methods (such as HPLC), the key references include:
* ICH Q2(R2) – “Validation of Analytical Procedures” (updated version, 2023),
* ICH Q14 – “Analytical Procedure Development” (for novel substances or new products),
* EU GMP Chapter 6 – “Quality Control,”
* EU GMP Annex 15 – “Qualification and Validation.”
These documents provide the regulatory expectations and technical requirements for method validation.
Of course! You’ve covered the key ideas really well — you just need a more polished and professional structure, correct technical English, and slightly more clarity (especially for viva or audit situations).
Here’s your revised, clean model answer:
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Model Answer:
Q: Where would you find guidance on how to validate chromatographic methods such as HPLC?
To validate chromatographic testing methods (such as HPLC), the key references include:
* ICH Q2(R2) – “Validation of Analytical Procedures” (updated version, 2023),
* ICH Q14 – “Analytical Procedure Development” (for novel substances or new products),
* EU GMP Chapter 6 – “Quality Control,”
* EU GMP Annex 15 – “Qualification and Validation.”
These documents provide the regulatory expectations and technical requirements for method validation.
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Key Requirements for HPLC Method Validation:
You must develop a validation protocol that includes:
* Clear definition of the analytical method,
* Predefined acceptance criteria for each parameter,
* Staff training requirements,
* Deviation handling, investigation, and CAPA in case of failures during validation.
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During HPLC Method Validation, confirm the following elements (ICH Q2 parameters):
1. Accuracy:
* Measures how close the test results are to the true value.
* Perform at 3 different concentrations (e.g., 80%, 100%, 120% of target concentration) with 3 replicates each.
* Calculate the mean % recovery for each level.
* Acceptance: Mean % recovery between 98% and 102%.
2. Linearity:
* Demonstrates a linear relationship between analyte concentration and response (e.g., peak area).
* Prepare at least 5 concentration levels.
* Calculate the coefficient of determination (r²).
* Acceptance: r² ≥ 0.99.
3. Precision:
* Measures how close individual results are to each other.
* Repeatability: Same analyst, same equipment, same day.
* Intermediate Precision: Different analysts, different days, possibly different equipment.
* Reproducibility: (only if across different laboratories; less common for single-site validation).
* Acceptance: %RSD ≤ 2% (may allow ≤3% for more complex methods).
4. Specificity:
* Ability to clearly identify and quantify the analyte without interference from impurities, degradants, or excipients.
* Acceptance: Resolution between critical peaks ≥ 1.5.
5. Limit of Detection (LOD) and Limit of Quantitation (LOQ):
* Determined based on signal-to-noise ratio:
* LOD: S/N ≈ 3:1,
* LOQ: S/N ≈ 10:1.
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Summary Viva-Style Sentence:
“I would refer to ICH Q2(R2), ICH Q14, EU GMP Chapter 6, and Annex 15.
For HPLC validation, I would develop a protocol covering method definition, acceptance criteria, staff training, deviation handling, and CAPA.
The key validation elements I would confirm are accuracy, precision, linearity, specificity, LOD, and LOQ, following ICH Q2 principles.”
Can you describe the parameters that would be validated for an HPLC method? and what stats tool you’d use?
According to ICH Q2(R2), the key validation parameters for an HPLC method are:
1. Accuracy:
* Measures how close the test results are to the true value.
* Acceptance criteria: Mean % recovery between 98–102%.
* Statistical tool: Calculate mean % recovery across replicates.
2. Linearity:
* Demonstrates that the method response is directly proportional to analyte concentration across a defined range.
* Acceptance criteria: Coefficient of determination (r²) > 0.99.
* Statistical tool: Perform linear regression analysis and calculate r².
3. Precision:
* Measures the closeness of individual results under the same conditions.
* Includes:
* Repeatability (same analyst, same equipment, short time),
* Intermediate precision (different analysts, different days).
* Acceptance criteria: %RSD ≤ 2% for repeatability; may allow slightly higher (≤3%) for intermediate precision.
* Statistical tool: Calculate %RSD (Relative Standard Deviation).
4. Specificity:
* Confirms that the method can distinguish the analyte from impurities, degradation products, or matrix components.
* Acceptance criteria: Resolution between critical peaks ≥ 1.5.
