Active Substances and Excipients Flashcards
(38 cards)
Informed of change in API manufacturing process from 5 step to 4 step – what are my concerns?
a. Impurities concerns – guidance. Classifications of impurities (residual solvents and elemental)
b. I discussed catalysts, impact on the API (polymorphism etc) discussion with med info.
You are informed that the API manufacturing process has changed from a 5-step to a 4-step process. What are your concerns?
My primary concern is the potential impact on the quality of the API — specifically the impurity profile, residual solvents, elemental impurities, and physical properties such as polymorphism.
A reduction in synthetic steps could eliminate critical purification or reaction stages, which might lead to elevated levels of impurities, or the introduction of new ones.
As a QP, I would not certify a batch until I am assured that the new route has been fully evaluated through change control, and I have access to updated regulatory and analytical data demonstrating equivalence or superiority to the previous route.
What do you expect to change in the impurity profile?
The impurity profile might change significantly. The shortened synthesis could remove intermediate steps that eliminated specific impurities — this could result in either increased levels of known impurities or the appearance of new, route-specific impurities.
Also, depending on the reagents or solvents introduced, residual solvent levels could shift. Therefore, a thorough comparative impurity assessment should be conducted between the old and new routes.
What guidelines do you refer to for impurities?
would refer to the ICH Q3A(R2) for impurities in new drug substances, Q3C for residual solvents, and Q3D for elemental impurities.
If there is a potential for genotoxic impurities, ICH M7 would be relevant.
Also, Q6A helps define specifications, and Q11 covers the development of drug substances, including control of impurities
How would you assess the risk from residual solvents?
I would expect the API manufacturer to provide a residual solvent risk assessment in line with ICH Q3C.
They should demonstrate that Class 1 solvents (carcinogenic) are avoided unless justified; Class 2 solvents (toxic) are within permitted daily exposure (PDE); and Class 3 solvents are within 5000 ppm.
Analytical validation should confirm compliance with these limits.
What about elemental impurities?
Elemental impurities could be introduced through catalysts or reagents.
I’d expect a risk-based evaluation in accordance with ICH Q3D, addressing Class 1, 2A, 2B, and 3 elements.
I’d review data on potential sources, their control in the process, and confirm via analytical results — typically ICP-MS — that levels are below PDE thresholds
If the process introduces new catalysts, what do you do?
I’d want to understand the nature of the catalyst — is it metal-based, what class it falls under in ICH Q3D, and whether it is likely to carry through to the final API.
I’d require fate and purge data, showing that any residuals are removed to acceptable levels. If not, additional purification steps or tighter specifications may be needed.
Could this affect the polymorphic form of the API?
Yes, definitely. Polymorphism is often impacted by crystallisation conditions, solvents, temperature, or seeding — all of which could change in a revised route.
A new synthetic route could unintentionally generate a new or unstable polymorph, affecting solubility, bioavailability, and stability.
Why is polymorphism a concern for the QP?
Different polymorphs can have different solubility, dissolution rates, and stability profiles.
If the polymorphic form changes, the bioequivalence of the product could be affected, and dissolution specifications may no longer be appropriate.
I would expect XRPD or DSC data to confirm the same polymorphic form is produced as before.
You said you’d speak with Medical Information — why?
If there is a potential change in impurity profile or physical form, I would want to understand any impact on clinical safety or efficacy.
The Medical Information team or clinical safety group can provide insight into the toxicological relevance of new impurities or changes in exposure.
This is especially important if we are dealing with narrow therapeutic index drugs or high-risk patient populations.
Would this require a regulatory variation?
Yes, most likely. A change in the API manufacturing process is a registered detail in the dossier.
For a licensed product, this would normally require at least a Type II variation. For an IMP, the IMPD would need updating.
What data would you require from the API manufacturer?
