Pharmaceutical formulation and processing Flashcards
Give examples of products where the API is derived from a cell bank?
Monoclonal antibodies, recombinant proteins like EPO and insulin, certain viral and protein-based vaccines, and enzyme replacement therapies all rely on a defined MCB and WCB system to ensure batch consistency and regulatory compliance.
Q1:
What are the main types of Advanced Therapy Medicinal Products (ATMPs)?
Q2:
Can you give an example of a cell-based ATMP and briefly explain how it works?
Q3:
What is considered the API in CAR-T cell therapy?
- General Understanding of ATMPs
Q1: What are the main types of Advanced Therapy Medicinal Products (ATMPs)?
A1:
ATMPs include:
• Gene therapy products – deliver genes to treat or prevent disease.
• Somatic cell therapy products – use cells that have been manipulated ex vivo.
• Tissue-engineered products – use cells and scaffolds to regenerate, repair, or replace tissues.
• Combined ATMPs – contain a medical device as an integral part.
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Q2: Can you give an example of a cell-based ATMP and briefly explain how it works?
A2:
Yes, CAR-T therapy is a cell-based ATMP. Patient T-cells are collected, genetically modified using a viral vector to express a Chimeric Antigen Receptor (CAR) targeting tumor-specific antigens, expanded, and re-infused to attack cancer cells.
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Q3: What is considered the API in CAR-T cell therapy?
A3:
The genetically modified T-cells themselves are the API, as they provide the therapeutic effect.
- Process Knowledge
Q4:
Walk me through the key manufacturing steps for an autologous CAR-T cell therapy.
Q5:
What are the critical differences in manufacturing autologous vs allogeneic cell therapies?
Q6:
What are the potential risks during the transduction step, and how are they controlled?
Q7:
Why is cryopreservation important in ATMP manufacture, and what are the challenges it introduces?
- Process Knowledge
Q4: Walk me through the key manufacturing steps for an autologous CAR-T cell therapy.
A4:
1. Apheresis – patient T-cells collected.
2. Cell isolation – T-cells separated from leukocytes.
3. Transduction – T-cells genetically modified with a viral vector.
4. Expansion – modified cells multiplied under controlled conditions.
5. Formulation – formulated and cryopreserved for delivery.
6. Thaw & Infusion – thawed at site and infused into patient.
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Q5: What are the critical differences in manufacturing autologous vs allogeneic cell therapies?
A5:
• Autologous: patient-specific, one batch = one patient, higher variability, more logistical control needed.
• Allogeneic: donor-derived, one batch for multiple patients, allows for cell banking and standardization.
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Q6: What are the potential risks during the transduction step, and how are they controlled?
A6:
Risks include:
• Incomplete transduction
• Insertional mutagenesis
• Contamination with replication-competent virus
Controls:
• Use of GMP-grade viral vectors
• In-process monitoring of transduction efficiency
• QC testing for replication-competent virus
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Q7: Why is cryopreservation important in ATMP manufacture, and what are the challenges it introduces?
A7:
It preserves cell viability for transport and scheduling flexibility. Challenges include:
• Cell viability upon thawing
• Cold chain integrity
• DMSO toxicity (cryoprotectant)
- GMP and QP Certification Perspective
Q8:
What GMP guidelines apply to ATMPs?
Q9:
As a QP, what specific documentation or evidence would you review before certifying an ATMP batch for release?
Q10:
If sterility test results are not available due to short shelf-life, how would you justify release?
Q11:
Would you consider releasing an ATMP batch that is out of specification for sterility? Under what circumstances?
- GMP and QP Certification Perspective
Q8: What GMP guidelines apply to ATMPs?
A8:
EudraLex Volume 4, Part IV – GMP for ATMPs. It requires a risk-based approach, tailored control strategies, and specific traceability for human tissues. Also, relevant sections of Annex 1 apply for aseptic processing.
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Q9: As a QP, what specific documentation or evidence would you review before certifying an ATMP batch for release?
A9:
• Batch manufacturing record
• Apheresis documentation
• QC results (sterility, endotoxin, viability, identity, potency)
• Chain of identity and custody records
• Cold chain monitoring
• Any deviations/investigations
• Certificate of analysis
• Confirmation of traceability
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Q10: If sterility test results are not available due to short shelf-life, how would you justify release?
A10:
Justify release based on parametric release:
• A validated aseptic process
• Environmental monitoring data
• Filter integrity test
• Endotoxin test passed
• A predefined risk assessment approved by QP and inspectorate
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Q11: Would you consider releasing an ATMP batch that is out of specification for sterility? Under what circumstances?
A11:
In exceptional cases only.
• Requires clinical need and no alternative therapy
• Physician and QP agreement
• MHRA notified
• Organism identified and risk assessed
• Administered under a “specials” exemption—not certified by QP
- Regulatory and Traceability
Q12:
How does traceability differ between ATMPs and traditional biologics?
Q13:
What role does the Human Tissue Authority (HTA) play in ATMP manufacturing in the UK?
Q14:
What agreements must be in place if ATMP manufacturing steps are performed at different sites?
- Regulatory and Traceability
Q12: How does traceability differ between ATMPs and traditional biologics?
A12:
ATMPs require full bidirectional traceability from donation to administration due to patient-specific material. This includes donor, processing, and distribution data—especially under Directive 2004/23/EC and Part IV GMP.
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Q13: What role does the Human Tissue Authority (HTA) play in ATMP manufacturing in the UK?
A13:
HTA ensures consent, procurement, testing, and traceability for human tissues and cells. For ATMPs involving tissues (e.g., stem cells), HTA licensing is required under the Human Tissue (Quality and Safety for Human Application) Regulations 2007.