* Statistical tool: Use system suitability parameters (e.g., USP resolution formula).
5. Limit of Detection (LOD):
* The lowest amount of analyte detectable, not necessarily quantifiable.
* Acceptance criteria: Signal-to-noise (S/N) ratio approximately 3:1.
* Statistical tool: Measure S/N ratio.
6. Limit of Quantitation (LOQ):
* The lowest amount of analyte that can be quantitatively determined with acceptable precision and accuracy.
* Acceptance criteria: Signal-to-noise (S/N) ratio approximately 10:1.
* Statistical tool: Measure S/N ratio.
7. Robustness:
* Assesses the reliability of the method when small deliberate variations are introduced (e.g., slight changes in flow rate, column temperature, mobile phase composition).
* Often evaluated by checking if %RSD remains within acceptable limits (typically ≤2%) when conditions vary.
* Statistical tool: Calculate %RSD and/or compare means across small method variations.
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Short viva-style Summary Sentence:
“For HPLC method validation under ICH Q2, I would confirm accuracy, linearity, precision, specificity, LOD, LOQ, and robustness.
I would use statistical tools such as mean % recovery, coefficient of determination (r²), %RSD, signal-to-noise ratio, and resolution calculations to assess method performance.”
You are working as a QP at a site and have been asked to support your QC team in carrying out method transfer of a HPLC method. How would you go about this?
To support the method transfer of an HPLC method, I would follow a structured, compliant, and risk-based approach, guided by:
* ICH Q2(R2) – Validation of Analytical Procedures
* ICH Q14 – Analytical Procedure Development (if applicable)
* EU GMP Annex 15 – Qualification and Validation
* EU GMP Chapter 6 – Quality Control
* MHRA Orange Guide (2022) and MHRA Inspectorate blog
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Step-by-step approach:
1. Initiate Change Control:
Formally raise change control to manage and document the method transfer, including impact and risk assessment.
2. Conduct Gap Analysis:
Performed by a senior analyst from the transferring lab, assessing:
* Equipment comparability (e.g. HPLC model, detector),
* Analytical methods and materials,
* SOPs, staff competence, and lab environment.
3. Impact Assessment:
* Assess whether the receiving lab is named in the Marketing Authorisation (MA); if not, a variation may be required.
* Evaluate GMP/GCP compliance, transport and handling of samples, and any potential impact on the finished product.
4. Develop Transfer Protocol:
The protocol must define:
* The method and scope of the transfer,
* Predefined acceptance criteria,
* Training requirements for analysts,
* How deviations will be handled (investigation + CAPA),
* Sample transport conditions,
* The comparative study design.
5. Conduct Comparative Testing:
* Analyze the same sample batch at both transferring and receiving labs.
* Perform statistical comparison using a paired t-test (or ANOVA if appropriate),
to ensure there is no significant difference in results.
* This forms a key part of confirming method equivalence.
6. Perform Validation Activities (ICH Q2):
Validate the method at the receiving lab for the following parameters:
* Accuracy:
Mean % recovery between 98–102% across 3 concentrations (e.g. 80%, 100%, 120%) in triplicate.
* Linearity:
Regression analysis over 5 concentration levels; r² ≥ 0.99.
* Precision:
Repeatability and intermediate precision; %RSD ≤ 2%.
* Specificity:
Resolution between analyte and closest peak ≥ 1.5.
* LOD / LOQ:
Based on signal-to-noise ratio: LOD ≈ 3:1, LOQ ≈ 10:1.
* Robustness:
Assess impact of small, deliberate changes (e.g., flow rate, temperature); ensure results remain within %RSD ≤ 2%.
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Final statement (for viva impact):
“As a QP, I would ensure the method transfer is executed under change control, using a risk-based approach in line with ICH Q2 and Annex 15.
The comparative study, supported by a t-test, is a key step to confirm equivalence between labs.
My role is to ensure the receiving lab can perform the method reliably, maintaining regulatory compliance and product quality.
Any other types of method transfer other than comparative testing?
- Comparative Testing
- The most common: both sending and receiving labs test the same samples and results are compared.
Other types include:
2. Re-Validation (Full or Partial)
* If the method cannot be reliably transferred or if there are changes (e.g., equipment is very different), you may need full or partial re-validation at the receiving site.