- Updated process description and flow chart
- Risk assessments (e.g. impurity fate and purge studies)
- Analytical comparison of impurity profiles (old vs. new)
- Validation of critical process parameters
- Stability data (if any form or impurity change)
- Batch analysis results
- Confirmation of GMP compliance and regulatory approval (variation approval letter or updated ASMF/IMPD)
Can you give an overview of the key differences between small molecule API vs Biotech/biological API?
Small Molecule APIs (Synthetic/Chemical):
• Produced via chemical synthesis (e.g. organic chemistry)
• Well-defined structure and low molecular weight
• Typically stable, with consistent quality and fewer critical process parameters
• Manufactured in GMP facilities under ICH Q7 guidance
• QC tests focus on:
• Assay (API content)
• Impurity profile (e.g. residual solvents, degradation products)
• Particle size, flow properties, melting point
• Stability testing per ICH Q1
• Often formulated as oral dosage forms (tablets, capsules)
Biotech/Biological APIs (Large Molecules):
• Produced using living systems (e.g. mammalian cells, bacteria)
• High molecular weight, complex 3D structures (e.g. monoclonal antibodies, proteins)
• Inherently variable due to biological systems — more sensitive to temperature, pH, shear stress
• Critical process parameters (CPPs) tightly controlled — cell line, media, bioreactor conditions
• QC tests focus on:
• Potency (bioassay or immunoassay)
• Sterility, mycoplasma, and viral safety
• Endotoxin, host cell protein/DNA
• Glycosylation pattern, aggregation
• Fall under ICH Q5A–Q5E, EudraLex Vol 4 Part I/II, and Annex 2 (biologicals)
• Usually formulated as injectables
What are the differences in between small molecule API vs Biotech/biological API facility requirements and specific examples?
- Buzzwords (to hit in your viva):
• ICH Q7 (all APIs)
• Annex 2 (Biologicals), EU GMP Part IV (ATMPs)
• Closed vs Open systems
• MCB/WCB (cell banks) vs Defined chemical starting materials
• Viral clearance / adventitious agents
• Grade A/B/C cleanrooms, biosafety cabinet, isolator
• Cross-contamination, bioburden, endotoxin
• Dedicated vs multipurpose, single-use systems, campaign manufacturing
• PDE/HBEL (health-based limits)
• CIP/SIP, environmental monitoring, EM
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- Structured Summary Answer:
GMP Guidelines:
• ICH Q7 applies to both small molecule and biotech APIs.
• Annex 2 provides additional GMP for biological APIs.
• ATMPs follow EU GMP Part IV – more flexibility, but strict traceability and aseptic handling.
Facility Design:
• Small molecule: Often open systems in non-classified areas; focus on chemical cross-contamination and cleaning validation.
• Biotech/biological: Use closed systems, Grade C/B cleanrooms, Grade A for open manipulations. Asepsis and segregation are key.
Contamination Control:
• Small molecule: Main concern is product-to-product contamination. Managed by validated cleaning and HBEL-based risk assessment.
• Biotech: Risk of microbial/viral contamination. Need bioburden control, viral inactivation, environmental & personnel monitoring.
Starting Materials:
• Small molecule: Use defined chemical starting materials, controlled by CoA and GMP sourcing.
• Biotech: Use MCB/WCB or seed lots, requiring extensive characterisation, storage, and biosafety controls.
Examples:
• Paracetamol (small molecule): Synthesised in closed reactors, multipurpose plant, cleaning focus.
• Monoclonal antibody (mAb): CHO cell culture, aseptic downstream, viral clearance, requires Grade C/A environment.
• CAR-T (ATMP): Autologous cells, aseptic manual handling, isolator-based, patient-specific controls and donor screening (e.g. HIV, syphilis).
Multipurpose vs Dedicated:
• Small molecule: Often multipurpose, justified by cleaning validation + HBEL.
• Biotech/ATMP: May require dedicated equipment or segregated campaigns, especially for live cells or viral vectors.
What is api QP declaration and structure of the template?