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Q14: What agreements must be in place if ATMP manufacturing steps are performed at different sites?
A14:
• Technical/Quality Agreements defining responsibilities (GMP compliance, documentation, deviations)
• Clear traceability between sites
• QP oversight of outsourced steps
• Annex 16 compliance (QP must have visibility and final decision-making authority)
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- Comparison with Biologics/Biotech
Q15: How does the use of cell banks in biologics differ from the approach used in ATMPs?
A15:
Biologics use Master and Working Cell Banks (MCB/WCB) for consistency across multiple batches.
ATMPs (especially autologous) use fresh patient-derived cells with no banking; variability is higher, and each batch is unique.
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Q16: Explain why master and working cell banks are not typically used in autologous ATMP manufacturing.
A16:
Because each autologous product is derived from an individual patient’s own cells, which are not banked or reused. The process is batch-specific and non-replicable, unlike standardised cell lines in biologics.
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Q17: How do the shelf-life and storage requirements of ATMPs affect the QP decision-making process?
A17:
Short shelf-life (often hours to days) limits time for QC release. QPs may rely on in-process controls, parametric release data, and real-time review of batch records to make timely certification decisions.
- Comparison with Biologics/Biotech
Q15:
How does the use of cell banks in biologics differ from the approach used in ATMPs?
Q16:
Explain why master and working cell banks are not typically used in autologous ATMP manufacturing.
Q17:
How do the shelf-life and storage requirements of ATMPs affect the QP decision-making process?
Can you describe the process of manufacturing Pressurised Metred Dose Inhalers?
What are the CPPs and facility requirements?
How the CPPs were relevant/influential to the CQAs?
Please give a summary of the key specifications of a PMDi?
You are a QP at a PMDi manufacturing site that has been dedicated to the manufacture of a salbutamol inhaler. Site leadership wants to introduce the capability to manufacture steroid inhalers too. How would you advise the site to make this introduction?
- CC and impact assessment
How Cleaning validation is conducted?
approach and requirements.
Can you tell me the formulation of a tablet and the purpose of each excipient?
What could cause ‘sticking’ during tablet manufacture?
Can you give some reasons why you might coat a tablet? b. Can you give some reasons why you might coat a tablet?
What is classed as low and high pH and where in GI tract you get these pH ?
High level controls / concerns when making a cream?
can remember exactly what question was but I remember I said micro concerns due to the amount of water present
Do creams have to be sterile? What facility classification is needed?
Can you think of any reasons why you would want a sterile cream?
Later another batch manufacturing lead again holding to repair mixing equipment. - Detail about qualification validation of the equipment, led to viscosity change led to Analytical method change, and AMV
What are the ideal properties of a cream how could you manage?
How could you manage the consistency of the cream?
What types of flows are there in a semisolid preparation?
What will be generalized to the cream and what measures would you take in your manufacturing steps for consistency and flow?
-process validation and continuous Verification
You are a virtual QP, and you received a call from your multiproduct CMO that they found a yellow powder during granulation of your product which is white powder. What do you do? What are your concerns? I was shown a picture of a granulator with the yellow contaminant. Then I was shown another picture showing the root cause of this issue – which was a valve connector that accumulated product residues previous batch.
Who is responsible for determining the PDE values? Is it you the QP ?
Can you tell us what the main excipients used in tablet manufacture are?
What is the difference between a glidant and a lubricant?
What is the difference between a cream and an ointment?
In cream manufacture process where would you expect the API to be added?
What is the difference between creams, ointments, and lotions? How would you manufacture typical cream? List excipients with examples?
What is cracking? What are the key areas to investigate?
What is the difference between creams, ointments, and lotions? How would you manufacture typical cream? List excipients with examples? (Formulation)
Key word – emulsifier
What are the different phases in cream and ointment?
You are certifying an creams and you see that appearance is not matching. The registered spec says to be white/whitish, but you see it is pale yellow/yellow. You received a numerous complaint that your cream is cracking?What would you do? There are several batches which are certified with yellow appearance.
The talk led to nitrosamine contamination and recall.
Describe the wet granulation process for tablet manufacturing.
The key steps are:
- Blending of the API with excipients (e.g. diluents, disintegrants).
- Addition of a binder solution (e.g. purified water with povidone or starch paste) to form a wet mass.
- Wet massing or kneading to ensure uniform distribution of moisture.
- Granulation through a sieve or screen to form granules of desired size.
- Drying using a fluid bed dryer or tray dryer to remove excess moisture.
6 .Sizing or milling to break up oversized granules and achieve a consistent particle size distribution.
- Final blending with external phase (e.g. lubricants like magnesium stearate, glidants).
- Compression into tablets using a tablet press.
- Optional: Film coating or enteric coating, if needed.
What are the critical quality attributes (CQAs) and critical process parameters (CPPs) for tablets?
For tablets, CQAs typically include:
Uniformity
Tablet weight variation
Disintegration time
Dissolution profile
Hardness
Friability
Content uniformity
Appearance
Moisture content
CPPs are process parameters that, when varied beyond a certain limit, may impact one or more CQAs.
CPPs during wet granulation include:
Blending time and speed (affect content uniformity)
Binder addition rate and volume
Granulation endpoint (e.g. torque, wet mass consistency)
Drying temperature and time (affects moisture content, stability)
Milling screen size and speed (affects granule size distribution)
Compression force and dwell time (affects hardness, disintegration)
Tablet press speed (impacts weight uniformity and friability)