3. Transfer Waiver
* If justified (e.g., the same company group, same equipment, trained personnel, method already validated and proven equivalent), a formal transfer may be waived with proper documented risk assessment.
4. Co-Validation (Concurrent Validation)
* Sometimes the method is transferred and validated during routine sample testing — used mainly when the method is very robust or urgency is high. It’s riskier and needs strong justification.
You also mentioned Process Verification —
* Process verification usually refers more to manufacturing process (not analytical method transfer). It’s about verifying that a process consistently produces a product meeting its specifications — not transferring analytical methods.
* So, process verification would not typically be classified as a method transfer type.
Stability assay is OOS (one in spec one slightly out of spec); batches on the market; what do you do? Oncology drug everything else is in spec.
Initial Information Gathering:
0. Gather key information:
* What is the product, indication, and patient group (oncology patients are highly vulnerable)?
* Are there alternative treatments available on the market?
* What test showed OOS?
(E.g., assay slightly outside spec — critical for efficacy.)
* Are other tests (e.g., impurities, dissolution) within specification?
* Confirm stability trends over time.
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Immediate Actions:
1. Quarantine the affected batch on-site immediately as a precaution, while investigation proceeds.
2. Initiate OOS Investigation:
* Phase 1a Investigation (Analyst Level):
* Check for clear assignable causes:
* Calculation errors, wrong SOP version, expired reagents, equipment malfunction.
* Phase 1b Investigation (Supervisor/Senior Analyst Level):
* Detailed checklist: Recheck calculations, equipment calibration/maintenance records, reagents and solutions.
* Hypothesis testing: If needed, reanalysis with predefined and QA-approved protocols to rule out hypothetical causes.
* If no assignable cause found:
Proceed to Phase 2 — product quality investigation (Deviation raised).
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Deviation Management:
* Open a deviation record:
* Describe “who, what, when, where, and how” the OOS occurred.
* Perform impact assessment:
* Marketing Authorisation (MA):
* Batch is OOS — impacts authorised specifications.
* GMP:
* Possible process or equipment failure; systematic issue risk.
* Patient safety:
* Consult medical team:
* Is the small % deviation in assay clinically significant?
* What is the risk to the patient (underdosing, treatment failure)?
* Market risk:
* Oncology drugs often have no alternatives — risk/benefit must be weighed very carefully.
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Additional Immediate Actions:
* Review stability data of other batches — trend analysis.
* Test retention/reference samples from released batches.
* Increase testing points to strengthen statistical reliability.
* Consider additional testing (e.g., impurities) depending on risk.
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Recall Decision:
* Organize a recall risk assessment meeting with a multidisciplinary team:
* QA, QC, QP, Regulatory, Medical, Manufacturing, and Supply Chain.
* Review findings and decide:
* Recall class (Class I, II, III based on patient risk),
* Scope (all batches affected?),
* Level (wholesale, pharmacy, patient).
* Contact DMRC (Defective Medicines Report Centre, MHRA) early for advice and notify if recall is decided.
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Root Cause Analysis (RCA):
Conduct thorough RCA covering:
* QMS: Deviations, CAPA records, change controls, OOS history, PQR data.
* Personnel: Training, analyst qualification.
* Equipment/Facility: Equipment calibration, maintenance (PPM) logs, validation status.
* Process: Process validation, any interventions during manufacturing?
* Materials: Supplier quality — any change/issues with starting materials or packaging?
* Documentation: Batch Manufacturing Records (BMR) for anomalies.
* Self-inspection findings: Any relevant audit observations.
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CAPA and Follow-up:
* Open CAPAs based on the identified root cause:
* Prevent recurrence,
* Improve control measures,
* Conduct effectiveness checks.
* Finalize the investigation report.
* Submit a final report to the DMRC (including root cause, impact, recall outcome, and CAPAs).
* Update regulatory authorities as required if patient risk remains acceptable.
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Closing Statement (for viva impact):
“In this situation, as a QP, my first priority is patient safety, followed by regulatory compliance and product quality assurance.
A thorough investigation, multidisciplinary risk assessment, and regulatory communication must be conducted, leading to appropriate CAPA to prevent recurrence.