Buzzwords (Memory Aids):
• EU GMP Vol 4 Part III Template
• ICH Q7 compliance
• Annex 16 – QP legal responsibility
• Due diligence
• On-site GMP audit
• Contract giver/acceptor
• Audit justification (>3 years)
• Article 46(f) Directive 2001/83/EC
• QP declaration – GMP responsibility
• Availability for inspection
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Structured QP Viva Answer:
Q: What is the QP declaration template for API GMP compliance, and what is its structure?
A:
The Qualified Person’s Declaration concerning GMP compliance of the active substance manufacture is a formal EU template found in Volume 4, Part III of the EU GMP Guide. It is used to support Marketing Authorisation Applications (MAA) by confirming that the active substance (API) used in the finished product is manufactured in accordance with ICH Q7 GMP principles, as required under Article 46(f) of Directive 2001/83/EC.
The declaration is signed by a Qualified Person (QP) and confirms that appropriate due diligence has been undertaken, including on-site audits of the API manufacturing sites, whether directly or via a qualified third party.
Structure of the Template:
• Reference Number: Unique identifier for the declaration.
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PART A – Concerned Active Substance Manufacturing Sites
• API name.
• Name and address of all manufacturing sites involved in the synthesis, starting from the introduction of the starting material.
• Type of activity at each site (e.g., synthesis, purification, micronisation).
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PART B – Manufacturing/Importer Authorisation Holders (MIAHs)
• List of MIA holders to which the declaration applies.
• MIAH numbers and manufacturing activities.
• This includes any site responsible for QP certification of the finished product.
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PART C – Basis of the QP’s GMP Declaration
• (i) Confirm on-site audit was conducted.
• (ii) Table listing:
• MIAH or Contract Giver
• Auditing body (Contract Acceptor)
• Site audited and audit date
• Justification if audit >3 years ago
• (iii) Optional: Attach supporting documents (e.g., EEA GMP certificates, MRA inspection results).
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PART D – QP Declaration
The QP formally declares:
• They are responsible and authorised to make this statement.
• GMP compliance is confirmed for each site based on audit outcome.
• All audit documentation is available for inspection.
• For third-party audits:
• The contract acceptor was qualified.
• Technical agreements exist.
• Audits were done by trained staff under approved procedures.
• In multi-MIAH cases:
• Responsibilities are clearly documented, and
• Agreements exist between QPs/MIAHs.
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PART E – QP Signature
• QP name, signature, and date of declaration.
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Regulatory Significance:
This declaration is crucial for ensuring that the API supply chain meets regulatory expectations and that QP certification of the final product is based on APIs manufactured under appropriate GMP.
It supports compliance with Annex 16, ICH Q7, and the Human Medicines Regulations 2012 in the UK context.
What is Nitrosamines?
What are Nitrosamines?
Nitrosamines are a class of compounds classified as probable human carcinogens. They may form during the manufacture of active substances or finished products, as degradation products, or through interactions with container closure systems. In line with EU GMP and MHRA requirements, Marketing Authorisation Holders (MAHs) are required to conduct a risk assessment for the potential presence of nitrosamines, investigate root causes, and implement appropriate control strategies to mitigate the risk. This requirement is outlined in the EMA’s nitrosamine Q&A and MHRA’s published guidance.
Setting up new API supplier - How would you do that?
- Change Control
Initiate a formal Change Control (CC) to document the rationale, scope, and risk associated with introducing a new API source. Cross-functional assessment involving QA, Regulatory Affairs, Procurement, and Manufacturing should be documented.
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- Impact Assessment
Evaluate impact on:
• The Marketing Authorisation (MA) – e.g. is a variation required to register the new supplier?
• MIA(IMP)/MS licence – e.g. changes to supplier lists or importation responsibilities.
• Regulatory filings – ensure that the new supplier’s details are reflected in Module 3.2.S of the CTD.
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- GMP Compliance
Verify that the API supplier is operating under EU GMP or equivalent standards:
• If in the EEA or MRA country, confirm they have a valid EU GMP certificate.
• If in a non-EU third country, obtain a valid Written Confirmation (per Article 46b, Directive 2001/83/EC).