MHRA OOS guidance - tell me the process
dissolution failure
Step 1: Initiate OOS Investigation
* Conduct an OOS investigation in accordance with MHRA expectations and site OOS SOP.
* Immediately quarantine all affected batches (both released and unreleased) to prevent further distribution.
Phase 1a — Initial Laboratory Investigation
* The original analyst and supervisor conduct an immediate investigation.
* Check for obvious errors such as calculation mistakes, incorrect sample preparation, instrument malfunctions (e.g., power outage).
* QA approval is not required for Phase 1a.
* If an assignable cause is identified (e.g., proven calculation error), invalidate the result following documented procedure.
* If no assignable cause is found, proceed to Phase 1b.
Phase 1b — Extended Laboratory Investigation
* Senior analyst/supervisor conducts a detailed structured investigation, using a pre-defined checklist (e.g., reagent quality, equipment calibration, environmental conditions).
* Hypothesis testing may be performed to rule out probable causes.
* A written protocol must be approved by QA prior to conducting any hypothesis testing.
* If no assignable cause is found after Phase 1b, treat the OOS result as a true result and escalate.
Step 2: Open Deviation
* Raise a formal deviation or non-conformance.
* Document the situation clearly:
* Who found it, When, Where, How the deviation was identified.
* Cross-reference the deviation report to the OOS investigation.
* Identify all batches affected.
Step 3: Conduct Impact Assessment
* Marketing Authorisation (MA):
* Failure to meet dissolution specifications may breach the MA — review SmPC/registered specifications.
* GMP:
* Consider whether there may be a systemic failure (process, equipment, environmental control).
* Patient Safety:
* A dissolution failure may impact the drug’s bioavailability, leading to under-dosing or lack of efficacy.
* Classify the deviation as Major (or Critical if there is direct patient impact).
Step 4: Organise Recall Decision Meeting
* If batches have already been released:
* Convene a recall committee including QA, Regulatory Affairs, Medical Team.
* Decide on recall class and level (likely Class 2 or 3; patient-level recall if needed).
* Confirm classification and recall strategy internally before external action.
Step 5: Notify Authorities
* Contact the Defective Medicines Report Centre (DMRC) at the MHRA before starting the recall.
* Early notification is essential even if investigation is ongoing.
Step 6: Conduct Root Cause Analysis (RCA)
* Use an Ishikawa (Fishbone) Diagram to systematically investigate potential causes.
* Cover all key elements:
* Quality Management System
* Facilities and Equipment
* Personnel
* Documentation
* Manufacturing Process
* Quality Control
* Suppliers/Outsourcing
* Self-Inspection/Internal Audit Findings
Step 7: Implement Corrective and Preventive Actions (CAPA)
* Define clear CAPAs based on the root cause.
* Include effectiveness checks (e.g., trend monitoring, re-training, system upgrades).
Step 8: Complete Reporting
* Prepare a closing investigation report.
* Submit final reports and updates to the DMRC as required, including recall effectiveness checks.
You are moving testing from a site in India to UK – how would you do this?
After completion of method transfer there is an OOS on the first batch tested in UK lab but Indian lab is showing passing result – what do you do?
- Initiate OOS Investigation (UK Receiving Lab)
- Conduct a full OOS investigation following MHRA guidance and site SOP.
- Determine whether the OOS result is due to an identifiable laboratory error (e.g., analyst error, equipment failure) or represents a true batch failure.
- If no assignable cause is found, treat the OOS result as valid.
- Quarantine the Batch
- Immediately place the affected batch under quarantine.
- If any product has been released, perform a risk assessment and consider product recall if necessary.
- Investigate Method Transfer Execution
- Review the method transfer protocol and acceptance criteria.
- Compare critical method parameters and equipment between the Indian and UK labs.
- Assess whether the method is truly robust and reproducible across sites — differences in instrumentation, analyst technique, or sample preparation may reveal the issue.
- Confirm whether the sending lab results (India) were accurately and compliantly reported.
- If the UK OOS is Confirmed as a True Result:
- Reject and dispose of the batch under QA oversight.
- Document the rejection decision with cross-reference to the OOS investigation and batch records.