• Confirm that the UK/EU importer holds a valid MIA(IMP)/MS licence to import APIs.
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- Quality and Finished Product Impact
• Assess impurity profile differences, including:
• Elemental impurities – ICH Q3D
• Residual solvents – ICH Q3C
• Nitrosamines – ICH M7, EMA Q&A
• Evaluate differences in polymorphism, particle size, or salt form, which may affect bioavailability or process performance.
• Perform comparative testing or validation batches if needed.
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- GMP Audit
Conduct a GMP audit of the new API supplier in line with ICH Q7 and EU GMP Part II.
• Audit may be on-site or remote, based on risk-based vendor qualification.
• Assess supply chain integrity, change control, traceability, and cross-contamination controls.
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- Quality Technical Agreement (QTA)
Establish a QTA defining responsibilities for:
• GMP compliance
• Deviation and OOS/OOT handling
• Change notification
• Document retention
between the API supplier and the MAH or manufacturer.
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- Supply Chain Mapping
Update the supply chain map to reflect the new supplier, including all intermediate brokers, transportation routes, and storage locations.
• Evaluate for GDP risks, falsified medicines, and supply chain transparency.
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- Stability Study Requirements (Add-On Section)
When a new API supplier or batch is introduced, assess whether the change affects product stability. Based on ICH Q1A(R2):
• Conduct a comparative stability study if the API is similar but not identical (e.g. minor differences in impurity profile or physical form).
• Initiate a bridging stability study or new stability programme if there are significant differences (e.g. new polymorph, degradation profile, or different impurity classes).
• Confirm that the product’s shelf-life and retest period remain justified.
• For IMPs, ensure at least accelerated (e.g. 3-month) data is available before use.
• Update the regulatory filing (e.g. MA variation or stability commitment) as required.
API site address change; no change control; no MA variation. What would you do?
Buzzwords for QP Viva:
• Change control failure
• Deviation / non-conformance registration
• MA discrepancy – Module 3.2.S
• Type IB variation
• API site qualification
• Annex 16 – QP responsibilities
• QTA not updated
• Validation gap – process, analytical, stability
• Quarantine product and API
• Supplier complaint
• Recall classification
• DMRC notification
• DHSC notification (supply disruption)
• PQR and trend analysis
• Regulatory non-compliance risk
As a QP, discovering that an API site address has changed without a corresponding change control and no variation filed in the Marketing Authorisation (MA) raises serious regulatory, GMP, and quality compliance risks.
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- Deviation Management
• Immediately register the issue in the QMS as a deviation (or non-conformance).
• Perform a structured impact assessment involving QA, Regulatory Affairs, and Manufacturing.
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- Regulatory Impact
• There is a discrepancy between the actual API source and the approved MA (Module 3.2.S) — this constitutes non-compliance.
• A Type IB variation should have been submitted to update the API site address.
• Batch release based on an incorrect MA source may render batches technically unlicensed.
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- GMP Impact
• No Change Control was raised, so no GMP assessment or oversight was performed.
• No evidence of site qualification, method transfer, validation, or QTA update.
• This violates EU GMP Part I & II, and Annex 16 principles for QP certification.
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- Finished Product Risk
• If the API was materially different or manufactured at a site with different processes or risks, finished product quality could be impacted.
• No comparative validation or stability studies may have been conducted.
• Risk of OOS trends, impurity profile changes, or reduced shelf life.
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- Immediate Actions
• Identify all batches of finished product manufactured using the affected API batch(es).
• Quarantine any finished product still within the site, and quarantine API stock at manufacturing site or warehouse.
• Contact the MAH immediately and notify them of:
• The regulatory breach
• Potential supply chain disruption
• Need for variation submission and possible recall
• Raise a formal supplier complaint.
• Request retrospective validation, analytical method transfer, and audit documentation.
• Suspend use of API from the affected site until full technical and GMP assessment is complete.
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- Risk Assessment and Recall Consideration
• Review PQRs, QC trends, and stability data for impacted finished batches.
• Convene an internal Recall Meeting with QP, QA, RA, and Production.
• Determine if recall is warranted based on risk to patient and product quality.
• If recall is necessary, classify according to MHRA recall classification (Class 1–3).
• Draft communications and prepare recall notification form.
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- External Notifications
• Contact DMRC (Defective Medicines Report Centre) to notify of the issue before initiating any recall.
• If marketed product is impacted, liaise with DHSC to inform of potential supply disruption.
You’ve got a new blockbuster product and your team has told you that they are making some changes to the API: they have been able to reduce from 5 steps to 4 and are also changing to a different manufacturing site (same company but different address) and also scaling up – thoughts ?
Buzzwords for QP Viva:
• Change Control
• ICH Q9 – Risk Assessment
• ICH Q10 – Knowledge & Lifecycle Management
• ICH Q3A/B/C/D – Impurities, Solvents, Elements
• ICH M7 – Nitrosamines, TTC
• ICH Q1A – Stability Testing
• ICH Q2 – Analytical Method Transfer
• Polymorphism / Particle Size – ICH Q6A
• Type II Variation – EMA guideline (B.I.a.2.b / B.I.a.1)
• Module 3.2.S – CTD
• QP Declaration – EU GMP Annex 16
• GMP Certificate / Written Confirmation
• Process Validation / Method Validation
• Comparative / Bridging Stability Study
• No release before variation approval
For a blockbuster product where the API process is being shortened from 5 to 4 steps, transferred to a new site (same company, different address), and scaled up, I would first ensure this is managed through a formal change control under the Pharmaceutical Quality System (PQS).
Step 1: Change Control & Risk Assessment
I would initiate a cross-functional impact assessment, using ICH Q9 risk management principles. Key considerations include potential changes to the impurity profile, residual solvents, and API physical characteristics like polymorphism or particle size.
Step 2: MA Impact
The shortened synthesis route and site change will likely trigger a Type II variation, per EMA Variation Guidelines (B.I.a.2.b and B.I.a.1). I would ensure the MA (Module 3.2.S) is updated with revised process, site details, and validation data. No batches from the new route/site should be released until the variation is approved.
Step 3: GMP Compliance
I’d confirm the new site has a valid EU GMP certificate or Written Confirmation if it’s outside the EU/UK. Process validation at the new scale is required, as is analytical method transfer or revalidation per ICH Q2. A QP Declaration is also needed to confirm GMP compliance at the API site.
Step 4: Finished Product Quality
I’d assess the impact on impurity profile (ICH Q3A/B), residual solvents (ICH Q3C), elemental impurities (ICH Q3D), and mutagenic impurities/nitrosamines (ICH M7). I’d also consider if the new process affects shelf-life or dissolution. If necessary, initiate bridging or comparative stability studies (ICH Q1A).
Final QP Responsibility
As QP, I would only certify product once I’m assured that:
• The MA is updated,
• The change control and validations are complete, and
• The new API meets all quality, safety, and GMP requirements.
Your site has got a new API for the manufacturing of a new product. What are your concerns.
Buzzwords for Viva:
• Change Control
• Module 3.2.S.2.1 – CTD
• CEP / ASMF
• Type IA / Type II Variation
• EudraGMDP
• ICH Q7 – GMP audit
• QP Declaration
• Written Confirmation – Article 46b
• ICH Q3C / Q3D / M7 / Q1A
• Polymorphism, Particle Size
• QTA – Quality Technical Agreement
• Supply chain mapping
• GDP risks, falsified medicines
• Analytical method validation (ICH Q2)
- Change Control
• Ensure the introduction of the new API is formally documented via change control, with a full cross-functional impact assessment.
• The change should be logged in the change control register, with QA oversight and clear responsibilities assigned.
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- Regulatory/MA Impact
• Confirm the API manufacturer is listed in Module 3.2.S.2.1 of the CTD.
• If not listed, a Type IA or Type II variation is required (depending on whether it’s an additional site or new route of synthesis).