- Root Cause Analysis (RCA)
- Conduct RCA to understand the discrepancy between sending and receiving lab results.
- Use tools like the Ishikawa diagram to explore:
- Method variability,
- Analyst competency,
- Equipment calibration and sensitivity,
- Environmental factors,
- Sample handling and preparation.
- Corrective and Preventive Actions (CAPA)
- Raise a deviation in the QMS.
- Implement appropriate CAPAs, such as:
- Re-assessment or re-validation of the analytical method,
- Analyst re-training,
- Instrument qualification review,
- Enhanced oversight during early-phase testing after transfer.
- CAPA Effectiveness Check
- Define measurable success criteria (e.g., consistent passing results on future batches, stability of system suitability parameters).
- Monitor trends in analytical data from subsequent batches.
- Regulatory and Quality Oversight
- If product was released or distributed, assess need to notify MHRA via DMRC.
- Document investigation, RCA, CAPA, and final decision in a comprehensive investigation report.
Give examples of what you would look at in Phase 1a/b?
Phase 1a – Immediate Laboratory Checks (No QA Approval Needed)
Conducted by the original analyst and supervisor to identify any obvious errors:
* Calculation errors (e.g., incorrect formula or unit conversion)
* Sample mix-up or mislabelling
* Equipment failure (e.g., power outage, instrument crash during analysis)
* Incorrect reagent or diluent used
* Incorrect sample preparation technique (e.g., pipetting error, dilution mistake)
* Missed steps in the test method or SOP deviation
* Obvious analyst error (e.g., misreading a balance or spectrophotometer)
Phase 1b – Extended Laboratory Investigation (QA Approval Required Before Hypothesis Testing)
Conducted by senior analyst/supervisor with QA oversight, using a structured checklist:
* Out-of-date reagents or reference standards
* Equipment calibration out of date or instrument drift
* Preventive maintenance (PM) overdue (e.g., HPLC pump not serviced)
* Method ruggedness issues (e.g., sensitivity to small changes in temperature or pH)
* Analyst variability — review of training and performance records
* Review of chromatography system suitability results or baseline noise
* Environmental conditions during analysis (e.g., humidity, temperature excursions)
* Software/system access issues or audit trail anomalies
* Hypothesis testing (e.g., repeat test with fresh reagents, different column or analyst — if pre-approved by QA)
Turns out it’s a true OOS – can you release the batch?
That batch was scrapped and we released another batch, 3 months later there is an OOT for an impurity – what are your thoughts?
Immediate Actions:
1. Quarantine any affected batches:
* Immediately quarantine any batch currently awaiting release.
* Identify all batches already released to market that may be impacted by this impurity OOT.
2. Review Other Analytical Results:
* Check the full analytical profile (e.g., assay, dissolution, other impurities) to ensure no other abnormalities.
3. Initiate OOT Investigation:
* Perform a structured OOT investigation according to site SOP.
* Determine if the OOT is:
* A genuine trend (e.g., slow increase in impurity)
* Or due to analytical/laboratory variation (e.g., instrument drift, analyst error).
4. If OOT is Confirmed as True:
* Use statistical analysis:
* Extrapolate impurity levels over time.
* Apply linear regression or 95% confidence interval to predict when the batch would breach specification (OOS).
* Assess remaining shelf-life viability.
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Deviation Management and Impact Assessment:
* Deviation:
* Open a formal deviation in the QMS system linked to the OOT finding.
* Impact Assessment:
* MA Compliance:
* Although currently within specification, projected future OOS is a potential MA breach.
* GMP Compliance:
* Potential systemic issues to be investigated — manufacturing process, contamination risks, API quality, environmental controls.
* Patient Safety:
* Evaluate whether the impurity is toxic or otherwise harmful. Check toxicology data (e.g., ICH M7 if genotoxicity).
* Market Impact:
* Assess whether alternative products are available.
* Patient Impact:
* Identify patient groups affected — vulnerable groups (e.g., paediatrics, oncology) need greater caution.
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Recall Decision:
* If extrapolation shows the batch will soon exceed specification, even if currently compliant:
* Organise a recall meeting with QA, Regulatory Affairs, Medical, and Management teams.
* Likely Class 3 recall (precautionary)
* Level: pharmacy/hospital recall (as product is still within specification at the time of action).