• Ensure Regulatory Affairs updates the MA dossier, and any CEP or ASMF is valid and current.
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- GMP Compliance
• Verify the API manufacturer is appropriately licensed:
• Holds a valid EU GMP certificate (EudraGMDP)
• If outside the EU/UK, confirm a valid Written Confirmation is available
• Check if the site is covered under a CEP (check EDQM database), or if an ASMF has been assessed.
• Ensure a GMP audit has been conducted (or planned) in accordance with ICH Q7.
• A QP Declaration must be issued, confirming GMP compliance of the API manufacturing site.
• Confirm technical transfer (including analytical method transfer) has been completed, or if revalidation is needed.
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- Finished Product Impact Assessment
• Assess whether the new API has any differences that could impact the finished product:
• Impurity profile – ensure conformance with ICH Q3A/B
• Residual solvents – evaluate per ICH Q3C
• Elemental impurities – risk assess per ICH Q3D and confirm PDE limits not exceeded
• Nitrosamine risk assessment – follow ICH M7 and MHRA/EMA guidance
• Polymorphism, particle size distribution – assess impact on solubility, dissolution, content uniformity
• Stability studies – initiate if required to confirm shelf-life is not impacted (ICH Q1A(R2))
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What to Add (Key Enhancements):
- QTA (Quality Technical Agreement)
• Ensure a Quality Technical Agreement is in place between the MA holder and API supplier, defining responsibilities (e.g. OOS, change notification, testing responsibilities). - Supply Chain Mapping / GDP Risk
• Update the supply chain map to reflect the new supplier, intermediaries, and transport/storage routes.
• Assess for GDP risks, falsified medicines concerns, and ensure full traceability. - Analytical Testing Preparedness
• Confirm if analytical methods for the new API are in place and validated (ICH Q2).
• If performed at a different lab, ensure method transfer protocol is followed.
What are the main synthesis and manufacturing steps for a chemical API?
Buzzwords for Viva:
• Reaction steps: acid–base, oxidation, coupling
• Work-up, intermediate isolation
• Crystallisation / Recrystallisation
• Drying, milling, blending
• ICH Q3A/B/C, particle size, polymorphism
• GMP compliance, ICH Q7
• Module 3.2.S – API manufacture and control
Model Answer: Main Synthesis and Manufacturing Steps for a Chemical API
The manufacturing of a chemical API typically involves two phases:
- Synthesis (Chemical Reaction Steps)
These steps involve building the molecular structure of the API through:
• Acid–base reactions
• Redox reactions (oxidation/reduction)
• Substitution / addition / elimination reactions
• Coupling reactions (e.g. amide bond formation, Suzuki coupling)
• Protection / deprotection of functional groups
• Use of catalysts, reagents, solvents
Each step may be followed by work-up and intermediate purification (e.g. filtration, washing).
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- Downstream Processing (Purification and Finishing Steps)
After synthesis, the API undergoes:
• Crystallisation – to purify and define physical form
• Filtration and washing – to remove impurities or solvents
• Solvent exchange / drying – to remove residual solvents (ICH Q3C control)
• Milling / micronisation – to achieve target particle size distribution
• Final purification – e.g. recrystallisation, chromatography (if needed)
• Blending – to ensure uniformity
• Packaging – under GMP controls
You receive an ADR from your QPPV stating that for a tablet product you make there is no efficacy, you also make the product in an injection and a liquid but have received no events of lack of efficacy from those products. What are you going to do?
Point: cqa difference between the formulation.
- Initiate Quality Management System (QMS) Documentation:
• Log the ADR as a deviation or quality incident within the QMS.
• Commence a formal investigation, ensuring cross-functional team involvement.- Verify Product Authenticity:
• Obtain the affected batch number(s) and, if possible, physical samples from the complainant.
• Confirm the product is genuine and manufactured by your facility. - Review Complaint History:
• Examine the complaint database for similar reports associated with the tablet formulation.
• Assess trends or recurring issues that may indicate a broader problem. - Collaborate with QPPV:
• Determine whether the issue is pharmacovigilance-related or indicative of a quality defect.
• Evaluate the clinical context, including patient demographics, indication, and concomitant medications.  - Conduct Batch Analysis:
• Retrieve and test retained samples from the affected batch for:
• Assay (potency)
• Impurity profile
• Dissolution and disintegration
• Uniformity of content
• Compare results against product specifications and historical data. - Assess API Consistency Across Formulations:
• Determine if the same API batch was used in the injection and liquid formulations.
• If so, evaluate whether the issue is formulation-specific. - Evaluate Manufacturing and Distribution Records:
• Review manufacturing records for deviations or anomalies during production of the affected batch.
• Examine distribution records to identify the scope of product released from the affected batch.  - Assess Impact on Marketing Authorisation (MA):
• Determine if the issue could affect the product’s benefit-risk profile.
• Evaluate whether a variation to the MA is necessary. - Implement Risk Mitigation Measures:
• If a quality defect is confirmed:
• Quarantine remaining stock of the affected batch.
• Notify relevant stakeholders, including regulatory authorities and supply chain partners.
• Consider a product recall based on risk assessment. - Engage with Regulatory Authorities:
• Report the issue to the Medicines and Healthcare products Regulatory Agency (MHRA) via the Defective Medicines Report Centre (DMRC).
• Provide updates on investigation findings and corrective actions. - Conduct Root Cause Analysis (RCA):
• Identify underlying causes of the lack of efficacy.
• Implement corrective and preventive actions (CAPA) to address identified issues. - Monitor Effectiveness of CAPA:
• Establish metrics to assess the effectiveness of implemented CAPA.
• Review periodically to ensure sustained resolution of the issue.
- Verify Product Authenticity:
You find out that the API has changed supplier for this batch. The new API has also been used for injections and liquid batches.
The lack of efficacy in the tablet formulation, despite using the same API batch as the liquid and injection forms, suggests formulation-specific issues. A thorough investigation encompassing manufacturing processes, storage conditions, and patient usage is essential to identify and rectify the root cause.
You find out that the process uses recycled solvents . What are your concerns?
Primary Concern: The impact of recycled solvents on the impurity profile of the API, which may affect product quality and patient safety.
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Key Considerations and Actions:
1. Compliance with Standard Operating Procedures (SOPs):
• Verify whether the use of recycled solvents is conducted within the framework of approved SOPs.
• Determine if the process is a planned operation or constitutes a rework, which would require additional oversight and documentation.
2. Confirmation from API Supplier:
• Obtain written confirmation that the affected API batch meets all specifications outlined in the Marketing Authorisation (MA).
• Ensure that the supplier has conducted appropriate testing to confirm compliance.
3. Notification and Documentation:
• Assess whether the manufacturing site has notified relevant parties about the use of recycled solvents, in line with the Quality Technical Agreement (QTA).
• Ensure that all deviations are properly documented and investigated.
4. Risk Assessment of Residual Solvents:
• Conduct a thorough risk assessment in accordance with ICH Q3C (R9) guidelines, which classify solvents based on their toxicity and recommend acceptable limits.
• Ensure that the levels of residual solvents in the API do not exceed the Permitted Daily Exposure (PDE) limits.
5. Analytical Testing:
• Perform comprehensive analytical testing on the API batch to detect any unexpected impurities or elevated levels of residual solvents.
• Utilize validated methods, such as gas chromatography, to ensure accurate results.
6. Impact on Finished Product:
• Evaluate whether the impurity profile of the API affects the quality, safety, or efficacy of the finished product.
• Consider conducting stability studies to assess any potential impact over the product’s shelf life.
7. Regulatory Compliance:
• Review the MA to determine if the use of recycled solvents is permitted.
• If not specified, consult with regulatory authorities to assess whether a variation application is necessary.
8. Quality Management System (QMS) Actions:
• Document the incident within the QMS.
• Initiate a root cause analysis and implement corrective and preventive actions (CAPA) to prevent recurrence.