* Notify the Defective Medicines Report Centre (DMRC) before any public action if needed.
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Root Cause Analysis (RCA):
Use an Ishikawa Diagram to systematically investigate:
Category
Areas to Investigate
QMS
Deviation logs, PQR, Change Control history
Facilities/Equipment
Temperature excursions, environmental trends, maintenance logs, cleaning records
Process
Cleaning validation, line clearance failures, manufacturing records (BMRs)
Quality Control
Reference standard stability, lab equipment performance, audit trails
Personnel
Analyst and operator training records
Supplier Management
API quality (CoA, retesting, reprocessing, audits)
Self-Inspection
Any relevant audit findings linked to manufacturing, storage, or testing
Corrective and Preventive Actions (CAPA):
* Implement CAPAs based on root cause findings:
* Strengthen supplier qualification.
* Improve cleaning processes.
* Revise method validation if necessary (e.g., impurity stability).
* Additional stability testing or reduced shelf-life if appropriate.
* Conduct effectiveness checks:
* Monitor future batches for similar trends.
* Additional sampling/testing if needed.
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Regulatory Communication:
* Submit a closing investigation report to MHRA DMRC, especially if recall or public health risk is involved.
* Update stability protocols if necessary.
Describe the recall procedure .
You have a stability batch and there was an oos at 18 months for Tablet, shelf life was 24 months. Cancer drug.
Why will you not reject this batch when I said I will not, then justify – cancer drug
A routine stability batch OOT for assay at 18 months for another product, which drilled more detailed about the concern with MDI.
What confidence interval, its calculation and why do you keep 95% confidence interval?
A confidence interval is a statistical range that is likely to contain the true population parameter (e.g. mean, slope, intercept) with a specified level of confidence — most commonly 95%.
In simple terms:
A 95% confidence interval means: “We are 95% confident that the true value lies within this range.”
It’s not that 95% of the data lies in this range — it’s that if the experiment were repeated many times, 95% of those intervals would include the true value.
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How is it calculated?
For a mean, the confidence interval is calculated using:
CI = x̄ ± (t × s/√n)
Where:
• x̄ = sample mean
• t = t-statistic (from Student’s t-distribution for the chosen confidence level and degrees of freedom)
• s = sample standard deviation
• n = number of observations
So, the CI widens when:
• Your data is more variable (larger standard deviation),
• You have fewer samples (smaller n),
• You choose a higher confidence level (e.g., 99%).
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Why use 95% confidence interval?
• 95% is a regulatory standard accepted by authorities like ICH, EMA, MHRA, FDA, etc.
• It provides a good balance between certainty and practicality — high enough confidence without requiring an unmanageably large sample size.
• Specifically, in ICH Q1E, confidence intervals are used when performing regression analysis for stability data, especially to justify shelf life assignments.
Example: A 95% one-sided confidence limit on the regression line is used to ensure that the assay remains above the lower specification limit throughout the proposed shelf life.
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Viva-ready sentence:
“A confidence interval defines the range within which the true population parameter is likely to fall.
I use the 95% confidence interval because it is the regulatory standard per ICH Q1E for stability data and provides sufficient assurance that the drug product will remain within specification throughout shelf life.”
How would you set up a stability programme for a tablet product?
Where would you find guidance bracketing and matrixing ? Can you please explain what do they mean?
You receive a call on Friday evening from QC informing about OOT for tablet assay testing at 9 months. Shelf life is 36months. What are your concerns?
You have now been told that batch will fail at 12 months. What do you do?
Which type of stats would you use to estimate shelf life?
I drew a graph to explain this and the assessor was happy.
Are you allowed to perform extrapolation?
Shelf-life extrapolation is only allowed when stability trends are clear and statistically supported. ICH Q1E requires regression analysis (95% CI), a minimum of 3 batches, and testing of batch poolability  . The extension beyond the last data point is limited (typically ≤ +6 m with stats, or +3 m without)  . Accelerated/intermediate results must show stability to permit extrapolation  . EMA/MHRA guidance (including Q1A, Q1E and clinical trial guidelines) echoes these rules   . All extrapolations must include a commitment to obtain longer-term data to verify the shelf life.
